bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repurposing anti-inflammatory drugs for fighting planktonic and biofilm growth. New carbazole derivatives based on the NSAID carprofen: synthesis, in silico and in vitro bioevaluation
Authors: Dumitrascu Florea , Caira Mino R. , Avram Speranta , Buiu Catalin , Udrea Ana Maria , Vlad Ilinca Margareta , Zarafu Irina , Ioniță Petre , Nuță Diana Camelia , Popa Marcela , Chifiriuc Mariana-Carmen , Limban Carmen 
Published: August 2023

IntroductionOne of the promising leads for the rapid discovery of alternative antimicrobial agents is to repurpose other drugs, such as nonsteroidal anti-inflammatory agents (NSAIDs) for fighting bacterial infections and antimicrobial resistance.MethodsA series of new carbazole derivatives based on the readily available anti-inflammatory drug carprofen has been obtained by nitration, halogenation and N-alkylation of carprofen and its esters. The structures of these carbazole compounds were assigned by NMR and IR spectroscopy. Regioselective electrophilic substitution by nitration and halogenation at the carbazole ring was assigned from H NMR spectra. The single crystal X-ray structures of two representative derivatives obtained by dibromination of carprofen, were also determined. The total antioxidant capacity (TAC) was measured using the DPPH method. The antimicrobial activity assay was performed using quantitative methods, allowing establishment of the minimal inhibitory/bactericidal/biofilm eradication concentrations (MIC/MBC/MBEC) on Gram-positive (Staphylococcus aureus, Enterococcus faecalis) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) strains. Computational assays have been performed to assess the drug- and lead-likeness, pharmacokinetics (ADME-Tox) and pharmacogenomics profiles.Results and discussionThe crystal X-ray structures of 3,8-dibromocarprofen and its methyl ester have revealed significant differences in their supramolecular assemblies. The most active antioxidant compound was 1i, bearing one chlorine and two bromine atoms, as well as the CO2Me group. Among the tested derivatives, 1h bearing one chlorine and two bromine atoms has exhibited the widest antibacterial spectrum and the most intensive inhibitory activity, especially against the Gram-positive strains, in planktonic and biofilm growth state. The compounds 1a (bearing one chlorine, one NO2 and one CO2Me group) and 1i (bearing one chlorine, two bromine atoms and a CO2Me group) exhibited the best antibiofilm activity in the case of the P. aeruginosa strain. Moreover, these compounds comply with the drug-likeness rules, have good oral bioavailability and are not carcinogenic or mutagenic. The results demonstrate that these new carbazole derivatives have a molecular profile which deserves to be explored further for the development of novel antibacterial and antibiofilm agents.
Emotional responses to climate change information and their effects on policy support
Authors: Myers Teresa A. , Roser-Renouf Connie , Maibach Edward 
Published: August 2023

IntroductionAs emotions are strong predictors of climate policy support, we examined multiple discrete emotions that people experience in reaction to various types of information about climate change: its causes, the scientific consensus, its impacts, and solutions. Specifically, we assessed the relationships between four types of messages and five discrete emotions (guilt, anger, hope, fear, and sadness), testing whether these emotions mediate the impacts of information on support for climate policy.MethodsAn online experiment exposed participants (N = 3,023) to one of four informational messages, assessing participants' emotional reactions to the message and their support for climate change mitigation policies as compared to a no-message control group.ResultsEach message, except the consensus message, enhanced the feeling of one or more emotions, and all of the emotions, except guilt, were positively associated with policy support. Two of the messages had positive indirect effects on policy support: the impacts message increased sadness, which in turn increased policy support, and the solutions message increased hope, which increased policy support. However, the solutions message also reduced every emotion except hope, while the impacts, causes, and consensus messages each suppressed hope.DiscussionThese findings indicate that climate information influences multiple emotions simultaneously and that the aroused emotions may conflict with one another in terms of fostering support for climate change mitigation policies. To avoid simultaneously arousing a positive motivator while depressing another, message designers should focus on developing content that engages audiences across multiple emotional fronts.
High school mathematics texts construction of statistics practices
Authors: Weiland Travis 
Published: August 2023

