bluuebunny/crossref_metadata_2025 huggingface dataset:
The effects of formulation on the pharmacokinetics of itraconazole and amiodarone in dogs after oral administration of a combination product, commercial products, and compounded products
Authors: Hunter Robert P. , Madigan Roy
Published: October 2023

This study evaluated four different formulations of itraconazole and amiodarone. Formulation 1 was Vida's combination tablet containing both active pharmaceutical ingredients (APIs). Formulation 2 was separate, commercially available human generic capsules and tablets of itraconazole and amiodarone, respectively. Formulation 3 was separate, compounded suspensions of itraconazole and amiodarone. Formulation 4 was a compounded chewable tablet of itraconazole. Eight female dogs were dosed with 5 mg/kg of itraconazole and 15 mg/kg amiodarone (except for formulation 4, which only received 5 mg/kg itraconazole) once weekly for 4 weeks using a modified Latin Square design, ensuring that all dogs received all formulations with a 7‐day washout between treatments. Animals were fasted overnight prior to each dose administration, with food returned to all animals 4 h post‐dose. Blood samples (3 mL) were collected pre‐treatment (0) and at appropriate time points over 72 h after each dose for a total of 14 samples per dog per treatment. There was high variability in the serum concentration data within treatment groups for itraconazole. The compounded suspensions were difficult to dose due to the nature of the formulations. The volumes dosed were accurate and consistent, but the suspension was thin and settled immediately when shaking was stopped for both itraconazole and amiodarone. All serum samples following itraconazole chewable tablet administration were not detectable or just above itraconazole's LOQ and thus did not allow for pharmacokinetic determination.
An investigation of the acaricidal activity of benzyl alcohol on Rhipicephalus annulatus and Rhipicephalus sanguineus and its synergistic or antagonistic interaction with commonly used acaricides
Authors: Aboelhadid Shawky M. , Ibrahium Samar M. , Abdel‐Baki Abdel‐Azeem S. , Hassan Khaled M. , Arafa Waleed M. , Aboud Heba M. , Mohy Sarah , Al‐Quraishy Saleh , Hassan Ahmed O. , Abdelgelil Noha H. , Gadelhaq Sahar M.
Published: October 2023

The most economically significant ectoparasites in the tropics and subtropics are ixodid ticks, especially Rhipicephalus annulatus and Rhipicephalus sanguineus. Years of extensive use of the readily available acaricides have resulted in widespread resistance development in these ticks, as well as negative environmental consequences. Benzyl alcohol (BA) has been frequently used to treat pediculosis and scabies, and it may be an effective alternative to commonly used acaricides. The main aim of the present study was to evaluate the acaricide activity of BA and its combination with the regularly used chemical acaricides against R. annulatus and R. sanguineus. Different concentrations of BA alone and in combination with deltamethrin, cypermethrin and chlorpyrifos were tested in vitro against adult and larvae of both tick species. The results showed that BA is toxic to R. annulatus and R. sanguineus larvae, with 100% larval mortality at concentrations of ≥50 mL/L, and LC50 and LC90 attained the concentrations of 19.8 and 33.8 mL/L for R. annulatus and 18.8 and 31.8 mL/L for R. sanguineus, respectively. Furthermore, BA in combination with deltamethrin, cypermethrin and chlorpyrifos exhibited synergistic factors of 2.48, 1.26 and 1.68 against R. annulatus larvae and 1.64, 11.1 and 1.14 against R. sanguineus larvae for deltamethrin + BA, cypermethrin + BA and chlorpyrifos + BA, respectively. BA induced 100% mortality in adult R. annulatus at concentrations of ≥250 mL/L with LC50 and LC90 reached the concentrations of 111 and 154 mL/L, respectively. Additionally, BA had ovicidal activity causing complete inhibition of larval hatching at 100 mL/L. The combination of BA with deltamethrin and cypermethrin increased acetylcholinesterase inhibition, whereas the combination of BA with chlorpyrifos decreased glutathione (GSH) activity and malondialdehyde levels. In the field application, the combination of BA 50 mL/L and deltamethrin (DBA) resulted in a significant reduction in the percentage of ticks by 30.9% 28 days post‐treatment when compared with groups treated with deltamethrin alone. In conclusion, BA causes mortality in laboratory and field studies alone and in combination with cypermethrin or deltamethrin. BA can be used for control of ticks of different life stages, that is, eggs and larvae, through application to the ground.
No indication of aberrant neutrophil extracellular trap release in indolent or advanced systemic mastocytosis
Authors: Rosell Axel , Karlström Cecilia , Dahlin Joakim S. , Boey Daryl , Klimkowska Monika , Ax Kajsa , Thålin Charlotte , Ungerstedt Johanna
Published: October 2023

In disease states with chronic inflammation, there is a crosstalk between mast cells and neutrophil granulocytes in the inflamed microenvironment, which may be potentiated by tryptase. In systemic mastocytosis (SM), mast cells are constitutively active and tryptase is elevated in blood. Mast cell activation in SM leads to symptoms from various organs depending on where the active mast cells reside, for example, palpitations, flush, allergic symptoms including anaphylactic reactions, and osteoporosis. Whether neutrophil function is altered in SM is not well understood. In the current study, we assessed nucleosomal citrullinated histone H3 (H3Cit‐DNA) as a proxy for neutrophil extracellular trap release in plasma from 55 patients with indolent and advanced SM. We observed a strong trend towards a correlation between leukocyte count, eosinophil count and neutrophil count and H3Cit‐DNA levels in patients with advanced SM but not in indolent SM; however, no differences in H3Cit‐DNA levels in SM patients compared with healthy controls. H3Cit‐DNA levels did not correlate with SM disease burden, tryptase levels, history of anaphylaxis or presence of cutaneous mastocytosis; thus, there is no evidence of a general neutrophil extracellular trap release in SM. Interestingly, H3Cit‐DNA levels and leukocyte counts were elevated in a subgroup of SM patients with aberrant mast cell CD2 expression, which warrants further investigation. In conclusion, we found no evidence of global increase in neutrophil extracellular trap release in SM.
In defense of verb‐stranding VP ellipsis
Authors: Simpson Andrew
Published: October 2023

