bluuebunny/crossref_metadata_2025 huggingface dataset:
The sublimity of darkness and its affective transmission and subduing in picturebooks
Authors: Ylönen Susanne C. , Mustola Marleena
Published: January 2023

Darkness intrigues, promises mysteries, provides anonymity, and creates atmospheres of both safety and danger. As such, it is a source of the sublime. This chapter uses Edmund Burke’s separation of the beautiful and the sublime as a starting point to analyze affective differences in the presentation of darkness in picturebooks. By examining a selection of North American and European picturebooks dealing with the fear of darkness, we argue that some books seek to transmit the awesomeness of darkness, while many seek to curb its frightening sublimity via familiarity, anthropomorphism, cuteness, and humor. In choosing these kinds of representations, picturebooks adhere, variously, to discourses of risk, protection, and/or agency.
Sad girls
Authors: Dennison Robyn
Published: January 2023

This chapter explores melancholy’s rich signifying potential beyond psychoanalytic frameworks. To do so, it explores its expression as a unique cluster of emotions characterised by sadness without a clear cause in both Julia Lawrinson’s Skating the Edge (2002) and Margo Lanagan’s Touching Earth Lightly (1996). In both books, melancholy girl protagonists are confronted with the death of a friend, mobilizing a journey towards happiness that is, I argue, emblematic of the way Western society treats girls and their feelings. Because girls are subjugated as both adolescents and women, their feelings – especially those deemed bad, unnecessary, or indulgent – are strenuously policed. Situating my analysis within discussions of the centrality of happiness (or at least its promise) to Western neoliberalism, I show how feelings that might be radical or resistant must be sacrificed in order to achieve ‘successful’ adult womanhood, marked by pursuits of work, romance, and happiness.
Solipsistic and inter-subjective attitude reports
Authors: Laurenti Enzo , Mari Alda
Published: January 2023

This paper establishes a difference between solipistic and inter-subjective profiles of the attitudes across the epistemic and the bouletic domain. Revisiting the classical Hamblinian view, we propose that attitudes feature speech-act like content, which present p for uptake in the common ground and argue that the uptake with bouletics is ‘realization’. Focusing on a debated distinction between action-oriented vs. mere desire reports, we derive actionability as a felicity condition on the inter-subjective use of want in particular. We study a variety of bouletics in Italian, and show how their temporal and rationality constraints relate to their private or public status and how the default inter-subjective interpretation of want can be manipulated by specific lexical material.
Epistemic futures and aspect
Authors: Rivero María Luisa
Published: January 2023

A comparative study of futures in Bulgarian and Slovenian, Turkish and Iranian Azeri, Hindi-Urdu, and Spanish. It argues that future morphology encodes a modal category FUT without inherent temporality. Temporal Orientation derives from Viewpoint Aspect categories embedded under FUT, which may differ in phonological content. Such a phonological contrast is significant for the syntax-morphology interface, but has no effect on the syntax-semantics interface. The semantics of future constructions are importantly constrained by formal structural factors such as locality and intervention. Viewpoint plays a primary role in the interpretation of futures since as a higher category in the clausal architecture it often neutralizes the effects on FUT of Lexical Aspect as a lower category in the structure.
La influència de la identitat en la configuració de la consciència lingüística dels valencians entre 1854 i 1906
Authors: Martí-Badia Adrià
Published: January 2023

This paper analyses the influence of identity on the configuration of linguistic awareness in Valencian Country between 1854 and 1906. In this period, the identification of Valencian regional identity coincides with the Spanish national identity in most of Valencian people and it is relevant to know how this element influenced the configuration of the contemporary linguistic awareness in Valencian Country regarding the Catalan language.
Morphological case, ɸ-agreement, and overt movement interactions in Arabic grammar
Authors: Jarrah Marwan
Published: January 2023

Following Alshamari (2017) and Jarrah (2019), this article offers evidence in favor of systematic interactions of morphological case, ɸ-agreement and overt movement in Arabic grammar. It essentially argues that these three aspects of grammar serve one specific purpose, namely to record (i.e., express) Agree dependencies (of the Agree operation; cf. Chomsky, 2001) at the interface level of Phonetic Form (PF). To this end, constructions that include subject-verb agreement, (non-)agreeing discourse markers, and complementizer agreement in Standard Arabic and Arabic dialects (particularly Jordanian Arabic and Najdi Arabic) are examined. The study proposes that Agree dependencies, which occur in the narrow syntax (before spellout), are recorded at PF through morphological case (assigned by the probe on the goal), and if not, then by ɸ-inflections (of the goal on the probe) or, if not, by overt movement of the goal to (Spec of XP headed by) the probe. Such interactions imply that morphological case bleeds ɸ-agreement which in turn is found to bleed overt movement. Exceptions to this rule are discussed and independently motivated.
Is morphological case a feature of individual nominal elements?
Authors: Al-Raba’a Basem Ibrahim Malawi
Published: January 2023

This study examines morphological Case marking in Standard Arabic. Hypotheses of Case distribution inside the determiner phrase are contrasted with the hypothesis that Case is a property of lexical elements only. I will show that Case is realized on nominal elements as a result of a head-to-head relation between the Case-assigner and assignee rather than a relation between a head and the whole phrase. This argument is supported by empirical evidence from Arabic as well as from other languages. I will also show that Arabic differs from other languages in that a nominal element can receive Case from a non-local head, and that Case marking does not always result from phi-agreement relations, as seems to be standardly assumed in the syntactic literature.
First language acquisition of relativisation in Moroccan Arabic
Authors: Gavarró Anna , El Hadef Hammad Iman
Published: January 2023