IntroductionA robust understanding of statistics has become crucial in our data centric societies. In the school setting the teaching of statistics is situated within the mathematics curriculum in the U.S. However, many mathematics teachers often have little to no past experiences with statistics before teaching it. Given such circumstances, textbooks likely play a strong role influencing the statistics curriculum teachers enact for students. In this study, I investigate how the discourse of two common high school textbook series form what the actions are for doing statistics.MethodsFor this study I used a Foucauldian discourse analysis to inductively analyze the texts for the actions they create.ResultsOne of the main results of the study was that the actions are very routinized/algorithmic in nature. Furthermore, most actions were associated with analyzing data. I also contrast the findings of the analysis to the discourse of the field of statistics education, namely through the Guidelines for Assessment and Instruction in Statistics Education, which highlighted some significant absences including statistical questions to drive investigation and discussion of collecting data.DiscussionThe findings have implications for teacher education in terms of topics to focus teachers’ attention on and to help provide them further support with teaching to their students.
Long-term efficacy and safety of osilodrostat in patients with Cushing’s disease: results from the LINC 4 study extension
Authors: Gadelha Mônica , Snyder Peter J. , Witek Przemysław , Bex Marie , Belaya Zhanna , Turcu Adina F. , Feelders Richard A. , Heaney Anthony P. , Paul Michaela , Pedroncelli Alberto M. , Auchus Richard J. 
Published: August 2023

ObjectiveTo evaluate the long-term efficacy and safety of osilodrostat in patients with Cushing’s disease.MethodsThe multicenter, 48-week, Phase III LINC 4 clinical trial had an optional extension period that was initially intended to continue to week 96. Patients could continue in the extension until a managed-access program or alternative treatment became available locally, or until a protocol amendment was approved at their site that specified that patients should come for an end-of-treatment visit within 4 weeks or by week 96, whichever occurred first. Study outcomes assessed in the extension included: mean urinary free cortisol (mUFC) response rates; changes in mUFC, serum cortisol and late-night salivary cortisol (LNSC); changes in cardiovascular and metabolic-related parameters; blood pressure, waist circumference and weight; changes in physical manifestations of Cushing’s disease; changes in patient-reported outcomes for health-related quality of life; changes in tumor volume; and adverse events. Results were analyzed descriptively; no formal statistical testing was performed.ResultsOf 60 patients who entered, 53 completed the extension, with 29 patients receiving osilodrostat for more than 96 weeks (median osilodrostat duration: 87.1 weeks). The proportion of patients with normalized mUFC observed in the core period was maintained throughout the extension. At their end-of-trial visit, 72.4% of patients had achieved normal mUFC. Substantial reductions in serum cortisol and LNSC were also observed. Improvements in most cardiovascular and metabolic-related parameters, as well as physical manifestations of Cushing’s disease, observed in the core period were maintained or continued to improve in the extension. Osilodrostat was generally well tolerated; the safety profile was consistent with previous reports.ConclusionOsilodrostat provided long-term control of cortisol secretion that was associated with sustained improvements in clinical signs and physical manifestations of hypercortisolism. Osilodrostat is an effective long-term treatment for patients with Cushing’s disease.Clinical trial registrationClinicalTrials.gov, identifier NCT02180217
No NLRP3 inflammasome activity in kidney epithelial cells, not even when the NLRP3-A350V Muckle-Wells variant is expressed in podocytes of diabetic mice
Authors: Kunte Sophie Carina , Marschner Julian A. , Klaus Martin , Honda Tâmisa , Li Chenyu , Motrapu Manga , Walz Christoph , Angelotti Maria Lucia , Antonelli Giulia , Melica Maria Elena , De Chiara Letizia , Semeraro Roberto , Nelson Peter J. , Anders Hans-Joachim 
Published: August 2023