This remark offers arguments against recent challenges to analyses that postulate verb‐stranding VP ellipsis (Idan Landau, “On the nonexistence of verb‐stranding VP‐ellipsis,” 2020, Linguistic Inquiry 51.2.341–365; Satoshi Oku, “A note on ellipsis‐resistant constituents,” 2016, Nanzan Linguistics 11.56–70). The article defends the verb‐stranding‐VP‐ellipsis hypothesis, arguing that it remains the strongest hypothesis available to account for many instances of ellipsis with null objects in languages such as Hindi, Bangla, and Japanese.
bla
KPC-2
overexpression and
bla
GES-5
carriage as major imipenem/relebactam resistance mechanisms in
Pseudomonas aeruginosa
high-risk clones ST463 and ST235, respectively, in China
Authors: Li Yue , Fang Li , Dong Mengqian , Cai Heng , Hua Xiaoting , Jiang Yan , Yu Yunsong , Yang Qing
Published: October 2023

Pseudomonas aeruginosa
high-risk clones pose severe threats to public health. Here, we characterize the imipenem/relebactam (IR) resistance mechanisms in
P. aeruginosa
high-risk clones sequence type 235 (ST235) and ST463 in China. Minimum inhibitory concentrations (MICs) were determined, and Illumina short-read sequencing was performed for 1,168 clinical carbapenem-resistant
P. aeruginosa
(CRPA) isolates. The gene copy number and expression level were analyzed by Illumina sequencing depth and reverse transcription-quantitative PCR, respectively. Resistance conferred by
bla
GES-5
was evaluated by cloning experiments. ST463 and ST235 accounted for 9.8% (115/1,168) and 4.5% (53/1,168) of total isolates, respectively, and showed high frequencies of extensively drug-resistant and difficult-to-treat resistant phenotypes. The overall IR-resistant rate in CRPA was 21.0% (245/1,168). However, the IR resistance rate was 81.7% (94/115) in ST463-PA and 52.8% (28/53) in ST235-PA. Of the ST463 isolates, 92.2% (106/115) were
Klebsiella pneumoniae
carbapenemase-producing
P. aeruginosa
(KPC-PA), and all 94 IR-resistant ST463-PA produced KPC-2. Compared to IR-susceptible ST463 KPC-2-PA, IR-resistant ST463 KPC-2-PA exhibited significantly higher
bla
KPC-2
copy numbers and expression levels. In ST463 KPC-2-PA, 16 mg/L relebactam resulted in additional fourfold reductions in imipenem MIC
50/90
values compared to 4 mg/L relebactam. In ST235, 1.9% (1/53) carried
bla
IMP
carbapenemase and 54.7% (29/53) carried
bla
GES
carbapenemase. Other than the IMP producer, all 27 IR-resistant ST235-PA produced GES-5. Cloning experiments revealed that imipenem resistance in
bla
GES-5
-carrying PAO1 transformants was generally unaffected by relebactam. In conclusion, IR-resistant CRPA isolates in China were mainly distributed in
P. aeruginosa
high-risk clones ST463 and ST235. The major underlying IR resistance mechanisms were
bla
KPC-2
overexpression and
bla
GES-5
carriage.
Characterization of a novel aromatic ring-hydroxylating oxygenase, NarA2B2, from thermophilic
Hydrogenibacillus
sp. strain N12
Authors: Guo Lihua , Ouyang Xingyu , Wang Weiwei , Huang Yiqun , Qiu Xiaoyu , Xu Ping , Tang Hongzhi
Published: October 2023

Polycyclic aromatic hydrocarbons (PAHs) are harmful to human health due to their carcinogenic, teratogenic, and mutagenic effects. A thermophilic
Hydrogenibacillus
sp. strain N12 capable of degrading a variety of PAHs and derivatives was previously isolated. In this study, an aromatic ring-hydroxylating oxygenase, NarA2B2, was identified from strain N12, with substrate specificity including naphthalene, phenanthrene, dibenzothiophene, fluorene, acenaphthene, carbazole, biphenyl, and pyrene. NarA2B2 was proposed to add one or two atoms of molecular oxygen to the substrate and catalyze biphenyl at C-2, 2 or C-3, 4 positions with different characteristics than before. The key catalytic amino acids, H222, H227, and D379, were identified as playing a pivotal role in the formation of the 2-his-1-carboxylate facial triad. Furthermore, we conducted molecular docking and molecular dynamics simulations, notably, D219 enhanced the stability of the iron center by forming two stable hydrogen bonds with H222, while the mutation of F216, T223, and H302 modulated the catalytic activity by altering the pocket’s size and shape. Compared to the wild-type (WT) enzyme, the degradation ratios of acenaphthene by F216A, T223A, and H302A had an improvement of 23.08%, 26.87%, and 29.52%, the degradation ratios of naphthalene by T223A and H302A had an improvement of 51.30% and 65.17%, while the degradation ratio of biphenyl by V236A had an improvement of 77.94%. The purified NarA2B2 was oxygen-sensitive when it was incubated with L-ascorbic acid in an anaerobic environment, and its catalytic activity was restored
in vitro
. These results contribute to a better understanding of the molecular mechanism responsible for PAHs’ degradation in thermophilic microorganisms.