In this paper, we investigate the acquisition of relativisation in young children exposed to Moroccan Arabic. The aim of the experiment reported is to test the hypothesis by Friedmann, Belletti and Rizzi (2009) according to which children follow a stricter version of Relativised Minimality (RM) in sentence comprehension, to the effect that dependencies in which lexical objects move across lexical subjects are not understood. The work of Belletti, Friedmann, Brunato and Rizzi (2012) further shows that gender mismatch boosts comprehension of similar structures when gender is a criterial feature, as would be the case in Moroccan Arabic. We designed a sentence-picture matching task testing subject and object relativisation, with gender-matched and mismatched subject and object. The experiment was administered to 24 children in the age range of 4 to 5 and a group of adults. The results indicate that, in accordance with the predictions of child RM, the comprehension of subject and object relatives does not differ when subject and object are mismatched in gender; however, object relatives are less well understood when the head of the relative and the intervening subject share the gender feature specification.
When the leak becomes a flood
Authors: McNeil Karen
Published: January 2023

Social and technological changes over the past several decades have led to widespread writing of “spoken” Arabic dialects. In Tunisia, there has been a noticeable growth of vernacular prose literature, part of a larger development of Tunisian Arabic as a written language. Tunisia does not have a history of colloquial literature: previously even the use of “dɛ̄rja” in literary dialogue was rare. From this nearly non-existent base, a small “leak” of vernacular writing appeared in the latter part of the 20th century, followed by a flood–first online and increasingly in print–in the first two decades of the 21st. This has culminated in over a dozen vernacular novels and literary translations.
Transformative experience and the right to revelatory autonomy
Authors: Akhlaghi Farbod
Published: December 2022

Sometimes it is not us but those to whom we stand in special relations that face transformative choices: our friends, family or beloved. A focus upon first-personal rational choice and agency has left crucial ethical questions regarding what we owe to those who face transformative choices largely unexplored. In this paper I ask: under what conditions, if any, is it morally permissible to interfere to try to prevent another from making a transformative choice? Some seemingly plausible answers to this question fail precisely because they concern transformative experiences. I argue that we have a distinctive moral right to revelatory autonomy grounded in the value of autonomous self-making. If this right is outweighed then, I argue, interfering to prevent another making a transformative choice is permissible. This conditional answer lays the groundwork for a promising ethics of transformative experience.
Empowering Students Through the Construction of a Translanguaging Space in an English as a First Language Classroom
Authors: Tai Kevin W H , Wong Chiu-Yin (CATHY)
Published: December 2022

Despite the extensive research on translanguaging in bi/multilingual classrooms, research on the context of first language (L1) classrooms remains scarce. This study fills the research gap by examining how a translanguaging space was created in an L1 classroom to prepare students to inhabit a world with different linguistic and cultural practices. The data were based on a linguistic ethnographic project in a first-grade L1 English Language Arts classroom in the U.S. Multimodal Conversation Analysis and Interpretative Phenomenological Analysis methods were employed for data analysis. This study revealed that such a translanguaging space encouraged students to view diverse languages as resources and appreciate linguistic and cultural diversity in the community. The teacher’s ability to create a translanguaging space for her L1 English students was shaped by the pedagogical translanguaging knowledge gained from her teacher training programme. As such, we posit the significance for all pre- and in-service teachers to acquire knowledge of translanguaging to develop students’ social-emotional well-being and their identities as citizens in this multilingual and multicultural world.
Finding Influencers in Complex Networks: An Effective Deep Reinforcement Learning Approach
Authors: Liu Changan , Fan Changjun , Zhang Zhongzhi
Published: December 2022

Maximizing influences in complex networks is a practically important but computationally challenging task for social network analysis, due to its nondeterministic polynomial time (NP)-hard nature. Most current approximation or heuristic methods either require tremendous human design efforts or achieve unsatisfying balances between effectiveness and efficiency. Recent machine learning attempts only focus on speed but lack performance enhancement. In this paper, different from previous attempts, we propose an effective deep reinforcement learning model that achieves superior performances over traditional best influence maximization algorithms. Specifically, we design an end-to-end learning framework that combines graph neural network as the encoder and reinforcement learning as the decoder, named DREIM. Through extensive training on small synthetic graphs, DREIM outperforms the state-of-the-art baseline methods on very large synthetic and real-world networks on solution quality, and we also empirically show its linear scalability with regard to the network size, which demonstrates its superiority in solving this problem.
Improving Parenting Practices for Early Child Development: Experimental Evidence from Rwanda
Authors: Justino Patricia , Leone Marinella , Rolla Pierfrancesco , Abimpaye Monique , Dusabe Caroline , Uwamahoro Marie D , Germond Richard
Published: January 2023