BackgroundThe NLRP3 inflammasome integrates several danger signals into the activation of innate immunity and inflammation by secreting IL-1β and IL-18. Most published data relate to the NLRP3 inflammasome in immune cells, but some reports claim similar roles in parenchymal, namely epithelial, cells. For example, podocytes, epithelial cells critical for the maintenance of kidney filtration, have been reported to express NLRP3 and to release IL-β in diabetic kidney disease, contributing to filtration barrier dysfunction and kidney injury. We questioned this and hence performed independent verification experiments.MethodsWe studied the expression of inflammasome components in human and mouse kidneys and human podocytes using single-cell transcriptome analysis. Human podocytes were exposed to NLRP3 inflammasome agonists in vitro and we induced diabetes in mice with a podocyte-specific expression of the Muckle-Wells variant of NLRP3, leading to overactivation of the Nlrp3 inflammasome (Nphs2Cre;Nlrp3A350V) versus wildtype controls. Phenotype analysis included deep learning-based glomerular and podocyte morphometry, tissue clearing, and STED microscopy of the glomerular filtration barrier. The Nlrp3 inflammasome was blocked by feeding ß-hydroxy-butyrate.ResultsSingle-cell transcriptome analysis did not support relevant NLRP3 expression in parenchymal cells of the kidney. The same applied to primary human podocytes in which NLRP3 agonists did not induce IL-1β or IL-18 secretion. Diabetes induced identical glomerulomegaly in wildtype and Nphs2Cre;Nlrp3A350V mice but hyperfiltration-induced podocyte loss was attenuated and podocytes were larger in Nphs2Cre;Nlrp3A350V mice, an effect reversible with feeding the NLRP3 inflammasome antagonist ß-hydroxy-butyrate. Ultrastructural analysis of the slit diaphragm was genotype-independent hence albuminuria was identical.ConclusionPodocytes express low amounts of the NLRP3 inflammasome, if at all, and do not produce IL-1β and IL-18, not even upon introduction of the A350V Muckle-Wells NLRP3 variant and upon induction of podocyte stress. NLRP3-mediated glomerular inflammation is limited to immune cells.
De novo identification of complex traits associated with asthma
Authors: Zaied Roan E. , Fadason Tayaza , O’Sullivan Justin M. 
Published: August 2023

IntroductionAsthma is a heterogeneous inflammatory disease often associated with other complex phenotypes. Identifying asthma-associated diseases and uncovering the molecular mechanisms mediating their interaction can help detangle the heterogeneity of asthma. Network analysis is a powerful approach for untangling such inter-disease relationships.MethodsHere, we integrated information on physical contacts between common single nucleotide polymorphisms (SNPs) and gene expression with expression quantitative trait loci (eQTL) data from the lung and whole blood to construct two tissue-specific spatial gene regulatory networks (GRN). We then located the asthma GRN (level 0) within each tissue-specific GRN by identifying the genes that are functionally affected by asthma-associated spatial eQTLs. Curated protein interaction partners were subsequently identified up to four edges or levels away from the asthma GRN. The eQTLs spatially regulating genes on levels 0–4 were queried against the GWAS Catalog to identify the traits enriched (hypergeometric test; FDR ≤ 0.05) in each level.ResultsWe identified 80 and 82 traits significantly enriched in the lung and blood GRNs, respectively. All identified traits were previously reported to be comorbid or associated (positively or negatively) with asthma (e.g., depressive symptoms and lung cancer), except 8 traits whose association with asthma is yet to be confirmed (e.g., reticulocyte count). Our analysis additionally pinpoints the variants and genes that link asthma to the identified asthma-associated traits, a subset of which was replicated in a comorbidity analysis using health records of 26,781 asthma patients in New Zealand.DiscussionOur discovery approach identifies enriched traits in the regulatory space proximal to asthma, in the tissue of interest, without a priori selection of the interacting traits. The predictions it makes expand our understanding of possible shared molecular interactions and therapeutic targets for asthma, where no cure is currently available.
ED95 of remimazolam in nasal administration for attenuating preoperative anxiety in children
Authors: Long Xiang , Wen Li-xia , Yang Hu , Zhu Guo-hong , Zhang Qing-yun , Jiang Jing-jing , Gong Yuan 
Published: August 2023