IMPORTANCE

(i) A novel aromatic ring-hydroxylating oxygenase named NarA2B2, capable of degrading multiple polycyclic aromatic hydrocarbons and derivatives, was identified from the thermophilic microorganism
Hydrogenibacillus
sp. N12. (ii) The degradation characteristics of NarA2B2 were characterized by adding one or two atoms of molecular oxygen to the substrate. Unlike the previous study, NarA2B2 catalyzed biphenyl at C-2, 2 or C-3, 4 positions. (iii) Catalytic sites of NarA2B2 were conserved, and key amino acids F216, D219, H222, T223, H227, V236, F243, Y300, H302, W316, F369, and D379 played pivotal roles in catalysis, as confirmed by protein structure prediction, molecular docking, molecular dynamics simulations, and point mutation.
Comparison of intestinal microbes and metabolites in active VKH versus acute anterior uveitis associated with ankylosing spondylitis
Authors: Li Mengyao , Liu Mingzhu , Wang Xia , Wei Haihui , Jin Siyan , Liu Xiaoli
Published: October 2023

Background

It has been reported that the gut microbiome is involved in the pathogenesis of uveitis, but the specific pathogenic microbes and metabolites in different types of uveitis are still unclear.

Methods

Microbiome and metabolites were detected using 16S ribosomal DNA and LC‒MS/MS (liquid chromatography tandem mass spectrometry) in 45 individuals, including 16 patients with Vogt Koyanagi Harada (VKH), 11 patients with acute anterior uveitis (AAU) and 18 healthy controls.

Result

The diversity of intestinal microbes among the VKH, AAU and control groups was not significantly different. Thirteen specific microbes and 38 metabolites were detected in the VKH group, and 7 metabolites (vanillin, erythro-isoleucine, pyrimidine, 1-aminocyclopropanecarboxylic acid, beta-tocopherol, (-)-gallocatechin and N1-methyl-4-pyridone-3-carboxamide) significantly changed only in patients with VKH, which mainly acted on nicotinamide and nicotinamide metabolism and biotin metabolism (p<0.05). Compared with the VKH group, the AAU group had milder intestinal changes. Only 11 specific microbes and 29 metabolites changed in the AAU group, while these metabolites were not specific (p<0.05). These metabolites mainly acted on arachidonic acid metabolism. In addition, three microbes and two metabolites had the same changes in the VKH and AAU groups (p<0.05). Multiple correlations were found between gut microbes and metabolites in the VKH and AAU groups. Six microbes (Pediococcus, Pseudomonas, Rhodococcus, Photobacterium, Gardnerella and Lawsonia) and two metabolites (pyrimidine and gallocatechin) as biomarkers could effectively distinguish patients with VKH from patients with AAU and healthy individuals, with AUC (area under the curve) values greater than 82%. Four microbes (Lentilactobacillus, Lachnospiraceae_UCG-010, Cetobacterium, Liquorilactobacillus) could distinguish patients with AAU from patients with VKH and healthy controls with AUC>76%.

Conclusion

Significant differences in intestinal microbes and metabolites suggest their different roles in the pathogenesis of uveitis entities. Changes in the metabolism of certain B vitamins may be involved in the pathogenesis of VKH.
Effect of Elastic-band Baduanjin exercise on older adults with type 2 diabetes mellitus in China: protocol for a randomised controlled trial
Authors: Wang Hui , Pei Changle , Liu Jingxia , Wang Yan , Chen Chao , Lyu Weibo , Cheng Kangyao
Published: October 2023

Introduction

In China, older adults have the highest incidence of type 2 diabetes mellitus (T2DM). Bone, joint and physical endurance limit the types of exercise available to older adults with T2DM. Baduanjin is recommended and encouraged as an exercise option. However, Baduanjin exercise alone cannot account for the loss of muscle mass. Resistance training is recommended in the guidelines and offers new options for increasing muscle strength. The purpose of this study is to compare the effects of Elastic-band Baduanjin exercise training with those of Baduanjin alone.

Methods and analysis

This study is a reworking exercise programme, consisting of Baduanjin combined with elastic band resistance exercise training. A 12-week randomised controlled trial will be conducted. Patients aged 60–80 years with T2DM will be assigned to the Elastic-band Baduanjin (intervention) and Baduanjin (control) groups using cluster random sampling. A sample of 70 participants will be conducted. Indicators of muscle strength, body composition, blood glucose and balance function will be collected before and after the intervention. Meanwhile, exercise will be monitored using the International Physical Activity Questionnaire.

Ethics and dissemination

The trial was approved by the Chinese Ethics Committee of Registering Clinical Trials on 19 June 2022 (ChiECRCT20220210). The research results will be published in peer-­reviewed publications.

Trial registration number

Chinese Clinical Trials Registry (ChiCTR2200062424).
Analysis on personnel costs and working time for implementing a more person-centred care approach: a case study with embedded units in a Swedish region
Authors: Gyllensten Hanna , Tistad Malin , Fridberg Helena , Wallin Lars
Published: October 2023

Objectives

Our aim was to describe the time and costs used during the implementation of a more person-centred care (PCC) approach as part of ordinary practice.

Design

A case study with embedded units.

Setting

Region Dalarna, Sweden.