This paper investigates the short- and medium-term impact of a randomized group-based early child development program targeting parents of children aged 6–24 months in a poor, rural district of Rwanda. This low-intensity, short-duration, and low-cost program engaged parents through sessions that included a novel radio show and facilitated discussions during 17 weekly village-level meetings. The intervention included two treatment arms, with different components. Twelve months after baseline, children’s communication, problem-solving, and personal social skills improved in treated groups and persisted almost 3 years later in the full treatment arm. Positive effects on maternal time investments, attitudes, and beliefs, as well as investments in play resources, also persisted over time. A mediation analysis shows that the positive impact observed in child development can be attributed to positive changes in parental and home environment inputs, particularly in the longer term. This study offers important insights for the design and delivery at scale of early child development interventions among some of the most disadvantaged communities in the world.
Environmental Legal Research is Changing: Alternating Tenor/Terror of Scholarship, Despair and Self-Care
Authors: French Duncan , Dawson David L , Golijani-Moghaddam Nima
Published: December 2022

No one can tell us—as individuals—how we should feel about environmental harm, be it upset at individual species loss, distress at systemic level change, or deeper existential angst. That universal truism applies as much to us, as scholars, as it does to us as world-citizens. Recognising that environmental harm is increasingly impacting lived experiences, this commentary both argues that we should not only reflect consciously on how this might affect our scholarship, but that we should proactively take steps to improve our mental health and self-care. Written collaboratively by an environmental lawyer and research clinical psychologists, the commentary concludes that acceptance of the challenges confronting us, and that it is all right to be anxious about them in our own lives, will not necessarily make our scholarship any better but it might allow us to avoid unhelpful, artificial, and potentially painful deep-seated, divisions within ourselves.
Augmenting the bioavailability of iron in rice grains from field soils through the application of iron-solubilizing bacteria
Authors: Kartik Vinodbhai Patel , Chandwani Sapna , Amaresan Natarajan
Published: January 2023

The biofortification approach has been widely used to enhance mineral nutrients in staple foods such as rice (Oryza sativa). In the present study, iron-solubilizing plant growth-promoting bacteria (PGPB) were evaluated for iron fortification of rice grains and NPK via field experiments. Inoculation of iron-solubilizing bacteria showed significant improvements in growth parameters, such as plant height, root and shoot dry weight, panicle length, grain yield, and nitrogen, potassium, phosphorus, and iron uptake. The mobilization of iron was ranged from 53.88% to 89.05% in rice grains compared to the uninoculated plants. The present study results revealed that application of PGPB strains is vital approach to combat the problem of iron deficiency in rice and subsequently in humans.
Lactobacillus fermentum 1.2133 display probiotic potential in vitro and protect against Salmonella pullorum in chicken of infection
Authors: Wang Min , Hu Jie , Yu Han , Li Wenhui , He Guangyu , Dong Jinsheng , Liu Yannan , Shi Shuiqin
Published: January 2023

The efficacy of Lactobacillus as an antibiotic substitute has been investigated as one of the potential strategies to prevent Salmonella infection in poultry. The purpose of this study was to explore the antibacterial activity of Lactobacillus fermentum 1.2133 (Lact. fermentum 1.2133) against Salmonella pullorum CVCC533 (Salm. pullorum CVCC533) and its effect on chickens infected with Salm. pullorum CVCC533. Results showed that Lact. fermentans 1.2133 has antibacterial activity against Salm. pullorum CVCC533 and the cell-free fermentation supernatant of Lact. fermentum 1.2133 had a bactericidal effect on the bacteria in the Salm. pullorum CVCC533 biofilm by significantly reducing the number of Salmonella and aerobic bacteria in the chicken duodenum, ileum, and cecum, including Escherichia shigella (P < 0.05), improved the species abundance of Lactobacilli (P < 0.05). The damage to the chicken intestine by Salm. pullorum CVCC533 was reduced as the expression of avian beta-defensin 2 (AvBD2) mRNA in chicken small intestine was increased (P < 0.05). The results showed that Lact. fermentum 1.2133 had the potential to be a probiotic for poultry due to its regulation of intestinal AvBD2 mRNA as well as its intestinal flora.
Characterisation of ESBL/AmpC-Producing Enterobacteriaceae isolated from poultry farms in Peninsular Malaysia
Authors: Tan Hui-Shee , Yan Pan , Agustie Hollysia Alda , Loh Hwei-San , Rayamajhi Nabin , Fang Chee-Mun
Published: January 2023

Extended-spectrum beta-lactamases (ESBLs) and AmpC beta-lactamases (AmpCs)-producing Enterobacteriaceae have been increasingly reported and imposing significant threat to public. Livestock production industry might be the important source for clinically important ESBL-producing Enterobacteriaceae. This study aims to investigate the resistance profile, phenotypic ESBL production, beta-lactamase genes, virulence factors, and plasmid replicon types among 59 Enterobacteriaceae strains isolated from poultry faecal samples in Malaysia’s commercial poultry farm. There were 38.7% and 32.3% of Escherichia coli resistant to cefotaxime and cefoxitin, respectively, while Klebsiellaspp. demonstrated resistance rate of 52.6% to both mentioned antimicrobials. Majority of the E. coli isolates carried blaTEM and blaCMY-2 group. blaSHV was the most prevalent gene detected in Klebsiellaspp., followed by blaDHA and blaTEM. Resistance to extended spectrum cephalosporin in our isolates was primarily mediated by plasmid mediated AmpC beta-lactamase such as CMY-2 group and DHA enzyme. The CTX-M genes were found in two ESBL-producing E. coli. IncF, IncI1, and IncN plasmids were most frequently detected in E. coli and Klebsiellaspp. The virulence factor, including EAST1 and pAA were identified at low frequency. This study highlights the poultry as a reservoir of resistance and virulence determinants and prevalence of plasmids in Enterobacteriaceae might drive their dissemination.
In vitro antiviral activity of persimmon-derived tannin against avian influenza viruses
Authors: Fujimoto Yoshikazu , Ijiri Moe , Matsuo Tomohide , Kawaguchi Hiroaki
Published: January 2023