BackgroundPreoperative anxiety often prevails in children at higher levels than adults, which is a common impediment for surgeons and anesthesiologists. It is of great necessity to explore an appropriate medication to improve this situation. Remimazolam, a type of benzodiazepine drug, has been indicated for the induction and maintenance of procedural sedation in adults since 2020. To date, rare studies were reported to investigate the effect of remimazolam on children. In this study, we investigated the safety and efficacy of intranasal drops of remimazolam and tried to determine the 95% effective dose (ED95) of remimazolam in single intranasal administration in attenuating preoperative anxiety in children.MethodsIn this study, 114 children were enrolled who underwent laparoscopic high-level inguinal hernia ligation between January 2021 and December 2022 and were divided into an early childhood children group and a pre-school children group. The biased coin design (BCD) was used to determine the target doses. A positive response was defined as the effective relief of preoperative anxiety (modified Yale Preoperative Anxiety Scale, mYPAS &lt; 30). The initial nasal dose of remimazolam was 0.5 mg·kg−1 in the two groups. An increment or decrement of 0.1 mg·kg−1 was applied depending on the sedative responses. Isotonic regression and bootstrapping methods were used to calculate the ED95 and 95% confidence intervals (CIs), respectively.ResultsA total of 80 children completed the study, including 40 in the early childhood group and 40 in the pre-school children group. As statistical analysis indicated, the ED95 of a single intranasal infusion of remimazolam for the relief of preoperative anxiety is 1.57 mg·kg−1 (95% CI: 1.45–1.59 mg·kg−1) in early childhood children and 1.09 mg·kg−1 (95% CI: 0.99–1.11 mg·kg−1) in pre-school children, and the CIs did not overlap each other.ConclusionRemimazolam is an effective medication to relieve preoperative anxiety in children. Moreover, the ED95 of single nasal administration of remimazolam for effective relief of preoperative anxiety was 1.57 and 1.09 mg·kg−1 in early childhood children and pre-school children, respectively.
Age and sex differences in the association between APOE genotype and Alzheimer’s disease in a Taiwan Chinese population
Authors: Huang Ling-Chun , Lee Mei-Yueh , Chien Ching-Fang , Chang Yang-Pei , Li Kuan-Ying , Yang Yuan-Han 
Published: August 2023

IntroductionThe Apolipoprotein E (APOE) epsilon (ε) 4 allele is a well-established risk factor for late-onset Alzheimer’s disease (AD). Reports on white ancestry populations have showed that age, sex, and ethnicity have different effects on the association between APOE genotype and AD. However, studies on Asian populations such as Taiwan Chinese populations are limited. This study aimed to evaluate the association between APOE genotype and AD in a Taiwan Chinese population, and to explore if the association varies by age and sex.MethodsWe conducted a case-control study in 725 patients with AD and 1,067 age- and sex- matched controls without dementia from a Taiwan Chinese population. Logistic regression models were used to test the association between AD and APOE genotypes. Secondary analyses considered age (&lt;75 or ≥75 years old), and sex stratified models.ResultsThe risk of AD was significantly increased for people with at least one copy of APOE ε4 (OR = 2.52, 95% CI = 2.01–3.17, p &lt; 0.001) and in a dose-dependent manner. Our results did not show an statistically significance different in AD risk when women and men carrying APOEε4 were compared. Despite not reaching statistical significance, the risk of APOE ε4 for AD was higher among younger participants (OR = 3.21, 95% CI = 2.26–4.56, p &lt; 0.001) compared to older ones (OR = 2.13, 95% CI = 1.53–2.97, p &lt; 0.001). When considering both sex and age, the risk of AD was higher among older men carrying APOE ε4 (OR = 2.64, 95% CI = 1.51–4.60 in men; OR = 1.90, 95% CI = 1.26–2.86 in women), while women carrying APOE ε4 appeared to have an increased risk at a younger age (OR = 3.29, 95% CI = 2.20–4.93 in women; OR = 2.91, 95% CI = 1.40–6.05 in men).DiscussionThe APOE ε4 allele represents a major risk factor for AD in the Taiwanese population. The effect of APOE ε4 allele on AD risk appeared to be stronger among men aged 75 years or more and among younger women.
Elicitation of trustworthiness requirements for highly dexterous teleoperation systems with signal latency
Authors: Louca Joe , Vrublevskis John , Eder Kerstin , Tzemanaki Antonia 
Published: August 2023