Participants

The Department for Development (DD) staff who provided a central support function in the implementation and six healthcare units: nephrology, two geriatric care and rehabilitation units, two psychiatry units and primary care.

Interventions

More PCC.

Primary and secondary outcome measures

Working days and related salary costs reported by categories indicating costs for implementation strategies, service delivery, and research/development costs.

Results

The healthcare units logged on average 5.5 working days per staff member. In the healthcare units, 6%–57% of the time reported was used for implementation strategies, 40%–90% for service delivery and 2%–12% for research/development. Of the time reported by the DD, 88% was assigned to implementation strategies. Costs associated with reported time indicated 23% of costs for this implementation occurred in the DD. Using the budgeted cost, this proportion increased to 48%. The budget for the DD corresponded to SEK 2.30 per citizen per year and 0.009% of the total healthcare budget of the region.

Conclusions

The study found that a large part of resources used for this implementation of more PCC occurred in the DD, although at least half of the costs occurred in the healthcare units. Moreover, the cost of providing a central support function corresponds to a tiny proportion of the total health budget.
Implementation status and consideration for the globalisation of decentralised clinical trials: a cross-sectional analysis of clinical trial databases
Authors: Sato Takahiro , Mizumoto Shota , Ota Midori , Shikano Mayumi
Published: October 2023

Objective

To comprehensively elucidate the current landscape of decentralised clinical trials (DCTs) and identify notable aspects that can facilitate DCT implementation.

Design

Cross-sectional analysis.

Setting

Data were extracted using selected DCT-specific search terms on 4 June 2022, from the ClinicalTrials.gov database and on 2 September 2022, from the Japan Registry of Clinical Trials and Japic Clinical Trials Information.

Primary outcome measure

We characterised trials based on the four components of DCT: telemedicine, home healthcare, direct-to-patient and the Internet of Healthcare Things (IoHTs)/Internet of Medical Things.

Results

Data obtained from ClinicalTrials.gov indicated that the number of DCTs has increased annually and exponentially since 2020. DCTs for cardiovascular diseases are the most common, and the digital platform for patient monitoring is used the most in DCTs. The Japanese databases also showed that DCTs have increased in recent years, and the data on disease areas and IoHTs were similar to those obtained from the ClinicalTrials.gov database, except for the number of studies. Approximately 9.2% of DCTs were conducted across multiple regions, whereas over 80% were conducted within a single country.

Conclusions

This study revealed the comprehensive trend of DCTs in the USA and Japan and helped identify widely implemented DCT components and the therapeutic areas in which they are implemented. International consensus guidelines for DCTs are necessary to promote multiregional clinical trials with DCT components.
Are housing circumstances associated with faster epigenetic ageing?
Authors: Clair Amy , Baker Emma , Kumari Meena
Published: October 2023

Background

Numerous aspects of housing are associated with health. However, the pathways between housing and health, particularly the psychosocial elements of housing, are less well understood. Epigenetic information alongside social survey data offers an opportunity to explore biological ageing, measured using DNA methylation, as a potential pathway through which housing affects health.

Methods

We use data on housing and DNA methylation from the UK Household Longitudinal Study, linked with prior survey responses from the British Household Panel Survey, covering adults in Great Britain. We explore the association between epigenetic ageing and housing circumstances, both contemporary and historical, using hierarchical regression.

Results

We find that living in a privately rented home is related to faster biological ageing. Importantly, the impact of private renting (coefficient (SE) 0.046 years (0.011) vs owned outright, p<0.001) is greater than the impact of experiencing unemployment (coefficient 0.027 years (0.012) vs employed, p<0.05) or being a former smoker (coefficient 0.021 years (0.005) vs never smoker, p<0.001). When we include historical housing circumstances in the analysis, we find that repeated housing arrears and exposure to pollution/environmental problems are also associated with faster biological ageing.

Conclusion

Our results suggest that challenging housing circumstances negatively affect health through faster biological ageing. However, biological ageing is reversible, highlighting the significant potential for housing policy changes to improve health.
Ultrasensitive assay technology and fluid biomarkers for the evaluation of peripheral nerve disease
Authors: Bellanti Roberto , Keddie Stephen , Lunn Michael P , Rinaldi Simon
Published: October 2023

The field of biomarker discovery is rapidly expanding. The introduction of ultrasensitive immunoassays and the growing precision of genetic technologies are poised to revolutionise the assessment and monitoring of many diseases. Given the difficulties in imaging and tissue diagnosis, there is mounting interest in serum and cerebrospinal fluid biomarkers of peripheral neuropathy. Realised and potential fluid biomarkers of peripheral nerve disease include neuronal biomarkers of axonal degeneration, glial biomarkers for peripheral demyelinating disorders, immunopathogenic biomarkers (such as the presence and titre of antibodies or the levels of cytokines) and genetic biomarkers. Several are already starting to inform clinical practice, whereas others remain under evaluation as potential indicators of disease activity and treatment response. As more biomarkers become available for clinical use, it has become increasingly difficult for clinicians and researchers to keep up-to-date with the most recent discovery and interpretation. In this review, we aim to inform practising neurologists, neuroscientists and other clinicians about recent advances in fluid biomarker technology, with a focus on single molecule arrays (Simoa), chemiluminescent enzyme immunoassays (CLEIA), electrochemiluminescence (ECL), proximity extension assays (PEA), and microfluidic technology. We discuss established and emerging fluid biomarkers of peripheral neuropathy, their clinical applications, limitations and potential future developments.
Perspectives on limiting tobacco access and supporting access to nicotine vaping products among clients of residential drug and alcohol treatment services in Australia
Authors: Trigg Joshua , Rich Jane , Williams Edwina , Gartner Coral E , Guillaumier Ashleigh , Bonevski Billie
Published: October 2023

Introduction

Tobacco endgame strategies aim to drive down population smoking rates, the success of which can be improved with public buy-in, including from populations with high smoking rates such as alcohol and other drug (AOD) service clients. This study aimed to explore acceptability of tobacco retail and nicotine reduction, and subsidised nicotine vaping to support AOD service clients following a smoking cessation attempt.