Tannins derived from natural plant sources are known to provide many health benefits to humans and animals. Among the various tannins, those derived from persimmon (Diospyros kaki) have exhibited strong inactivating effects against pathogens that induce diseases in humans. However, few studies have focused on the antiviral effects of persimmon tannin against pathogen-induced diseases in animals. In this study, we investigated the antiviral effects of persimmon tannin against various avian influenza viruses revealing that tannin at a concentration of 1.0 mg ml−1 reduced viral infectivity in >6.0-log scale against all tested avian influenza viruses. In addition, this persimmon tannin concentration effectively inhibited the receptor binding and membrane fusion abilities of viral hemagglutinin (HA), which play important roles in avian influenza virus infection. These results suggest that persimmon tannin inactivates the HA of avian influenza viruses and reduces their infectivity. Persimmon tannin is a safer natural substance than the currently used chemical compound related to antiviral substance. When inactivation of the viruses which are present in environmental water such as roosting water of wild birds will be needed, persimmon tannin is expected to become an antiviral resource that may prevent the spread of several avian influenza virus subtypes.
The Faraday Rotation Measure Grid of the LOFAR Two-metre Sky Survey: Data Release 2
Authors: O’Sullivan S P , Shimwell T W , Hardcastle M J , Tasse C , Heald G , Carretti E , Brüggen M , Vacca V , Sobey C , Van Eck C L , Horellou C , Beck R , Bilicki M , Bourke S , Botteon A , Croston J H , Drabent A , Duncan K , Heesen V , Ideguchi S , Kirwan M , Lawlor L , Mingo B , Nikiel-Wroczyński B , Piotrowska J , Scaife A M M , van Weeren R J
Published: January 2023

A Faraday rotation measure (RM) catalogue, or RM Grid, is a valuable resource for the study of cosmic magnetism. Using the second data release (DR2) from the LOFAR Two-metre Sky Survey (LoTSS), we have produced a catalogue of 2461 extragalactic high-precision RM values across 5720 deg2 of sky (corresponding to a polarized source areal number density of ∼0.43 deg−2). The linear polarization and RM properties were derived using RM synthesis from the Stokes Q and U channel images at an angular resolution of 20 arcsec across a frequency range of 120 to 168 MHz with a channel bandwidth of 97.6 kHz. The fraction of total intensity sources (>1 mJy beam−1) found to be polarized was ∼0.2 per cent. The median detection threshold was 0.6 mJy beam−1 (8σQU), with a median RM uncertainty of 0.06 rad m−2 (although a systematic uncertainty of up to 0.3 rad m−2 is possible, after the ionosphere RM correction). The median degree of polarization of the detected sources is 1.8 per cent, with a range of 0.05 per cent to 31 per cent. Comparisons with cm-wavelength RMs indicate minimal amounts of Faraday complexity in the LoTSS detections, making them ideal sources for RM Grid studies. Host galaxy identifications were obtained for 88 per cent of the sources, along with redshifts for 79 per cent (both photometric and spectroscopic), with the median redshift being 0.6. The focus of the current catalogue was on reliability rather than completeness, and we expect future versions of the LoTSS RM Grid to have a higher areal number density. In addition, 25 pulsars were identified, mainly through their high degrees of linear polarization.
Targeted DNA methylation from cell-free DNA using hybridization probe capture
Authors: Buckley David N , Gooden Gerald , Feng Kuan , Enk Jacob , Salhia Bodour
Published: December 2022

Cell-free (cf)DNA signatures are quickly becoming the target of choice for non-invasive screening, diagnosis, treatment and monitoring of human tumors. DNA methylation changes occur early in tumorigenesis and are widespread, making cfDNA methylation an attractive cancer biomarker. Already a proven technology for targeted genome sequencing, hybridization probe capture is emerging as a method for high-throughput targeted methylation profiling suitable to liquid biopsy samples. However, to date there are no reports describing the performance of this approach in terms of reproducibility, scalability, and accuracy. In the current study we performed hybridization probe capture using the myBaits® Custom Methyl-seq kit on 172 plasma samples and standards to evaluate its performance on cfDNA methylation analysis. The myBaits® assay showed high target recovery (>90%), demonstrated excellent reproducibility between captures (R2 = 0.92 on average), and was unaffected by increasing the number of targets in a capture. Finally, myBaits® accurately replicated ‘gold standard’ beta values from WGBS (average R2 = 0.79). The results of this study show that custom targeted methylation sequencing with myBaits® offers a cost-effective, reliable platform to profile DNA methylation at a set of discrete custom regions, with potential applicability to liquid biopsies for cancer monitoring.
Cellular polyploidy in organ homeostasis and regeneration
Authors: Fang Juntao , de Bruin Alain , Villunger Andreas , Schiffelers Raymond , Lei Zhiyong , Sluijter Joost P G
Published: December 2022

