bluuebunny/crossref_metadata_2025 huggingface dataset:
Inadequate performance of a risk score to predict asymptomaticNeisseria gonorrhoeaeandChlamydia trachomatisinfection among cisgender men who have sex with men
Authors: Rowlinson Emily , Hughes James P. , Khosropour Christine M. , Manhart Lisa E. , Golden Matthew R. , Barbee Lindley A.
Published: January 2023

Objectives

Epidemiological treatment of persons who are sexual contacts to partners withNeisseria gonorrhoeae(NG) andChlamydia trachomatis(CT) often results in treatment of uninfected persons, which may increase the risk of antibiotic-resistant infections. We sought to identify the predictors of NG and/or CT infections to develop a risk score that could be used to limit epidemiological treatment to persons most likely to have these infections.

Methods

We included visits to the Public Health - Seattle & King County Sexual Health Clinic by asymptomatic cisgender men who have sex with men (MSM) aged ≥18 who presented as a sexual contact to partner(s) with CT or NG infection between 2011 and 2019. We used logistic regression to estimate the odds of CT and/or NG infections associated with demographic and clinical predictors, selecting the final set of predictors using the Akaike information criteria and obtaining score weights from model coefficients. We used a cross-validation approach to obtain average model discrimination from each of 10 models, leaving out 10% of the data, and evaluated sensitivity and specificity at various score cut-offs.

Results

The final model for predicting NG or CT infection included seven predictors (age <35 years, HIV status, receptive oral sex in the prior 2 months, CT diagnosis, condomless receptive anal intercourse, condomless insertive anal intercourse and methamphetamine use in the prior 12 months). Model discrimination, as measured by the receiver operating curve, was 0.60 (95% CI 0.54 to 0.66). Sensitivity for detection of infection was ≥90% for scores ≥3, ≥5 and ≥7; specificity for these cut-offs was <16%. At scores ≥9, ≥12 and ≥14, specificity increased but sensitivity decreased to ≤76%.

Conclusions

Our risk score did not sufficiently discriminate between asymptomatic MSM with and without NG/CT infection. Additional studies evaluating epidemiological treatment as a standard of care in diverse populations are needed to guide best practices in the management of contacts to NG/CT infection.
Electronic cigarette users’ reactions and responses to a hypothetical ban of flavoured electronic cigarette liquids
Authors: Soule Eric K , Mayne Shannon , Snipes William , Thomas Luke , Guy Mignonne C , Breland Alison , Fagan Pebbles
Published: January 2023

Background

Regulations have been proposed to limit e-cigarette flavours, but limited research has examined potential impacts of such policies. This study examined adult e-cigarette users’ reactions to a hypothetical e-cigarette flavour ban.

Methods

In 2019, a convenience sample of current e-cigarette users in the USA (n=81, 53.1% women, mean age=37.6, 59.3% dual users of cigarettes) completed an online concept mapping study. Participants provided statements describing anticipated reactions to a hypothetical policy in which only tobacco, menthol or unflavoured e-cigarettes were available for purchase. Seventy-one unique statements were generated. Participants sorted statements into thematic groups and rated statements on how likely they would be to have each reaction. Multidimensional scaling was used to identify thematic clusters of statements.

Results

Twelve clusters were identified: negative reaction, take action against flavour limitation, youth prevention effectiveness perception, tolerance, acceptance, willingness to try new flavours, maintain vaping, reduce vaping, new flavours as vaping cessation transition, alternative sources for banned flavours, do-it-yourself mixing behaviours and alternative tobacco products. The highest rated cluster (negative reaction) described being angry or upset that flavours were banned, while the lowest rated clusters related to quitting/reducing e-cigarette use or switching to other tobacco products. Non-tobacco or non-menthol/mint flavoured e-cigarette users had higher ratings for clusters describing negative sentiment for the hypothetical policy.

Conclusions

Some e-cigarette users may dislike an e-cigarette flavour ban; however, some e-cigarette users would likely be willing to use tobacco, menthol or unflavoured e-cigarette liquids with lower likelihood of quitting vaping or switching to other tobacco products.
Illicit cigarette purchasing after implementation of menthol cigarette bans in Canada: findings from the 2016–2018 ITC Four Country Smoking and Vaping Surveys
Authors: Chung-Hall Janet , Fong Geoffrey T , Meng Gang , Craig Lorraine V
Published: January 2023

Objective

To examine the impact of menthol cigarette bans on use and purchasing of illicit cigarettes among menthol and non-menthol smokers in seven Canadian provinces.

Methods

Data from 1098 non-menthol smokers and 138 menthol smokers in Canada who completed the ITC Four Country Smoking and Vaping Survey in 2016 (pre-ban) and 2018 (post-ban). Brand validation analysis was conducted to (1) compare self-reported use of menthols versus actual use of menthols as regular brand, and verify self-reported purchasing of menthols among pre-ban menthol smokers at post-ban; and (2) assess pre-post ban changes in purchasing of illicit cigarettes from First Nations reserves among non-menthol smokers and menthol smokers.

