bluuebunny/crossref_metadata_2025 huggingface dataset:
Intercellular Communication during Stomatal Development with a Focus on the Role of Symplastic Connection
Authors: Cui Yongqi , He Meiqing , Liu Datong , Liu Jinxin , Liu Jie , Yan Dawei
Published: January 2023

Stomata are microscopic pores on the plant epidermis that serve as a major passage for the gas and water exchange between a plant and the atmosphere. The formation of stomata requires a series of cell division and cell-fate transitions and some key regulators including transcription factors and peptides. Monocots have different stomatal patterning and a specific subsidiary cell formation process compared with dicots. Cell-to-cell symplastic trafficking mediated by plasmodesmata (PD) allows molecules including proteins, RNAs and hormones to function in neighboring cells by moving through the channels. During stomatal developmental process, the intercellular communication between stomata complex and adjacent epidermal cells are finely controlled at different stages. Thus, the stomata cells are isolated or connected with others to facilitate their formation or movement. In the review, we summarize the main regulation mechanism underlying stomata development in both dicots and monocots and especially the specific regulation of subsidiary cell formation in monocots. We aim to highlight the important role of symplastic connection modulation during stomata development, including the status of PD presence at different cell–cell interfaces and the function of relevant mobile factors in both dicots and monocots.
Reactivity Graph Yields Interpretable IgM Repertoire Signatures as Potential Tumor Biomarkers
Authors: Ferdinandov Dilyan , Kostov Viktor , Hadzhieva Maya , Shivarov Velizar , Petrov Peter , Bussarsky Assen , Pashov Anastas Dimitrov
Published: January 2023

Combining adaptive and innate immunity induction modes, the repertoire of immunoglobulin M (IgM) can reflect changes in the internal environment including malignancies. Previously, it was shown that a mimotope library reflecting the public IgM repertoire of healthy donors (IgM IgOme) can be mined for efficient probes of tumor biomarker antibody reactivities. To better explore the interpretability of this approach for IgM, solid tumor-related profiles of IgM reactivities to linear epitopes of actual tumor antigens and viral epitopes were studied. The probes were designed as oriented planar microarrays of 4526 peptide sequences (as overlapping 15-mers) derived from 24 tumor-associated antigens and 209 cancer-related B cell epitopes from 30 viral antigens. The IgM reactivity in sera from 21 patients with glioblastoma multiforme, brain metastases of other tumors, and non-tumor-bearing neurosurgery patients was thus probed in a proof-of-principle study. A graph representation of the binding data was developed, which mapped the cross-reactivity of the mixture of IgM (poly)specificities, delineating different antibody footprints in the features of the graph—neighborhoods and cliques. The reactivity graph mapped the major features of the IgM repertoire such as the magnitude of the reactivity (titer) and major cross-reactivities, which correlated with blood group reactivity, non-self recognition, and even idiotypic specificities. A correlation between an aspect of this image of the IgM IgOme, namely, small cliques reflecting rare self-reactivities and the capacity of subsets of the epitopes to separate the diagnostic groups studied was found. In this way, the graph representation helped the feature selection in its filtering step and provided reduced feature sets, which, after recursive feature elimination, produced a classifier containing 51 peptide reactivities separating the three diagnostic groups with an unexpected efficiency. Thus, IgM IgOme approaches to repertoire studies is greatly augmented when self/viral antigens are used and the data are represented as a reactivity graph. This approach is most general, and if it is applicable to tumors in immunologically privileged sites, it can be applied to any solid tumors, for instance, breast or lung cancer.
Evaluation of the Antiseizure Activity of Endemic Plant Halfordia kendack Guillaumin and Its Main Constituent, Halfordin, on a Zebrafish Pentylenetetrazole (PTZ)-Induced Seizure Model
Authors: Skiba Adrianna , Kozioł Ewelina , Luca Simon Vlad , Budzyńska Barbara , Podlasz Piotr , Van Der Ent Wietske , Shojaeinia Elham , Esguerra Camila V. , Nour Mohammed , Marcourt Laurence , Wolfender Jean-Luc , Skalicka-Woźniak Krystyna
Published: January 2023

Epilepsy is a neurological disease that burdens over 50 million people worldwide. Despite the considerable number of available antiseizure medications, it is estimated that around 30% of patients still do not respond to available treatment. Herbal medicines represent a promising source of new antiseizure drugs. This study aimed to identify new drug lead candidates with antiseizure activity from endemic plants of New Caledonia. The crude methanolic leaf extract of Halfordia kendack Guillaumin (Rutaceae) significantly decreased (75 μg/mL and 100 μg/mL) seizure-like behaviour compared to sodium valproate in a zebrafish pentylenetetrazole (PTZ)-induced acute seizure model. The main coumarin compound, halfordin, was subsequently isolated by liquid-liquid chromatography and subjected to locomotor, local field potential (LFP), and gene expression assays. Halfordin (20 μM) significantly decreased convulsive-like behaviour in the locomotor and LFP analysis (by 41.4% and 60%, respectively) and significantly modulated galn, and penka gene expression.
Constitutive Androstane Receptor Agonist, TCPOBOP: Maternal Exposure Impairs the Growth and Development of Female Offspring in Mice
Authors: Pan Shijia , Guo Yuan , Yu Wen , Zhang Jia , Qiao Xiaoxiao , Li Letong , Xu Pengfei , Zhai Yonggong
Published: January 2023