Polyploid cells, which contain more than one set of chromosome pairs, are very common in nature. Polyploidy can provide cells with several potential benefits over their diploid counterparts, including an increase in cell size, contributing to organ growth and tissue homeostasis and improving cellular robustness via increased tolerance to genomic stress and apoptotic signals. Here, we focus on why polyploidy in the cell occurs and which stress responses and molecular signals trigger cells to become polyploid. Moreover, we discuss its crucial roles in cell growth and tissue regeneration in the heart, liver and other tissues.
Does antenatal cholecalciferol supplementation affect the mode or timing of delivery? Post hoc analyses of the MAVIDOS randomized controlled trial
Authors: Moon Rebecca J , D’Angelo Stefania , Crozier Sarah R , Curtis Elizabeth M , Fernandes Michelle , Kermack Alexandra J , Davies Justin H , Godfrey Keith M , Bishop Nicholas J , Kennedy Stephen H , Prentice Ann , Schoenmakers Inez , Fraser Robert , Gandhi Saurabh V , Inskip Hazel M , Javaid Muhammad Kassim , Papageorghiou Aris T , Cooper Cyrus , Harvey Nicholas C
Published: December 2022

Background

Observational studies relating maternal 25-hydroxyvitamin D status to timing and mode of delivery have reported inconsistent results. We assessed the effect of antenatal cholecalciferol supplementation on the incidence of preterm birth, delivery mode and post-partum haemorrhage (PPH).

Methods

MAVIDOS was a randomized, double-blind, placebo-controlled trial of 1000 IU/day cholecalciferol from 14 weeks’ gestation until delivery. Gestational age, mode of delivery [categorized as spontaneous vaginal delivery (SVD), instrumental (including forceps and vacuum extraction) or Caesarean section] and PPH (>500 ml estimated blood loss) were determined from medical records.

Results

A total of 965 women participated in the study until delivery. Gestation at birth and incidence of preterm birth (cholecalciferol 5.7%, placebo 4.5%, P = 0.43) were similar between the two treatment groups. SVD (versus instrumental or Caesarean delivery) was more likely in women randomized to cholecalciferol [Relative Risk (RR) 1.13, 95% confidence interval (CI) 1.02,1.25] due to lower instrumental (RR 0.68, 95%CI 0.51,0.91) but similar risk of Caesarean delivery (RR 0.94, 95%CI 0.74,1.19). PPH was less common in women randomized to cholecalciferol [32.1% compared with placebo (38.1%, P = 0.054) overall], but similar when stratified by delivery mode.

Conclusions

Antenatal cholecalciferol supplementation did not alter timing of birth or prevalence of preterm birth but demonstrated a possible effect on the likelihood of SVD.
Advanced algebraic thinking processes in students’ modelling activities
Authors: Lopes Aldo Peres Campos e
Published: December 2022

This paper presents results of a study aimed at describing and discussing evidence/features of advanced algebraic thinking processes. To achieve these objectives, we analysed the written production of students enrolled in engineering courses working on mathematical modelling tasks related to differential equations. Our guiding question was as follows: how are students’ advanced algebraic thinking processes expressed (or not) in modelling activities that involve differential equations? Additionally, we presented the concept of advanced algebraic thinking as an extension of the (elementary) algebraic thinking notion and as a relevant part of advanced mathematical thinking. We included written records of two models that were produced and used in two classes and concluded that practically all groups showed processes of symbolic representation and representation translation. We also observed that around half of the groups presented suitable algebraic synthetization and development processes to solve the model equation. Another finding was that none of the groups applied generalization processes. Therefore, not all processes involved in advanced algebraic thinking were developed.
Safety and Effectiveness of SA58 Nasal Spray against COVID-19 Infection in Medical Personnel:An Open-label, Blank-controlled Study
Authors: Si Shujie , Jin Canrui , Li Jianping , Cao Yunlong , Kan Biao , Xue Feng , Xie Xiaoliang Sunney , Fang Liang , Zeng Gang , Zhang Shuo , Hu Yaling , Dong Xiaoping
Published: December 2022

Approved COVID-19 vaccines to date have limited effectiveness in protecting infection and blocking transmission. A nasal spray of broad-spectrum antibody against COVID-19 (SA58 Nasal Spray) has recently been developed by Sinovac Life Sciences Co., Ltd.. From October 31 to November 30, 2022, an open-label, blank controlled study on the SA58 Nasal Spray against COVID-19 infection was conducted with the medical personnel working in the designated COVID-19 hospitals and Fangcang shelter hospitals (alternate care sites) of COVID-19 cases in Hohhot city, the Inner Mongolia Autonomous Region. A total of 6662 medical personnel were involved in this study: 3368 used SA58 Nasal Spray from the drug group, and 3294 not used from blank control group. The medication was self-administered intranasally 1∼2 times per day with an interval of 6 hours for 30 days.. The safety results indicated that the SA58 Nasal Spray was well tolerant. The incidence of adverse events (AEs) was 28.6% (497/1736), and the majority of the AEs were mild and from administrative site. 135 COVID-19 cases were identified for SARS-CoV-2 by RT-PCR during the 30-day observation. The cumulative incidence of COVID-19 in the drug group and the control group were 0.026% and 0.116%, respectively. The effectiveness of the SA58 Nasal Spray for preventing COVID-19 infection among medical personnel was evaluated as 77.7% (95% CI: 52.2% - 89.6%). In conclusion, the SA58 Nasal Spray is well-tolerant and highly effective against COVID-19 infection.
Multinational Patterns of Second-line Anti-hyperglycemic Drug Initiation Across Cardiovascular Risk Groups: A Federated Pharmacoepidemiologic Evaluation in LEGEND-T2DM
Authors: Khera Rohan , Dhingra Lovedeep Singh , Aminorroaya Arya , Li Kelly , Zhou Jin J , Arshad Faaizah , Blacketer Clair , Bowring Mary G , Bu Fan , Cook Michael , Dorr David A , Duarte-Salles Talita , DuVall Scott L , Falconer Thomas , French Tina E , Hanchrow Elizabeth E , Horban Scott , Lau Wallis CY , Li Jing , Liu Yuntian , Lu Yuan , Man Kenneth KC , Matheny Michael E , Mathioudakis Nestoras , McLemore Michael F , Minty Evan , Morales Daniel R , Nagy Paul , Nishimura Akihiko , Ostropolets Anna , Pistillo Andrea , Posada Jose D , Pratt Nicole , Reyes Carlen , Ross Joseph , Seager Sarah L , Shah Nigam H , Simon Katherine R , Wan Eric YF , Yang Jianxiao , Yin Can , You Seng Chan , Schuemie Martijn J , Ryan Patrick B , Hripcsak George , Krumholz Harlan M , Suchard Marc A
Published: December 2022