Results

Among the subset of 138 pre-ban menthol smokers, 36 (19.5%) reported smoking menthols at post-ban. Brand validation analyses showed that 19 (9.0%) were actually using a non-menthol brand; of the 17 (10.5%) who were actually using a menthol brand, 13 (7.9%) bought a menthol brand at last purchase, and 4 (2.6%) bought a non-menthol brand. Among the full sample of smokers who purchased cigarettes from First Nations reserves at both pre-ban and post-ban, there was no change in purchasing of menthols (n=9 menthol smokers; 51.2% vs 51.2%, p=1.00), non-menthols (n=1024 non-menthol smokers; 9.1% vs 8.7%, p=0.69) or all cigarettes (menthol+non-menthol) (n=1086 smokers; 9.7% vs 9.2%, p=0.56).

Conclusions

Actual rates of brand-verified menthol smoking were substantially lower than self-reported rates at post-ban. After Canada’s menthol ban, there was no increase in illicit purchasing of menthol or non-menthol cigarettes from First Nations reserves.
Economic cost of cigarette smoking in Bosnia and Herzegovina
Authors: Gligorić Dragan , Preradović Kulovac Dragana , Micic Ljubisa , Vulovic Violeta
Published: January 2023

Background

Cigarette use is one of the major risk factors for non-communicable diseases in Bosnia and Herzegovina, with 41.1% of adults being current smokers in 2019 and almost half of current smokers using more than 20 cigarettes per day.

Methods

This study applies the prevalence-based, cost-of-illness approach to estimate the annual economic cost of smoking in Bosnia and Herzegovina in 2019.

Results

The study estimates that cigarette use by adults in Bosnia and Herzegovina caused between 24.4% and 42.8% of all deaths in 2019 and a total economic cost of between €367.5 and €635.1 million (2.0%–3.5% of gross domestic product). The direct costs represent the largest share of the total cost (between 1.0% and 1.7% of gross domestic product).

Conclusion

Cigarette use imposes a significant health and economic burden in the society of Bosnia and Herzegovina. Various tobacco control measures can be implemented to prevent and reduce tobacco consumption and the negative health consequences of tobacco use. Numerous studies have shown taxes on tobacco products are very effective in reducing tobacco use, especially among certain demographic groups, such as youth and low-income individuals. Smoke-free laws have also shown benefits. Other policy measures that can be implemented include restrictions to advertising, limitations on who can purchase tobacco products, how and where they can be purchased, etc. In addition, governments could also implement various education programmes on the negative health consequences of smoking. The results of this study provide information that calls for prompt and strengthened implementation of tobacco control measures to reduce cigarette consumption in the country and improve the health outcomes and productivity of its inhabitants.
An experimental baseline for ice-till strain indicators
Authors: Zoet L.K. , Hansen D.D. , Morgan-Witts N. , Menzies J. , Sobol P. , Lord N.
Published: January 2023

Subglacial till can deform when overriding ice exerts shear traction at the ice–till interface. This deformation leaves a strain signature in the till, aligning grains in the direction of ice flow and producing a range of diagnostic microstructures. Constraining the conditions that produce these kinematic indicators is key to interpreting the myriad of features found in basal till deposits. Here, we used a cryogenic ring shear device with transparent sample chamber walls to slip a ring of temperate ice over a till bed from which we examined the strain signature in the till. We used cameras mounted to the side of the ring shear and bead strings inserted in the till to estimate the strain distribution within the till layer. Following the completion of the experiment, we extracted and analyzed anisotropy of magnetic susceptibility (AMS) samples and created thin sections of the till bed for microstructure analysis. We then compared the AMS and microstructures with the observed strain history to examine the relationship between kinematic indicators and strain in a setting where shear traction is supplied by ice. We found that AMS fabrics show a high degree of clustering in regions of high strain near the ice–till interface. In the uppermost zone of till, k1 eigenvector azimuths are generally aligned with ice flow, and S1 eigenvalues are high. However, S1 eigenvalues and the alignment of the k1 eigenvector with ice flow decrease nonlinearly with distance from the ice–till interface. There is a high occurrence of microshears in the zone of increased deformation.
Fertilizing effect of wastewater-derived granular struvite on contrasting Manitoba soils
Authors: Thiessen Martens Joanne R. , Srinathan Oban D. , Amarakoon Inoka
Published: January 2023

Wastewater-derived struvite is a promising phosphorus (P) fertilizer but more information on its behaviour in soil is needed to guide management practices for this slow-release fertilizer. After 20 days of incubation in two contrasting low-P soils in Petri dishes at two temperatures, the Olsen-P concentrations in soil surrounding struvite granules were 30–122 mg kg−1, which were much lower than after amendment with monoammonium phosphate (MAP) (435–1063 mg kg−1). Olsen-P concentrations further from the granule showed that MAP fertilized a larger volume of soil than struvite. Thus, the fertilizing effect of struvite may be very localized in soil.
Online and Approximate Network Construction from Bounded Connectivity Constraints
Authors: Jansson Jesper , Levcopoulos Christos , Lingas Andrzej
Published: January 2023