Methods

We interviewed 31 Australian AOD service clients who currently or previously smoked, following a 12-week randomised trial comparing nicotine replacement therapy with nicotine vaping product (NVP) for smoking cessation. Participants were asked how effectively three scenarios would support tobacco cessation: tobacco retailer reduction, very low-nicotine cigarette standard and subsidised NVP access. We thematically analysed participant views on how each approach would support tobacco abstinence.

Results

Tobacco retailer reduction raised concerns about increasing travel and accessing cigarettes from alternate sources, with generally lower acceptability, though a range of perspectives were provided. Reducing nicotine in tobacco products was described as reducing appeal of smoking and potentially increasing illicit purchases of non-reduced nicotine products. Clients of AOD services were highly accepting of subsidised NVP access for tobacco cessation, as this would partly address financial and socioeconomic barriers.

Conclusions

Australian tobacco control policy should consider how these approaches impact ease and likelihood of tobacco access by AOD service clients in relation to the general population. Understanding clients’ acceptability of tobacco control and endgame measures can inform how to avoid potential unintended consequences for these clients.
Cosmological tests of $$f(R,G,\mathcal {T})$$ dark energy model in FRW universe
Authors: Chaudhary Himanshu , Bouali Amine , Molla Niyaz Uddin , Debnath Ujjal , Mustafa G.
Published: October 2023

The paper is devoted to study the observational signatures of$$f(R,G,\mathcal {T})$$f(R,G,T)gravity in FRW universe. In this research article, we present a new cosmological model formulated within the$$f(R,G,\mathcal {T})$$f(R,G,T)framework. To constrain the model parameters, we employ the Markov Chain Monte Carlo (MCMC) technique, which enables us to explore the parameter space effectively, and used the 36 points of cosmic chronometers and 1701 points from Pantheon Plus data. We compare our proposed$$f(R,G,\mathcal {T})$$f(R,G,T)model with the widely accepted$$\Lambda $$ΛCDM model, considering different cosmological parameters, including deceleration, snap, and jerk. By evaluating these parameters, we gain valuable insights into the dynamics and evolution of the universe within the context of our new model. Moreover, various diagnostic tests have been conducted, such as Statefinder andOmdiagnostic, to further investigate the behavior and consistency of our$$f(R,G,\mathcal {T})$$f(R,G,T)model. These tests offer deeper insights into the properties of our model and its compatibility with observational data. We subject our model to statistical analysis using Information Criteria, which serves as a rigorous quantitative assessment of the model’s goodness of fit to the data. This analysis aids in determining the level of agreement between our$$f(R,G,\mathcal {T})$$f(R,G,T)model and the observational data, thus establishing the viability and reliability of our proposed cosmological framework. Our findings highlight the potential of the$$f(R,G,\mathcal {T})$$f(R,G,T)framework in understanding the fundamental aspects of the universe’s evolution and dynamics. The comparative analysis with$$\Lambda $$ΛCDM, as well as the comprehensive diagnostic tests performed, demonstrate the efficacy and validity of our model in explaining the observed cosmological phenomena. These results contribute to the ongoing pursuit of accurate and comprehensive models that can provide a deeper understanding of the nature of our universe.
Action principle of Galilean relativistic Proca theory
Authors: Banerjee Rabin , Bhattacharya Soumya
Published: October 2023

In this paper, we discuss Galilean relativistic Proca theory in detail. We first provide a set of mapping relations, derived systematically, that connect the covariant and contravariant vectors in the Lorentz relativistic and Galilean relativistic formulations. Exploiting this map, we construct the two limits of Galilean relativistic Proca theory from usual Proca theory in the potential formalism for both contravariant and covariant vectors which are now distinct entities. An action formalism is thereby derived from which the field equations are obtained and their internal consistency is shown. Next we construct Noether currents and show their on-shell conservation. We introduce analogues of Maxwell’s electric and magnetic fields and recast the entire analysis in terms of these fields. Explicit invariance under Galilean transformations is shown for both electric/magnetic limits. We then move to discuss Stuckelberg embedded Proca model in the Galilean framework.
STUDY ON DYNAMIC BEHAVIORS OF TUBERCULOSIS MODEL WITH GENDER AND AGE-STRUCTURE
Authors: WANG SI , CAO HUI , ZHAO TINGTING
Published: October 2023

This paper deals with the dynamics of tuberculosis transmission model with different genders and age structures. The basic reproduction numbers [Formula: see text] are defined, where [Formula: see text] and [Formula: see text] are the basic reproduction number of tuberculosis transmission in female and male populations, respectively. The global stability of the disease-free equilibrium was discussed when [Formula: see text]; The existence, uniqueness and global stability of the endemic equilibrium, and the persistence of the system both were proved when [Formula: see text]. The findings indicate that the tuberculosis dynamical model with different genders and age structures will experience the classical threshold dynamic behaviors, that is, if [Formula: see text], the disease will disappear; while if [Formula: see text], the disease will spread within the population, and eventually lead to a endemic disease. Finally, the theoretical analysis of the model is verified by numerical simulation and we proposed that male infected individuals should be focused on in the prevention and control of tuberculosis in the future.
Artificial Intelligence for Safety-Critical Systems in Industrial and Transportation Domains: A Survey
Authors: Perez-Cerrolaza Jon , Abella Jaume , Borg Markus , Donzella Carlo , Cerquides Jesús , Cazorla Francisco J. , Englund Cristofer , Tauber Markus , Nikolakopoulos George , Flores Jose Luis
Published: October 2023