Objectives

To assess the uptake of second-line antihyperglycemic agents among patients with type-2 diabetes mellitus (T2DM) receiving metformin.

Design

Serial cross-sectional study (2011-2021).

Setting

Ten US and seven non-US electronic health record and administrative claims databases in the Observational Health Data Sciences and Informatics network.

Participants

4.8 million patients with T2DM receiving metformin.

Main Outcomes Measures

Calendar-year trends in the proportional initiation of second-line antihyperglycemic agents, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter 2 inhibitors (SGLT2is), dipeptidyl peptidase-4 inhibitors, and sulfonylureas, for each database. We also evaluated the relative drug class-level uptake across cardiovascular risk groups.

Results

We identified 4.6 million patients with T2DM in US databases, 61,382 from Spain, 32,442 from Germany, 25,173 from the UK, 13,270 from France, 5,580 from Scotland, 4,614 from Hong Kong, and 2,322 from Australia. During 2011-2021, the combined proportional initiation of cardioprotective antihyperglycemic agents, GLP-1 RAs and SGLT2is, increased across all data sources, with the combined initiation of these drugs as second-line agents in 2021 ranging from 35.2% to 68.2% in the US databases, 15.4% in France, 34.7% in Spain, 50.1% in Germany, and 54.8% in Scotland. From 2016 to 2021, in some US and non-US databases, uptake of GLP-1 RAs and SGLT2is increased more significantly among populations without cardiovascular disease compared to those with established cardiovascular disease, without any data source providing evidence of a greater increase in their uptake in the populations with cardiovascular disease.

Conclusions

Despite the increase in overall uptake of cardioprotective antihyperglycemic agents as second-line treatment for T2DM, their uptake was lower in patients with cardiovascular disease over the last decade. A strategy to ensure medication use concordant with guideline recommendations is essential to improve outcomes of patients with T2DM.
Antimicrobial Susceptibility Patterns in Adult Patients Hospitalized for Community-acquired Urinary Tract Infection in Tertiary Hospitals in Chile
Authors: Rojas Luis , Ceron Inés , Araos-Baeriswyl Esteban , Viviani Paola , Olivares Rodrigo , Valenzuela Andrés , Aizman Andrés
Published: December 2022

Background

The constant increase of factors associated with the presence of resistant strains makes empirical antibiotic selection a challenge in patients hospitalized for community-acquired urinary tract infection. We characterized the type of bacteria and their antimicrobial susceptibility pattern in cultures obtained from adult patients that needed hospitalization for this disease in two tertiary hospitals in Chile.

Methods

We conducted a cross-sectional study in adults hospitalized for community-acquired urinary tract infection between 2017 and 2022. A total of 830 patients were included. All patients with positive cultures were included in the analysis.

Results

Escherichia coli was the most frequent infectious agent (68.1%), followed by Klebsiella spp. (17.7%) and Enterococcus faecalis (6.7%). Among Enterobacteriaceae strains, 35.2%, 19.7% and 27.2% were resistant to first, second and third-generation cephalosporin, respectively. 36.9% were resistant to ciprofloxacin and 1.8% to amikacin. Gram-positive bacteria were resistant to oxacillin and ampicillin in 25% and 18%, respectively.

Conclusion

We detected a high prevalence of community-acquired urinary tract infections caused by bacteria resistant to commonly used antibiotics in adult patients that need to be hospitalized. In view of this, we believe that current medical guidelines should be reviewed and updated.
Association ofHLA-class IIalleles with risk of relapse in myeloperoxidase-antineutrophil cytoplasmic antibody positive vasculitis in the Japanese population
Authors: Kawasaki Aya , Sada Ken-ei , Kusumawati Premita Ari , Hirano Fumio , Kobayashi Shigeto , Nagasaka Kenji , Sugihara Takahiko , Ono Nobuyuki , Fujimoto Takashi , Kusaoi Makio , Tamura Naoto , Kusanagi Yasuyoshi , Itoh Kenji , Sumida Takayuki , Yamagata Kunihiro , Hashimoto Hiroshi , Makino Hirofumi , Arimura Yoshihiro , Harigai Masayoshi , Tsuchiya Naoyuki
Published: December 2022