The Network Construction problem, studied by Angluin et al., Hosoda et al., and others, asks for a minimum-cost network satisfying a set of connectivity constraints which specify subsets of the vertices in the network that have to form connected subgraphs. More formally, given a set [Formula: see text] of vertices, construction costs for all possible edges between pairs of vertices from [Formula: see text], and a sequence [Formula: see text] of connectivity constraints, the objective is to find a set [Formula: see text] of edges such that each [Formula: see text] induces a connected subgraph of the graph [Formula: see text] and the total cost of [Formula: see text] is minimized. First, we study the online version where every constraint must be satisfied immediately after its arrival and edges that have already been added can never be removed. We give an [Formula: see text]-competitive and [Formula: see text]-competitive polynomial-time algorithms, where [Formula: see text] is an upper bound on the size of constraints, while [Formula: see text] denote the number of constraints and the number of vertices, respectively. On the other hand, we observe that an [Formula: see text]-competitive lower bound as well as an [Formula: see text]-competitive lower bound in the cost-uniform case are implied by the known lower bounds for unbounded constraints. For the cost-uniform case with unbounded constraints, we provide an [Formula: see text]-competitive upper bound with high probability. The latter bound is against an oblivious adversary while our other randomized competitive bounds are against an adaptive adversary. Next, we discuss a hybrid approximation method for the (offline) Network Construction problem combining an approximation algorithm of Hosoda et al. with one of Angluin et al. and an application of the hybrid method to bioinformatics. Finally, we consider a natural strengthening of the connectivity requirements in the Network Construction problem, where each constraint has to induce a subgraph (of the constructed graph) of diameter at most [Formula: see text]. Among other things, we provide a polynomial-time [Formula: see text]-approximation algorithm for the Network Construction problem with the [Formula: see text]-diameter requirements, when each constraint has at most [Formula: see text] vertices, and show the APX-completeness of this variant.
MODELING AND ANALYZING QUARANTINE STRATEGIES OF EPIDEMIC ON TWO-LAYER NETWORKS: GAME THEORY APPROACH
Authors: ZHANG RONGPING , XIE BOLI , KANG YUN , LIU MAOXING
Published: January 2023

The quarantine strategy plays a crucial role in the prevention and control of infectious disease. In this paper, a two-layer network model coupling the transmission of infectious diseases and the dynamics of human behavior based on game theory is proposed. The basic reproduction number of the infectious disease in our proposed model is obtained by the next-generation matrix method and the stability of the disease-free equilibrium is analyzed. Theoretical results show that the spread of infectious diseases can be controlled when the voluntary quarantined individuals reach a certain proportion. The sensitivities of the parameters are analyzed by simulations, and the results show that increasing propaganda can directly accelerate quarantine, and reducing the relative cost of quarantine has a significant effect on preventing the infectious diseases. Increasing the detection rate will lead to overestimating the proportion of undiagnosed infected individuals, and can also promote individuals to quarantine.
Modified Fourier Approach for Vibration Analysis of Spinning Beam with Elastic Restraints
Authors: Guo Xiaodong , Su Zhu , Wang Lifeng
Published: January 2023

This paper presents a unified method for analyzing the dynamic behavior of spinning beams under elastic constraints. Based on the Timoshenko beam theory, a dynamic model of a spinning beam with elastic constraints is established. The displacement and bending angle are represented by a modified Fourier series. Compared with the traditional Fourier series, the improved Fourier series eliminates the discontinuity of the derivative at the boundary by introducing auxiliary polynomials, making it more suitable for elastic constraints. The governing equations and boundary conditions are coupled together using the energy method to form a set of standard linear equations. By solving this equation, the modes of the spinning beam structure under elastic constraints can be concisely and quickly obtained. Finally, by comparing with other methods, it is proved that the method has good convergence and practicability. Then, the effects of spinning speed, boundary stiffness and slenderness ratio on the whirling characteristics are analyzed. The results show that the linear spring has a more pronounced effect on the whirl frequency than the torsion spring. Different boundary constraints produce different elastic intervals. Mode exchange was found with increasing spinning speed. In the case of elastic constraints, the mode exchange occurs at lower spinning speed. This method has a certain universal applicability to the dynamic analysis of spinning beams under elastic constraints, and the research results can provide theoretical reference for subsequent research.
Development of Fragility Models for Precast Concrete Shear Walls and Columns Connected by Grouted Sleeves
Authors: Wang Xinyu , Xie Linlin , Li Aiqun , Yang Cantian
Published: January 2023

Performance-based seismic design and assessment of precast concrete (PC) structures have been widely studied. Fragility models for PC components have rarely been developed; however, it is a critical foundation for the above-mentioned design and assessment. Hence, this study was focused on developing fragility models for PC shear walls (PCSWs) and columns (PCCs) connected using grouted sleeves. To this end, 46 full-scale PCSWs and 45 full-scale PCCs, connected using grouted sleeves, were collected, and their test results were analyzed. Six damage states (DSs) were recommended based on the typical damage characteristics and with reference to the associated reinforced concrete (RC) components. Subsequently, the fragility models of PCSW and PCC were established for each DS using the drift ratio as the engineering demand parameter. In addition, the influence of the design axial load ratio on the fragility models was revealed. Through the comparison of fragility models between the PC and RC components, differences in parameters and curves of fragility models were quantitatively compared. These study achievements can serve as valuable references for performance-based seismic design and assessment of PC structures connected using grouted sleeves.
Quantitative Evaluation of Seismic Performance for Truss Structures Based on the Condition Number of Dynamic Matrix
Authors: Wang Dongwei , Shang Mengfei , Sun Panxu
Published: January 2023