Artificial Intelligence (AI)
can enable the development of next-generation autonomous safety-critical systems in which
Machine Learning (ML)
algorithms learn optimized and safe solutions. AI can also support and assist human safety engineers in developing safety-critical systems. However, reconciling both cutting-edge and state-of-the-art AI technology with safety engineering processes and safety standards is an open challenge that must be addressed before AI can be fully embraced in safety-critical systems. Many works already address this challenge, resulting in a vast and fragmented literature. Focusing on the industrial and transportation domains, this survey structures and analyzes challenges, techniques, and methods for developing AI-based safety-critical systems, from traditional functional safety systems to autonomous systems. AI
trustworthiness
spans several dimensions, such as engineering, ethics and legal, and this survey focuses on the safety engineering dimension.
Exploring the role of osteoglycin in type 2 diabetes: implications for insulin resistance and vascular pathophysiology
Authors: González-Salvatierra Sheila , García-Fontana Beatriz , Martínez-Heredia Luis , Lacal Jesus , Andújar-Vera Francisco , Sanabria-de la Torre Raquel , Moratalla-Aranda Enrique , Lozano-Alonso Silvia , García-Fontana Cristina , Muñoz-Torres Manuel
Published: October 2023

This study uncovers an increase of serum osteoglycin levels in patients with type 2 diabetes, which does not appear to be associated with the development of atherosclerosis, but rather with insulin resistance in this population. Overexpression of osteoglycin increased proliferation and upregulated the expression of autotaxin in vascular smooth muscle cells within calcified environments. Osteoglycin could be a biomarker of insulin resistance for type 2 diabetes and could be indirectly involved in the development of atherosclerosis.
Dynamic primitives in constrained action: systematic changes in the zero-force trajectory
Authors: Hermus James , Doeringer Joseph , Sternad Dagmar , Hogan Neville
Published: October 2023

Control using primitive dynamic actions may explain why human performance is superior to robots despite seemingly inferior “wetware”; however, this also implies limitations. For a crank-turning task, this work quantified two such informative limitations. Force was exerted even though it produced no mechanical work, the underlying zero-force trajectory was roughly elliptical, and its orientation differed with turning direction, evidence of oscillatory control. At slow speeds, speed variability increased substantially, indicating intermittent control via submovements.
Machine Learning Developed a Programmed Cell Death Signature for Predicting Prognosis, Ecosystem, and Drug Sensitivity in Ovarian Cancer
Authors: Wang Le , Chen Xi , Song Lei , Zou Hua
Published: October 2023

Background. Ovarian cancer (OC) is the leading cause of gynecological cancer death and the fifth most common cause of cancer‐related death in women in America. Programmed cell death played a vital role in tumor progression and immunotherapy response in cancer. Methods. The prognostic cell death signature (CDS) was constructed with an integrative machine learning procedure, including 10 methods, using TCGA, GSE14764, GSE26193, GSE26712, GSE63885, and GSE140082 datasets. Several methods and single‐cell analysis were used to explore the correlation between CDS and the ecosystem and therapy response of OC patients. Results. The prognostic CDS constructed by the combination of StepCox (n = both) + Enet (alpha = 0.2) acted as an independent risk factor for the overall survival (OS) of OC patients and showed stable and powerful performance in predicting the OS rate of OC patients. Compared with tumor grade, clinical stage, and many developed signatures, the CDS had a higher C‐index. OC patients with low CDS score had a higher level of CD8+ cytotoxic T, B cell, and M1‐like macrophage, representing a related immunoactivated ecosystem. A low CDS score indicated a higher PD1 and CTLA4 immunophenoscore, higher tumor mutation burden score, lower tumor immune dysfunction and exclusion score, and lower tumor escape score in OC, demonstrating a better immunotherapy response. OC patients with high CDS score had a higher gene set score of cancer‐related hallmarks, including angiogenesis, epithelial–mesenchymal transition, hypoxia, glycolysis, and notch signaling. Conclusion. The current study constructed a novel CDS for OC, which could serve as an indicator for predicting the prognosis, ecosystem, and immunotherapy benefits of OC patients.
Fredholm and Schatten Class Operators on Bergman Spaces with Exponential Weights
Authors: Ma Xuedi , Wang Xiaofeng , Xia Jin
Published: October 2023

In this paper, we give a characterization of Fredholmness of the Toeplitz operators on the Bergman spaces

A

φ

p

with exponential weights in

D

when

0
<
p
<
∞

. Also, we obtain the sufficient and necessary conditions which the Toeplitz and Hankel operators on

A

φ

2

belong to

h

-Schatten class, where

h

is a continuous increasing convex function.
Assessment of Subclinical Atherosclerosis in Children with Atopic Dermatitis
Authors: Mocan Çağlar Yasemin , Bekis Bozkurt Hayrunnisa , İsal Tosun Öykü , Cavkaytar Özlem , Arga Mustafa
Published: October 2023