Background

Disease relapse remains a major problem in the management of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In European populations,HLA-DPB1*04:01is associated with both susceptibility and relapse risk in proteinase 3-ANCA positive AAV. In a Japanese population, we previously reported an association betweenHLA-DRB1*09:01andDQB1*03:03with susceptibility to, andDRB1*13:02with protection from, myeloperoxidase-ANCA positive AAV (MPO-AAV). Subsequently, the association ofDQA1*03:02, which is in strong linkage disequilibrium withDRB1*09:01andDQB1*03:03, with MPO-AAV susceptibility was reported in a Chinese population. However, an association between these alleles and risk of relapse has not yet been reported. Here, we examined whetherHLA-class IIis associated with the risk of relapse in MPO-AAV.

Methods

First, the association ofHLA-DQA1*03:02with susceptibility to MPO-AAV and microscopic polyangiitis (MPA) and its relationship with previously reportedDRB1*09:01andDQB1*03:03were examined in 440 Japanese patients and 779 healthy controls. Next, the association with risk of relapse was analyzed in 199 MPO-ANCA positive, PR3-ANCA negative patients enrolled in previously reported cohort studies on remission induction therapy. Uncorrected P values (Puncorr) were corrected for multiple comparisons in each analysis using the false discovery rate method.

Results

The association ofDQA1*03:02with susceptibility to MPO-AAV and MPA was confirmed in a Japanese population (MPO-AAV: Puncorr=5.8×10−7, odds ratio [OR] 1.74, 95% confidence interval [CI] 1.40–2.16, MPA: Puncorr=1.1×10−5, OR 1.71, 95%CI 1.34–2.17).DQA1*03:02was in strong linkage disequilibrium withDRB1*09:01andDQB1*03:03, and the causal allele could not be determined using conditional logistic regression analysis. Relapse-free survival was shorter with nominal significance in carriers ofDRB1*09:01(Puncorr=0.049, Q=0.42, hazard ratio [HR]:1.87),DQA1*03:02(Puncorr=0.020, Q=0.22, HR:2.11) andDQB1*03:03(Puncorr=0.043, Q=0.48, HR:1.91) than in non-carriers in the log-rank test. Conversely, serine carriers at position 13 of HLA-DRβ1 (HLA-DRβ1_13S), includingDRB1*13:02carriers, showed longer relapse-free survival with nominal significance (Puncorr=0.010, Q=0.42, HR:0.31). By combiningDQA1*03:02and HLA-DRβ1_13S, a significant difference was detected between groups with the highest and lowest risk for relapse (Puncorr=0.0055, Q=0.033, HR:4.02).

Conclusion

HLA-class IIis associated not only with susceptibility to MPO-AAV but also with risk of relapse in the Japanese population.
Cost-effectiveness of the second COVID-19 booster vaccination in the United States
Authors: Li Rui , Lu Pengyi , Fairley Christopher K , Pagán José A. , Hu Wenyi , Yang Qianqian , Zhuang Guihua , Shen Mingwang , Li Yan , Zhang Lei
Published: December 2022

Background

The United States (US) authorized the second COVID-19 booster for individuals aged 50+ years on March 29, 2022. To date, the cost-effectiveness of the second booster strategy remains unassessed.

Methods

We developed a decision-analytic SEIR-Markov model by five age groups (0-4yrs, 5-11yrs 12-17yrs, 18-49yrs, and 50+yrs) and calibrated the model by actual mortality in each age group in the US. We conducted fives scenarios to evaluate the cost-effectiveness of the second booster strategy and incremental benefits if the strategy would expand to 18-49yrs and 12-17yrs, from a healthcare system perspective.

Findings

Implementing the second booster strategy for those aged 50+yrs would cost $807 million but reduce direct medical costs by $1,128 million, corresponding to a benefit-cost ratio of 1.40. Moreover, the strategy would also result in a gain of 1,048 quality-adjusted life-years (QALYs) during the 180 days, indicating it was cost-saving. Further, vaccinating individuals aged 18-49yrs with the second booster would result in an additional gain of $1,566 million and 2,276 QALYs. Similarly, expanding vaccination to individuals aged 12-17yrs would result in an additional gain of $15 million and 89 QALYs. However, if social interaction between all age groups was severed, vaccination expansion to 18-49yrs and 12-17yrs would no longer be cost-effective.

Interpretation

The second booster strategy was likely to be cost-effective in reducing the disease burden of the COVID-19 pandemic. Expanding the second booster strategy to 18-49yrs and 12-17yrs would remain cost-effective due to their social contacts with the older age group.