The quantitative analysis of seismic performance under small and moderate earthquakes is of great significance. However, only using the stiffness distribution index is no longer applicable to seismic performance evaluation, and the influence of mass distribution must be introduced. In this study, under the action of small and medium earthquakes, the equation of motion can be simplified into the equilibrium equation of the dynamic matrix by the quasi-static method. Furthermore, a condition number index of dynamic matrix is proposed to evaluate the seismic performance of truss structures, which can consider both stiffness distribution and mass distribution. Then, the correctness of the proposed index is verified by comparing with the displacement and strain indexes. In addition, the performance of truss structure is studied by the condition number of stiffness matrix, mass matrix and dynamic matrix. It is found that since the condition number of stiffness matrix and the condition number of mass matrix cannot consider both stiffness and mass, it is not comprehensive to use these two indexes to evaluate the seismic performance of truss structures. The evaluation result based on the condition number of dynamic matrix is more reasonable under small and medium earthquakes.
Study of Resonant Peak Characteristics of Flow-Induced Noise in Small-Aperture Cavity
Authors: Song Zhenan , Chang Daoqing , Sun Hongling
Published: January 2023

The influences of the length and width of small-aperture cavity are calculated with the [Formula: see text]–[Formula: see text] model and large eddy simulation on the frequencies of resonant peaks of flow-induced cavity noise at different flow velocities in water. The calculated results show that the semi-empirical Rossiter formulas are only suitable for large-aperture models. For small-aperture cavity models, the resonance peak frequencies predicted by these formulas deviate greatly from the corresponding numerical results. In addition, as the length of cavity opening decreases, the minimum flow velocity gradually increases, at which a resonant peak just appears. Finally, the range of this minimum flow velocity is given for the different opening lengths.
Predicting oil field performance using machine learning programming: a comparative case study from the UK continental shelf
Authors: Osah Ukari , Howell John
Published: January 2023

Predicting the performance of a subsurface oil field is a large, multivariant problem. Production is controlled and influenced by a wide array of geological and engineering parameters which overlap and interact in ways that are difficult to unravel in a manner that can be predictive. Supervised machine learning is a statistical approach which uses empirical learnings from a training dataset to create models and make predictions about future outcomes. The goal of this study is to test a number of supervised machine learning methods on a dataset of oil fields from the United Kingdom continental shelf (UKCS), in order to assess whether, (a) it is possible to predict future oil field performance and (b), which methods are the most effective. The study is based on a dataset of 60 fields with 5 controlling parameters, (gross depositional environment, average permeability, net-to-gross, gas–oil ratio and total number of wells) and 2 outcome parameters (recovery factor and maximum field rate) for each. The choice of controlling parameters was based on a PCA of a larger dataset from a wider project database. Five different machine learning algorithms were tested. These include linear regression, robust linear regression, linear kernel support vector regression, cubic kernel support vector regression and boosted trees regression. Overall, 83% of the data was used as a training dataset while 17% was used to test the predictability of the algorithms. Results were compared using R-Squared, Mean Square Error, Root Mean Square Error and Mean Absolute Error. Graphs of predicted responses v. true (actual) responses are also shown to give a visual illustration of model performance. Results of this analysis show that certain methods perform better than others, depending on the outcome variable in question (recovery factor or maximum field rate). The best method for both outcome variables was the support vector regression, where, depending on the kernel function applied, a reliable level of predictability with low error rates were achieved. This demonstrates a strong potential for statistics-based prediction models of reservoir performance.

Thematic collection:
This article is part of the Digitally enabled geoscience workflows: unlocking the power of our data collection available at
https://www.lyellcollection.org/topic/collections/digitally-enabled-geoscience-workflows
Unlocking national treasures: the core scanning approach
Authors: Damaschke M. , Fellgett M. W. , Howe M. P. A. , Watson C. J.
Published: January 2023

Drill core is a vital resource for subsurface characterization and informs process understanding. However, it is expensive to collect and, as a result, the geoscience community increasingly relies on data from legacy core to address today's energy challenges. Many countries store geological materials collected over decades in national archives. In the UK, over 600 km of drill core is currently stored at the UK national core repository, which covers a breadth of the UK's geology, including those targeted for resources, energy and waste storage. The challenge is to maximize the value of these analogue archives and new core when deposited – improving access to materials and associated data, whilst simultaneously maximizing preservation to ensure optimized use, now and in the future. This paper summarizes the BGS approach to characterize drill core more efficiently and consistently using a multiple-technique core scanning approach set within a project-specific core scanning workflow to increase core data acquisition and complement traditional core characterization practices. Thus, creating a digital record of the core, preserving it beyond its physical lifetime and improving accessibility. This paper highlights the benefits and challenges of this long-term endeavour, especially in making the data open access and discoverable.
Rise of the Planet of Serverless Computing: A Systematic Review
Authors: Wen Jinfeng , Chen Zhenpeng , Jin Xin , Liu Xuanzhe
Published: January 2023