Introduction: Data from studies conducted to date have evaluated clinical atherosclerotic conditions in adult patients with atopic dermatitis (AD). Subclinical atherosclerotic changes that are a precursor of atherosclerotic conditions may begin in childhood. The aim of this study was to investigate the presence of subclinical atherosclerosis in pediatric patients with AD and to determine the associated risk factors. Methods: A total of 59 patients who were referred to our department over a 6-month period and diagnosed with AD, and 53 healthy controls with a similar age and gender were included in the study. Subclinical atherosclerosis markers (carotid intima media thickness [CIMT], distensibility, stiffness, and strain) were measured using conventional echocardiography. The patients’ age, SCORAD index, and duration of symptoms were recorded. Serum total immunoglobulin E, C-reactive protein (CRP), blood lipid profile, and complete blood count markers were measured. Results: The median age of the patients was 61 (10–103) months, and 59.3% of them were male. The patients with AD had a higher CIMT (1.60 ± 0.35 vs. 1.30 ± 0.50 mm) and a lower distensibility (0.006 ± 0.009 vs. 0.01 ± 0.008) and strain (0.10 ± 0.14 vs. 0.19 ± 0.14) than the healthy controls (p < 0.01 for all), but there was no significant difference with regard to stiffness (10.16 ± 21.75 vs. 8.99 ± 12.66). Significant correlations between CIMT and disease duration, age, and the SCORAD index were found (p < 0.01, p < 0.01, and p < 0.05, respectively). No correlation between the subclinical atherosclerosis markers and the other laboratory results was found (p > 0.05 for all). Conclusion: This study demonstrates that pediatric patients with AD may express subclinical atherosclerosis markers. The evaluation of subclinical atherosclerosis in these patients revealed that CIMT may be the most important marker, as it displayed positive correlations with symptom duration, age, and disease severity.
miR-410 Regulates Helper T Cell Differentiation in Ovalbumin-Induced Asthma through the PI3K-AKT-VEGF Signaling Pathway
Authors: Tong Nianting , Liu Dongyun , Lu Ling , Lin Rongjun , Jin Rong
Published: October 2023

Introduction: Asthma has been attributed to Th1/Th2 imbalance and inappropriate Th2 responses to environmental allergens. MicroRNAs (miRNAs), 21 to 23 RNA molecules, are first found in mammals and have been implicated in various biological activities. Our previous study found that miR-410 effectively ameliorates airway inflammation in the ovalbumin (OVA)-induced asthma murine model. However, the role of miR-410 in regulating helper T (Th) cell differentiation is not clear. In the present study, we aimed to explore the regulatory effects of miR-410 on the differentiation of Th cells through both in vivo and in vitro studies. Methods: Dual-luciferase reporter assay was used to find if miR-410 has any direct binding position with VEGF mRNAs. PBMC and CD4+ T cells were isolated and stimulated with OVA. The miR-410 mimics and inhibitors were transfected into CD4+ T cells. The differentiation of Th cells was evaluated by enzyme-linked immunosorbent assay (ELISA) for the concentration of IL-4, IFN-γ, and TGF-β levels in supernatants. Western Blot was used to detect protein expression and phosphorylation of PI3K and AKT. BALB/c mice were kept in a specific pathogen-free condition and received sterile OVA-free food and water. OVA-induced asthmatic mice model was established. ELISA was used to measure the bronchoalveolar lavage fluid (BALF) concentrations of IL-4, IFN-γ, TGF-β, and VEGF. Hematoxylin and eosin staining and immunohistochemical staining were conducted to analyze inflammatory cell infiltration, pathological changes, and the expression of VEGF. Results: Dual-luciferase reporter assay showed that miR-410 has no direct binding position with VEGF mRNAs. In the OVA-primed mononuclear cells compared to normal cells, IFN-γ and TGF-β were decreased while IL-4 and VEGF were increased. This change was reversed while miRNA-410 mimics were transfected into CD4+ T cells. Besides, the OVA-primed CD4+ T cells treated with miR-410 decrease the proliferation of cytokine of Th2 cells as well as phosphorylation of PI3K, and AKT. In OVA-induced asthma mice, IFN-γ and TGF-β were decreased in BALF while the IL-4 and VEGF were increased. OVA-induced mice with asthma treated with miR-410 mimics showed marked reductions in the infiltration of inflammatory cells as well as IL-4 and VEGF in BALF. The immunohistochemical staining of the expression of VEGF also decreased in OVA-induced asthma mice with the instillation of miR-410. Conclusions: In this study, we revealed that miR-410 could regulate the differentiation of Th cells via the PI3K-AKT-VEGF signaling pathway in asthma.
Individualized Delivery of Vancomycin by Model-Informed Bayesian Dosing Approach to Maintain an AUC24 Target in Critically Ill Patients
Authors: Rao Zhi , Guo Si-ming , Wei Yan-ming
Published: October 2023