Funding

World Health Organization
Systemic effects of melanoma-secreted MIDKINE in the inhibition of dendritic cell differentiation and function
Authors: Catena Xavier , Contreras-Alcalde Marta , Cerezo-Wallis Daniela , Juan-Larrea Naiara , Olmeda David , Calvo Guadalupe G. , Mucientes Cynthia , Oterino Sergio , Soengas María S.
Published: December 2022

Cutaneous melanomas are a prime example of potentially immunogenic tumors, and as such, ideal targets for immune therapy. These lesions have the largest mutational burden described to date, and accumulate a broad spectrum of post-transcriptional and translational alterations that could conceptually result in a plethora of neoantigens for immune recognition. However, a significant fraction of metastatic melanoma patients is or becomes resistant to current immunotherapeutic agents. How lesions that should represent an inherently hot milieu for immune attack shift into immunologically cold or irresponsive neoplasms is not well understood. Combining cellular systems, mouse models and clinical datasets, here we identify the growth factor Midkine (MDK) as a multipronged blocker of antigen presentation. Mechanistically, we found MDK to repress all main aspects of the maturation, activation and function of dendritic cells, particularly of conventional type 1 (cDC1). These roles of MDK were found to involve primary tumors and lymph nodes, and were traced back to suppressive effects on myeloid precursor cells in the bone marrow. Moreover, MDK shifted the transcriptional profile of DCs towards a tolerogenic state that prevented and bypassed CD8+T cell activation. Blocking MDK enhanced the response to DC-based vaccination and improved the response to immune checkpoint blockade.Together, these data provide insight into how melanomas overcome immune surveillance and support MDK as a target for therapeutic intervention.
Artificial intelligence for automated thoracic aorta diameter measurement using different computed tomography protocols
Authors: Portugal Maria Fernanda , Pinheiro Lucas Lembrança , Lee Henrique Min Ho , Vieira Henrique Cursino , de Oliveira Lariza Laura , del Valle Matheus , Miyoshi Newton Shydeo Brandão , Oliveira-Ciabati Livia , Barone Ronaldo , Szarf Gilberto , Wolosker Nelson
Published: December 2022

Introduction

Thoracic aortic aneurysm diameter determination is paramount for the decision-making process regarding surgical management. Studies focusing in asymptomatic patients have determined prevalence of 0.16 to 0.36% of TAAs in imaging studies. Several groups have proposed automated aortic measurement tools as propaedeutic and therapeutic instruments. In this study we developed and tested an automatic 3-dimensional (3D) segmentation method for the thoracic aorta, applicable on computed tomography angiography (CTA) acquired using low-dose and standard dose protocol, with and without contrast enhancement; and to accurately calculate the 3D diameter information of the arterial segments.

Methods

a retrospective cohort of all CT scans acquired in our service between 2016 and 2021 led to the selection of 587 CT exams including low and standard-dose radiation, with and without contrast enhancement. 527 exams were used for neural network training of an algorithm capable of aptly measuring the aortic diameters, using manual measurements performed by three medical specialists as a baseline. Sixty exams were used for validation. The algorithm was developed both for use with the support of PyRadiomics and for a self-made approach.

Results

Aortic measurement using the algorithm supported by PyRadiomics resulted in mean absolute error values under 2mm. For the self-made approach, mean absolute error values were under 5mm.

Conclusion

This study presents an effective automated solution for thoracic aortic measurement with good results in sets of standard or low-radiation exams, as well as those acquired with or without contrast enhancement; presenting a possibility for an auxiliary tool for automation of the process of measuring the diameter of the thoracic aorta.
The P450 Sterol Side Chain Cleaving Enzyme (P450scc) for Digoxin Biosynthesis in the Foxglove Plant Belongs to the CYP87A Family
Authors: Carroll Emily , Gopal Baradwaj Ravi , Raghavan Indu , Wang Zhen Q.
Published: December 2022

Digoxin from the foxglove plant is a commonly prescribed plant natural product for treating heart failure and atrial fibrillation. Despite its medicinal prominence, how foxglove synthesizes digoxin is largely unknown, especially the cytochrome P450 sterol side chain cleaving enzyme (P450scc), which catalyzes the first and rate-limiting step in this pathway. Here we report the identification of the foxglove P450scc, the gatekeeping enzyme that channels sterols to digoxin. This enzyme converts both cholesterol and campesterol to pregnenolone, thus explaining how pregnenolone is synthesized in plants. Phylogenetic analysis indicates that this enzyme arose from a duplicatedCYP87Agene and does not share clear homology with the mammalian P450scc. Identifying this long-speculated plant P450sccenzyme suggests that the digoxin biosynthetic pathway starts from both cholesterol and phytosterols, instead of just cholesterol as previously thought. The identification of this gatekeeping enzyme is a key step towards complete elucidation of digoxin biosynthesis and expanding the therapeutic applications of digoxin analogs in future work.
WITHDRAWN: Screening for Poverty And Related Social determinants to improve Knowledge of and links to resources (SPARK): development and cognitive testing of a tool for primary care
Authors: Adekoya Itunuoluwa , Delahunty-Pike Alannah , Howse Dana , Kosowan Leanne , Seshie Zita , Abaga Eunice , Cooney Jane , Robinson Marjeiry , Senior Dorothy , Zsager Alexander , Aubrey-Bassler Kris , Irwin Mandi , Jackson Lois , Katz Alan , Marshall Emily , Muhajarine Nazeem , Neudorf Cory , Pinto Andrew D.
Published: December 2022

Withdrawal statement

“The authors have withdrawn this manuscript owing to one of the authors, Lynn Thompson, no longer standing by her participation in this work. Therefore, the authors do not wish this work to be cited as reference for the project. The remaining authors have since published the work inBMC Primary Care:Adekoya, I., Delahunty-Pike, A., Howse, D. et al. Screening for poverty and related social determinants to improve knowledge of and links to resources (SPARK): development and cognitive testing of a tool for primary care.BMC Prim. Care24, 247 (2023).https://doi.org/10.1186/s12875-023-02173-8. If you have any questions, please contact the corresponding author.”