Serverless computing is an emerging cloud computing paradigm, being adopted to develop a wide range of software applications. It allows developers to focus on the application logic in the granularity of function, thereby freeing developers from tedious and error-prone infrastructure management. Meanwhile, its unique characteristic poses new challenges to the development and deployment of serverless-based applications. To tackle these challenges, enormous research efforts have been devoted. This article provides a comprehensive literature review to characterize the current research state of serverless computing. Specifically, this article covers 164 articles on 17 research directions of serverless computing, including performance optimization, programming framework, application migration, multi-cloud development, testing and debugging, and so on. It also derives research trends, focus, and commonly-used platforms for serverless computing, as well as promising research opportunities.
Evolving roles of activins and inhibins in ovarian cancer pathophysiology
Authors: Evans Elizabeth T. , Horst Ben , Arend Rebecca C. , Mythreye Karthikeyan
Published: January 2023

Activins and inhibins are unique members of the transforming growth factor-β (TGFβ) family of growth factors, with the ability to exert autocrine, endocrine, and paracrine effects in a wide range of complex physiologic and pathologic processes. Although first isolated within the pituitary, emerging evidence suggests broader influence beyond reproductive development and function. Known roles of activin and inhibin in angiogenesis and immunity along with correlations between gene expression and cancer prognosis suggest potential roles in tumorigenesis. Here, we present a review of the current understanding of the biological role of activins and inhibins as it relates to ovarian cancers, summarizing the underlying signaling mechanisms and physiologic influence, followed by detailing their roles in cancer progression, diagnosis, and treatment.
Succinate-SUCNR1 induces renal tubular cell apoptosis
Authors: Pu Min , Zhang Jing , Zeng Yongcheng , Hong Fuyan , Qi Weiwei , Yang Xia , Gao Guoquan , Zhou Ti
Published: January 2023

Succinate has long been known to be only an intermediate product of the tricarboxylic acid cycle until identified as a natural ligand for SUCNR1 in 2004. SUCNR1 is widely expressed throughout the body, especially in the kidney. Abnormally elevated succinate is associated with many diseases, including obesity, type 2 diabetes, nonalcoholic fatty liver disease, and ischemia injury, but it is not known whether succinate can cause kidney damage. This study showed that succinate induced apparent renal injury after treatment for 12 wk, characterized by a reduction in 24 h urine and the significant detachment of the brush border of proximal tubular epithelial cells, tubular dilation, cast formation, and vacuolar degeneration of tubular cells in succinate-treated mice. Besides, succinate caused tubular epithelial cell apoptosis in kidneys and HK-2 cells. Mechanistically, succinate triggered cell apoptosis via SUCNR1 activation. In addition, succinate upregulated ERK by binding to SUCNR1, and inhibition of ERK using PD98059 abolished the proapoptotic effects of succinate in HK-2 cells. In summary, our study provides the first evidence that succinate acts as a risk factor and contributes to renal injury, and further research is required to discern the pathological effects of succinate on renal functions.
Gender differences in GRK2 in cardiovascular diseases and its interactions with estrogen
Authors: Fu Lu , Adu-Amankwaah Joseph , Sang Lili , Tang Ziqing , Gong Zheng , Zhang Xiaoyan , Li Tao , Sun Hong
Published: January 2023

G protein-coupled receptor kinase 2 (GRK2) is a multifunctional protein involved in regulating G protein-coupled receptor (GPCR) and non-GPCR signaling in the body. In the cardiovascular system, increased expression of GRK2 has been implicated in the occurrence and development of several cardiovascular diseases (CVDs). Recent studies have found gender differences in GRK2 in the cardiovascular system under physiological and pathological conditions, where GRK2’s expression and activity are increased in males than in females. The incidence of CVDs in premenopausal women is lower than in men of the same age, which is related to estrogen levels. Given the shared location of GRK2 and estrogen receptors, estrogen may interact with GRK2 by modulating vital molecules such as calmodulin (CaM), caveolin, RhoA, nitrate oxide (NO), and mouse double minute 2 homolog (Mdm2), via signaling pathways mediated by estrogen’s genomic (ERα and ERβ), and non-genomic (GPER) receptors, conferring cardiovascular protection in females. Highlighting the gender differences in GRK2 and understanding its interaction with estrogen in the cardiovascular system is pertinent in treating gender-related CVDs. As a result, this article explores the gender differences of GRK2 in the cardiovascular system and its relationship with estrogen during disease conditions. Estrogen’s protective and therapeutic effects and its mechanism on GRK2-related cardiovascular diseases have also been discussed.
Nonsteroidal anti-inflammatory drugs and implications for the cyclooxygenase pathway in embryonic development
Authors: Leathers Tess A. , Rogers Crystal D.
Published: January 2023

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of analgesics that inhibit the activity of cyclooxygenase isoenzymes, which drive tissue inflammation pathways. Caution should be exercised when taking these drugs during pregnancy as they increase the risk of developmental defects. Due to the high rates of NSAID use by individuals, possibilities for in utero exposure to NSAIDs are high, and it is vital that we define the potential risks these drugs pose during embryonic development. In this review, we characterize the identified roles of the cyclooxygenase signaling pathway components throughout pregnancy and discuss the effects of cyclooxygenase pathway perturbation on developmental outcomes.
Review: cellularity in bone marrow autografts for bone and fracture healing
Authors: Haeusner S. , Jauković A. , Kupczyk E. , Herrmann M.
Published: January 2023