IntroductionTeleoperated robotic manipulators allow us to bring human dexterity and cognition to hard-to-reach places on Earth and in space. In long-distance teleoperation, however, the limits of the speed of light results in an unavoidable and perceivable signal delay. The resultant disconnect between command, action, and feedback means that systems often behave unexpectedly, reducing operators' trust in their systems. If we are to widely adopt telemanipulation technology in high-latency applications, we must identify and specify what would make these systems trustworthy.MethodsIn this requirements elicitation study, we present the results of 13 interviews with expert operators of remote machinery from four different application areas—nuclear reactor maintenance, robot-assisted surgery, underwater exploration, and ordnance disposal—exploring which features, techniques, or experiences lead them to trust their systems.ResultsWe found that across all applications, except for surgery, the top-priority requirement for developing trust is that operators must have a comprehensive engineering understanding of the systems' capabilities and limitations. The remaining requirements can be summarized into three areas: improving situational awareness, facilitating operator training, and familiarity, and easing the operator's cognitive load.DiscussionWhile the inclusion of technical features to assist the operators was welcomed, these were given lower priority than non-technical, user-centric approaches. The signal delays in the participants' systems ranged from none perceived to 1 min, and included examples of successful dexterous telemanipulation for maintenance tasks with a 2 s delay. As this is comparable to Earth-to-orbit and Earth-to-Moon delays, the requirements discussed could be transferable to telemanipulation tasks in space.
Vitamin D deficiency prevention policies in Iran: a retrospective policy analysis
Authors: Aghapour Baharak , Kheirouri Sorayya , Alizadeh Mohammad , Khodayari-Zarnaq Rahim 
Published: August 2023

AimIran has a higher prevalence of vitamin D deficiency (VDD) than the global level. This study aimed to assess VDD prevention policies in Iran through a policy analysis of agenda setting using the multiple streams framework (MSF).MethodsUsing Kingdon's MSF model, this qualitative analytical study performed a policy analysis on vitamin D-related policies in Iran. The policy documents were reviewed, and in-depth interviews were conducted with stakeholders (n = 27) using the framework analysis method. To categorize data and extract the related themes, MAXQDA version 10 was used.ResultsAccording to Kingdon's MSF theory, the problem stream included the high prevalence of VDD among Iranian infants (23.3%), adolescents (76%), and adults (59.1%). The policy stream was identified to focus on preventing programs for non-communicable diseases in the health sector. The political stream indicated that national and international support could provide a political climate for this issue.ConclusionAccording to our results, a window of opportunity for policymaking on VDD prevention has opened. However, there are some challenges related to the implementation of these policies. These include the dominance of a treatment-based view rather than a prevention-based approach in the health sector, economic problems, and restricted access to health services due to the outbreak of coronavirus disease 2019 (COVID-19). To strengthen and implement VDD prevention policies, the stakeholders need support from high-level policymakers.
Three-dimensional ultrasound-based radiomics nomogram for the prediction of extrathyroidal extension features in papillary thyroid cancer
Authors: Lu Wen-Jie , Mao Lin , Li Jin , OuYang Liang-Yan , Chen Jia-Yao , Chen Shi-Yan , Lin Yun-Yong , Wu Yi-Wen , Chen Shao-Na , Qiu Shao-Dong , Chen Fei 
Published: August 2023

PurposeTo develop and validate a three-dimensional ultrasound (3D US) radiomics nomogram for the preoperative prediction of extrathyroidal extension (ETE) in papillary thyroid cancer (PTC).MethodsThis retrospective study included 168 patients with surgically proven PTC (non-ETE, n = 90; ETE, n = 78) who were divided into training (n = 117) and validation (n = 51) cohorts by a random stratified sampling strategy. The regions of interest (ROIs) were obtained manually from 3D US images. A larger number of radiomic features were automatically extracted. Finally, a nomogram was built, incorporating the radiomics scores and selected clinical predictors. Receiver operating characteristic (ROC) curves were performed to validate the capability of the nomogram on both the training and validation sets. The nomogram models were compared with conventional US models. The DeLong test was adopted to compare different ROC curves.ResultsThe area under the receiver operating characteristic curve (AUC) of the radiologist was 0.67 [95% confidence interval (CI), 0.580–0.757] in the training cohort and 0.62 (95% CI, 0.467–0.746) in the validation cohort. Sixteen features from 3D US images were used to build the radiomics signature. The radiomics nomogram, which incorporated the radiomics signature, tumor location, and tumor size showed good calibration and discrimination in the training cohort (AUC, 0.810; 95% CI, 0.727–0.876) and the validation cohort (AUC, 0.798; 95% CI, 0.662–0.897). The result suggested that the diagnostic efficiency of the 3D US-based radiomics nomogram was better than that of the radiologist and it had a favorable discriminate performance with a higher AUC (DeLong test: p &lt; 0.05).ConclusionsThe 3D US-based radiomics signature nomogram, a noninvasive preoperative prediction method that incorporates tumor location and tumor size, presented more advantages over radiologist-reported ETE statuses for PTC.