Introduction: Monitoring of AUC24 was updated recommendation in the guideline for the therapeutic drug monitoring (TDM) of vancomycin in Chinese pharmacological society published in 2020. Vancomycin pharmacokinetic profiles are diverse and unique in critically ill patients because of the drastic variability of the patients’ physiological parameters, while the study for population pharmacokinetic (PPK) models in Chinese critically ill patients has been rarely reported. The objectives of this study were to construct a PPK model to describe the pharmacokinetic characteristics of vancomycin in critically ill patients and to individualize vancomycin dosing by model-informed Bayesian estimation for maintenance of AUC24 target at 400–650 mg h/L recommended by the 2020 guideline. Methods: Vancomycin with different dosing was administered intravenously over 1 h for critically ill patients, TDM was started at 48 h or 72 h since initiation of vancomycin therapy for patients. Blood samples were collected from patients for trough concentrations or Cmax. Vancomycin concentrations were determined by high-performance liquid chromatography method with ultraviolet detection. PPK model was performed using the nonlinear mixed-effect model (NONMEM®). Individual PK parameters for critically ill patients treated with vancomycin were estimated using a post hoc empirical Bayesian method based on the final PPK model. AUC24 was calculated as the total daily dose divided by the clearance (L/h). Results: The PPK of vancomycin was determined by a one-compartment model with creatinine clearance as fixed effects. The PK estimates in the final model generally agreed with the median estimates and were contained within the 95% CI generated from the bootstrap results, indicating good precision and stability in the final model. The visual predictive check plots showed the adequate predictive performance of the final PK model and supported a good model fit. The model-informed Bayesian estimation was used to predict the AUC24 of critically ill patient by the acquired TDM results, and the dosing adjustment by maintenance of AUC24 at 400–650 mg h/L had made a great therapeutic effect for the case. Conclusion: This study established a PPK model of vancomycin in Chinese critically ill patients, and individualized dosing of vancomycin by model-informed Bayesian estimation to maintain an AUC24 target at 400–650 mg h/L has been successfully applied in clinic. This result supports the continued use of model-informed Bayesian estimation to vancomycin treatment in critically ill patients.
Improved Sleep Affects Epigastric Pain in Functional Dyspepsia by Reducing the Levels of Inflammatory Mediators
Authors: Du Huang , Lin Rongpan , Xiao Shuping , Zhao Yu , Wu Mingxia , Chen Wenhua , Cai Wangfeng , Wei Nating , Gong Guohua , Huang Kangming , Zhang Fajing , Chen Hongbin
Published: October 2023

Introduction: The pathogenesis of epigastric pain in functional dyspepsia (FD) is complex. The study aims to explore the effect of sleep improvement on this symptom. Methods: In total, 120 patients with FD-associated epigastric pain and insomnia were randomly divided into experimental and control groups using the envelope method. After applying the exclusion criteria, 107 patients were enrolled in the experimental (56 patients) and control (51 patients) groups. Insomnia was graded according to the Pittsburgh Sleep Quality Index (PSQI). In the experimental group, eszopiclone 3 mg, eszopiclone 3 mg + estazolam 1 mg, and eszopiclone 3 mg + estazolam 2 mg were given to patients with mild, moderate, and severe insomnia, respectively. In the control group, patients were given 1, 2, or 3 tablets of vitamin B complex. Patient sleep quality was monitored with Sleepthing. Epigastric pain was evaluated with a Numeric Rating Scale. The serum levels of IL-1β, IL-6, IL-8, and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunosorbent assay. Pain scores, sleep parameters, and serum levels of inflammatory mediators were compared before and after treatment. Results: After treatment, the pain scores, sleep parameters, and TNF-α and IL-6 levels in the experimental group were significantly lower than those in the control group (p < 0.05). PSQI insomnia scores were significantly associated with pain scores, IL-6, and TNF-α (p < 0.05) but not in IL-8 and IL-1β levels (p > 0.05) among the three groups. Conclusions: Improving sleep with eszopiclone and/or estazolam alleviates FD-associated epigastric pain, possibly by inhibiting related downstream transmission pathways and reducing the release of inflammatory mediators.
The Impact of Long-Term Conditions and Comorbidity Patterns on COVID-19 Infection and Hospitalisation: A Cohort Study
Authors: Huang Yun-Ting , Steptoe Andrew , Patel Riyaz S. , Fuller Thomson Esme , Cadar Dorina
Published: October 2023

Introduction: Older adults are more vulnerable to COVID-19 infections; however, little is known about which comorbidity patterns are related to a higher risk of COVID-19 infection. This study investigated the role of long-term conditions or comorbidity patterns on COVID-19 infection and related hospitalisations. Methods: This study included 4,428 individuals from Waves 8 (2016−2017) and 9 (2018−2019) of the English Longitudinal Study of Ageing (ELSA) who also participated in the ELSA COVID-19 Substudy in 2020. Comorbidity patterns were identified using an agglomerative hierarchical clustering method. The relationships between comorbidity patterns or long-term conditions and COVID-19-related outcomes were examined using multivariable logistic regression. Results: Among a representative sample of community-dwelling older adults in England, those with cardiovascular disease (CVD) and complex comorbidities had an almost double risk of COVID-19 infection (OR = 1.87, 95% CI = 1.42−2.46) but not of COVID-19-related hospitalisation. A similar pattern was observed for the heterogeneous comorbidities cluster (OR = 1.56, 95% CI = 1.24−1.96). The individual investigations of long-term conditions with COVID-19 infection highlighted primary associations with CVD (OR = 1.46, 95% CI = 1.23−1.74), lung diseases (OR = 1.40, 95% CI = 1.17−1.69), psychiatric conditions (OR = 1.40, 95% CI = 1.16−1.68), retinopathy/eye diseases (OR = 1.39, 95% CI = 1.18−1.64), and arthritis (OR = 1.27, 95% CI = 1.09−1.48). In contrast, metabolic disorders and diagnosed diabetes were not associated with any COVID-19 outcomes. Conclusion: This study provides novel insights into the comorbidity patterns that are more vulnerable to COVID-19 infections and hospitalisations, highlighting the vulnerability of those with CVD and other complex comorbidities. These findings facilitate crucial new evidence that should be considered for appropriate screening measures and tailored interventions for older adults in the ongoing global outbreak.