The use of autografts, as primary cell and tissue source, is the current gold standard approach to treat critical size bone defects and nonunion defects. The unique mixture of the autografts, containing bony compartments and bone marrow (BM), delivers promising results. Although BM mesenchymal stromal cells (BM-MSCs) still represent a major target for various healing approaches in current preclinical research and respective clinical trials, their occurrence in the human BM is typically low. In vitro expansion of this cell type is regulatory challenging as well as time and cost intensive. Compared with marginal percentages of resident BM-MSCs in BM, BM mononuclear cells (BM-MNCs) contained in BM aspirates, concentrates, and bone autografts represent a readily available abundant cell source, applicable within hours during surgical procedures without the need for time-consuming and regulatory challenging cell expansion. This benefit is one reason why autografting has become a clinical standard procedure. However, the exact anatomy and cellularity of BM-MNCs in humans, which is strongly correlated to their unique mode of action and wide application range remains to be elucidated. The aim of this review was to present an overview of the current knowledge on these specific cell types found in human BM, emphasize the contribution of BM-MNCs in bone healing, highlight donor site dependence, and discuss limitations in the current isolation and subsequent characterization procedures. Hereby, the most recent and relevant examples of human BM-MNC cell characterization, flow cytometric analyses, and findings are summarized, with a strong focus on bone therapy.
Molecular and cellular basis of praziquantel action in the cardiovascular system
Authors: Yahya Nawal A. , Lanham Janelle K. , Sprague Daniel J. , Palygin Oleg , McCorvy John D. , Marchant Jonathan S.
Published: January 2023

The anthelmintic drug praziquantel (PZQ) causes contraction of parasitic schistosomes as well as constriction of blood vessels within the mesenteric vasculature of the host where the adult blood flukes reside. The contractile action of PZQ on the vasculature is mediated by the activation of host serotonergic 5-HT2B receptors (5-HT2BRs). However, the molecular basis for PZQ interaction with these targets and the location of these 5-HT2B receptors in the vessel wall have not been experimentally defined. Evaluation of a PZQ docking pose within the 5-HT2BR orthosteric site, using both Ca2+ reporter and bioluminescence resonance energy transfer (BRET) assays, identified residues F3406.51 and F3416.52 (transmembrane helix 6, TM6) as well as L209EL2 (extracellular loop 2) as critical for PZQ-mediated agonist activity. A key determinant of PZQ selectivity for the 5-HT2B receptor over the 5-HT2A/2C receptors was determined by M2185.39 in transmembrane helix 5 (TM5) of the orthosteric site. Mutation of this residue to valine (M218V), as found in 5-HT2A and 5-HT2C, decreased PZQ agonist activity, whereas the reciprocal mutation (V215M) in 5-HT2C increased PZQ activity. Two-photon imaging in intact mesenteric arterial strips visualized PZQ-evoked Ca2+ transients within the smooth muscle cells of the vessel wall. PZQ also triggered cytoplasmic Ca2+ signals in arterial smooth muscle cells in primary culture that were isolated from mesenteric blood vessels. These data define the molecular basis for PZQ action on 5-HT2B receptors localized in vascular smooth muscle.
A high-sucrose diet exacerbates the left ventricular phenotype in a high fat-fed streptozotocin rat model of diabetic cardiomyopathy
Authors: Velagic Anida , Li Mandy , Deo Minh , Li Jasmin Chendi , Kiriazis Helen , Donner Daniel G. , Anderson Dovile , De Blasio Miles J. , Woodman Owen L. , Kemp-Harper Barbara K. , Qin Cheng Xue , Ritchie Rebecca H.
Published: January 2023

Left ventricular dysfunction and adverse remodeling were more pronounced in diabetic rats that received low-dose streptozotocin (STZ) and a high-sucrose high-fat diet (HFD) compared with those on a moderate-sucrose HFD in combination with STZ. Our findings highlight the importance of sucrose content in diet composition, particularly in preclinical studies of diabetic cardiomyopathy, and demonstrate that low-dose STZ combined with a high-sucrose HFD is an appropriate rodent model of cardiomyopathy in type 2 diabetes.
Impact of sex and diet-induced weight loss on vascular insulin sensitivity in type 2 diabetes
Authors: Manrique-Acevedo Camila , Soares Rogerio N. , Smith James A. , Park Lauren K. , Burr Katherine , Ramirez-Perez Francisco I. , McMillan Neil J. , Ferreira-Santos Larissa , Sharma Neekun , Olver T. Dylan , Emter Craig A. , Parks Elizabeth J. , Limberg Jacqueline K. , Martinez-Lemus Luis A. , Padilla Jaume
Published: January 2023

Vascular insulin resistance, a major characteristic of obesity and type 2 diabetes (T2D), manifests with blunting of insulin-induced vasodilation. Although there is evidence that females are more whole body insulin sensitive than males in the healthy state, whether sex differences exist in vascular insulin sensitivity is unclear. Also uncertain is whether weight loss can reestablish vascular insulin sensitivity in T2D. The purpose of this investigation was to 1) establish if sex differences in vasodilatory responses to insulin exist in absence of disease, 2) determine whether female sex affords protection against the development of vascular insulin resistance with long-term overnutrition and obesity, and 3) examine if diet-induced weight loss can restore vascular insulin sensitivity in men and women with T2D. First, we show in healthy mice and humans that sex does not influence insulin-induced femoral artery dilation and insulin-stimulated leg blood flow, respectively. Second, we provide evidence that female mice are protected against impairments in insulin-induced dilation caused by overnutrition-induced obesity. Third, we show that men and women exhibit comparable levels of vascular insulin resistance when T2D develops but that diet-induced weight loss is effective at improving insulin-stimulated leg blood flow, particularly in women. Finally, we provide indirect evidence that these beneficial effects of weight loss may be mediated by a reduction in endothelin-1. In aggregate, the present data indicate that female sex confers protection against obesity-induced vascular insulin resistance and provide supportive evidence that, in women with T2D, vascular insulin resistance can be remediated with diet-induced weight loss.
Intraperitoneal Delivery of Iopamidol to Assess Extracellular pH of Orthotopic Pancreatic Tumor Model by CEST-MRI
Authors: Jardim-Perassi Bruna Victorasso , Irrera Pietro , Lau Justin Y. C. , Budzevich Mikalai , Whelan Christopher J. , Abrahams Dominique , Ruiz Epifanio , Ibrahim-Hashim Arig , Damgaci Erturk Sultan , Longo Dario Livio , Pilon-Thomas Shari A. , Gillies Robert J.
Published: January 2023

The extracellular pH (pHe) of solid tumors is often acidic, as a consequence of the Warburg effect, and an altered metabolic state is often associated with malignancy. It has been shown that acidosis can promote tumor progression; thus, many therapeutic strategies have been adopted against tumor metabolism; one of these involves alkalinization therapies to raise tumor pH to inhibit tumor progression, improve immune surveillance, and overcome resistance to chemotherapies. Chemical exchange saturation transfer-magnetic resonance imaging (CEST-MRI) is a noninvasive technique that can measure pH in vivo using pH-sensitive contrast agents. Iopamidol, an iodinated contrast agent, clinically used for computed tomography (CT), contains amide group protons with pH-dependent exchange rates that can reveal the pHe of the tumor microenvironment. In this study, we optimized intraperitoneal (IP) delivery of iopamidol to facilitate longitudinal assessments of orthotopic pancreatic tumor pHe by CEST-MRI. Following IV-infusion and IP-bolus injections, we compared the two protocols for assessing tumor pH. Time-resolved CT imaging was used to evaluate the uptake of iopamidol in the tumor, revealing that IP-bolus delivered a high amount of contrast agent 40 min postinjection, which was similar to the amounts reached with the IV-infusion protocol. As expected, both IP and IV injection protocols produced comparable measurements of tumor pHe, showing no statistically significant difference between groups (

p
=
0.16

). In addition, we showed the ability to conduct longitudinal monitoring of tumor pHe using CEST-MRI with the IP injection protocol, revealing a statistically significant increase in tumor pHe following bicarbonate administration (

p
<
0.001

). In conclusion, this study shows the capability to measure pHe using an IP delivery of iopamidol into orthotopic pancreatic tumors, which is important to conduct longitudinal studies.
Ventricular Septal Rupture—The Resurgence of a Post-Myocardial Infarction Dreadful Complication during COVID-19 Pandemic
Authors: Reis João Ferreira , Morais Luís Almeida , Sousa Lídia , Fiarresga António
Published: January 2023

In the midst of the coronavirus disease-2019 (COVID-19) pandemic, an 84-year-old female patient was admitted due to non-exertional syncope preceded by retrosternal pain. She had experienced a prolonged episode of oppressive chest pain 6 days before her presentation, but due to the concern of contracting COVID-19, she did not present for medical care. Upon admission to the emergency department, the patient was in circulatory shock, with her physical examination being remarkable for the presence of a holosystolic murmur. Admission electrocardiogram revealed an inferior ST-segment elevation with Q waves with extension to the posterior wall, consistent with subacute infarct in the right coronary artery (RCA) territory, and the patient was transferred for primary percutaneous coronary intervention. Upon arrival to the catheterization laboratory, a summary transthoracic echocardiogram was performed, which revealed inferior wall and infero-septal akinesia with an 18 mm ventricular septal rupture. Coronary angiography documented occlusion of the proximal segment of a dominant RCA. Due to a high perioperative risk, the patient underwent successful retrograde percutaneous closure with a 24 mm MemoPart™ device, with mild to moderate residual shunt. Despite an immediate clinical improvement, the patient died 12 hours after the procedure due to refractory cardiogenic shock.
Determination of Caffeine, Theobromine, and Theophylline by HPLC-DAD in Beverages Commonly Consumed in Lima, Peru
Authors: Gonzales-Yépez Karolinhe A. , Vilela Jorge Luis , Reátegui Oscar
Published: January 2023

The purpose of this study was to determine the content of caffeine, theobromine, and theophylline by high-performance liquid chromatography with diode-array detection (HPLC-DAD) in beverages commonly consumed in Lima, Peru. The samples were divided into 6 groups (herbal teas, coffee powder, chocolate milks, soft drinks, sports drinks, and energy drinks) which included the five most commonly consumed beverages of the different groups. Caffeine was mainly identified in the soft drink and energy drink groups, with the latter having a more significant value (10.38±0.01vs.95.50±3.48 mg/L, respectively). In herbal teas, caffeine showed the highest content (0.47±0.01to4.91±0.05 mg/L), despite theophylline being a characteristic compound of tea leaves. Sports drinks presented very low caffeine levels (0.03±0.01to0.05±0.01 mg/L), and theobromine (0.48±0.01to6.00±0.02) was also identified. Caffeine (4.09±0.01to5.70±0.01 mg/L) and theobromine (1.70±0.01to12.24±0.01 mg/L) were found in the five commercial brands of chocolate milk evaluated. Moreover, the group of coffee powder samples had the highest level of caffeine content (49.25±0.24to964.40±4.93 mg/100 g). The results obtained in this study provide reliable information on the composition and quantification of methylxanthines in the beverages most consumed in Lima and impact consumer knowledge.
PCSK9-D374Y Suppresses Hepatocyte Migration through Downregulating Free Cholesterol Efflux Rate and Activity of Extracellular Signal‐Regulated Kinase
Authors: Huang Lei , Cheng Ying , Mu Yulian , Li Kui
Published: January 2023

Proprotein convertase subtilisin/kexin type 9 can mediate the intracellular lysosomal degradation of the low‐density lipoprotein receptor protein in hepatocytes and decrease the liver’s ability to scavenge low‐density lipoprotein cholesterol from circulation, resulting in high levels of cholesterol in the circulatory system. Current studies have primarily focused on the relationship between PCSK9 and blood lipid metabolism; however, the biological function of PCSK9 in hepatocytes is rarely addressed. In this study, we evaluate its effects in the human hepatoma carcinoma cell line HepG2, including proliferation, migration, and free cholesterol transport. PCSK9-D374Y is a gain‐of‐function mutation that does not affect proliferation but significantly suppresses the migration and cholesterol efflux capacity of these cells. The suppression of the transmembrane outflow of intracellular‐free cholesterol regulates small G proteins and the suppression of extracellular signal‐regulated kinase. In summary, PCSK9-D374Y affects hepatocyte features, including their migration and free cholesterol transport capabilities.
WNT5a Signaling through ROR2 Activates the Hippo Pathway to Suppress YAP1 Activity and Tumor Growth
Authors: Wang Keshan , Ma Fen , Arai Seiji , Wang Yun , Varkaris Andreas , Poluben Larysa , Voznesensky Olga , Xie Fang , Zhang Xiaoping , Yuan Xin , Balk Steven P.
Published: January 2023

Noncanonical Wnt signaling by WNT5a has oncogenic and tumor suppressive activities, but downstream pathways mediating these specific effects remain to be fully established. In a subset of prostate cancer organoid culture and xenograft models, inhibition of Wnt synthesis stimulated growth, whereas WNT5a or a WNT5a mimetic peptide (Foxy5) markedly suppressed tumor growth. WNT5a caused a ROR2-dependent decrease in YAP1 activity, which was associated with increased phosphorylation of MST1/2, LATS1, MOB1, and YAP1, indicating Hippo pathway activation. Deletion of MST1/2 abrogated the WNT5a response. WNT5a similarly activated Hippo in ROR2-expressing melanoma cells, whereas WNT5a in ROR2-negative cells suppressed Hippo. This suppression was associated with increased inhibitory phosphorylation of NF2/Merlin that was not observed in ROR2-expressing cells. WNT5a also increased mRNA encoding Hippo pathway components including MST1 and MST2 and was positively correlated with these components in prostate cancer clinical datasets. Conversely, ROR2 and WNT5a expression was stimulated by YAP1, and correlated with increased YAP1 activity in clinical datasets, revealing a WNT5a/ROR2 negative feedback loop to modulate YAP1 activity. Together these findings identify Hippo pathway activation as a mechanism that mediates the tumor suppressive effects of WNT5a and indicate that expression of ROR2 may be a predictive biomarker for responsiveness to WNT5a-mimetic drugs.

Significance:

WNT5a signaling through ROR2 activates the Hippo pathway to downregulate YAP1/TAZ activity and suppress tumor growth, identifying ROR2 as a potential biomarker to identify patients that could benefit from WNT5a-related agents.
The Importance of Recency of Cancer Diagnosis in Patients Hospitalized with COVID-19—Glimpses from an EHR-based Study
Authors: Egan Pamela C. , Jani Chinmay , Singh Harpreet , Mishra Sanjay , Warner Jeremy L.
Published: January 2023

Multiple prior studies have shown an increased risk of severe disease and death from SARS-CoV-2 infection in patients with cancer. Nolan and colleagues conducted a multi-institution, electronic health record (EHR)-based study of adults hospitalized with COVID-19 delineating the difference in outcomes when stratified by current versus former cancer diagnosis and found that only a current diagnosis appears to confer an increased risk of severe COVID-19 and death.

We review these findings in the context of other studies examining outcomes for individuals with cancer diagnoses and COVID-19. We also address questions raised by this type of study about the significant challenges of EHR-based studies and discuss potential avenues for future research in this arena.

See related article by Nolan et al., p. 12