Environmental chemicals, which are known to impact offspring health, have become a public concern. Constitutive activated receptor (CAR) is activated by various environmental chemicals and participates in xenobiotic metabolism. Here, we described the effects of maternal exposure to the CAR-specific ligand 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP, TC) on offspring health outcomes. Maternal TC exposure exhibited a stronger inhibition of body weight in 3-week-old and 8-week-old first-generation (F1) offspring female mice compared to controls. Further, maternal TC exposure obtained a strong increase in hepatic drug-metabolizing enzyme expression in 3-week-old female mice that persisted into 8-week-old adulthood. Interestingly, we observed distorted intestinal morphological features in 8-week-old F1 female mice in the TC-exposed group. Moreover, maternal TC exposure triggered a loss of intestinal barrier integrity by reducing the expression of intestinal tight junction proteins. Accordingly, maternal exposure to TC down-regulated serum triglyceride levels as well as decreased the expression of intestinal lipid uptake and transport marker genes. Mechanistically, maternal TC exposure activated the intestinal inflammatory response and disrupted the antioxidant system in the offspring female mice, thereby impeding the intestinal absorption of nutrients and seriously threatening offspring health. Altogether, these findings highlight that the effects of maternal TC exposure on offspring toxicity could not be ignored.
Modulating Glycolysis to Improve Cancer Therapy
Authors: Chelakkot Chaithanya , Chelakkot Vipin Shankar , Shin Youngkee , Song Kyoung
Published: January 2023

Cancer cells undergo metabolic reprogramming and switch to a ‘glycolysis-dominant’ metabolic profile to promote their survival and meet their requirements for energy and macromolecules. This phenomenon, also known as the ‘Warburg effect,’ provides a survival advantage to the cancer cells and make the tumor environment more pro-cancerous. Additionally, the increased glycolytic dependence also promotes chemo/radio resistance. A similar switch to a glycolytic metabolic profile is also shown by the immune cells in the tumor microenvironment, inducing a competition between the cancer cells and the tumor-infiltrating cells over nutrients. Several recent studies have shown that targeting the enhanced glycolysis in cancer cells is a promising strategy to make them more susceptible to treatment with other conventional treatment modalities, including chemotherapy, radiotherapy, hormonal therapy, immunotherapy, and photodynamic therapy. Although several targeting strategies have been developed and several of them are in different stages of pre-clinical and clinical evaluation, there is still a lack of effective strategies to specifically target cancer cell glycolysis to improve treatment efficacy. Herein, we have reviewed our current understanding of the role of metabolic reprogramming in cancer cells and how targeting this phenomenon could be a potential strategy to improve the efficacy of conventional cancer therapy.
Interaction of Varenicline with Classic Antiseizure Medications in the Mouse Maximal Electroshock-Induced Seizure Model
Authors: Bernat Piotr , Kołodziejczyk Patrycjusz , Łuszczki Jarogniew J. , Zagaja Mirosław , Tutka Piotr
Published: January 2023

Varenicline (VAR) is a partial agonist of brain α4β2 nicotinic acetylcholine receptors recommended as a first line pharmacotherapy for smoking cessation. The aim of this study was to examine whether VAR affects the protective activity of four classic antiseizure medications, i.e., carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and valproate (VPA) on maximal electroshock (MES)-induced seizures, which may serve as an experimental model of human-generalized tonic-clonic seizures in mice. VAR administered intraperitoneally (i.p.) at a subthreshold dose of 0.5 mg/kg decreased the protective activity of CBZ against MES-induced convulsions, increasing its median effective dose (ED50) from 10.92 ± 1.0 to 18.15 ± 1.73 mg/kg (p < 0.01). The effect of VAR was dose-dependent because a lower dose of VAR (0.25 mg/kg) failed to antagonize the protective activity of CBZ. VAR administered at the subthreshold dose of 0.5 mg/kg had no impact on the protective activity of PB, PHT, and VPA in the mouse MES model. The inhibitory effect of VAR on the protective activity of CBZ against tonic-clonic convulsions most likely resulted from the pharmacodynamic mechanism(s) and was not associated with the changes in total brain concentrations of CBZ. VAR-evoked alterations in the anticonvulsive activity of CBZ may be of serious concern for epileptic tobacco smokers.
Inflammatory Treatment Used to Mimic Osteoarthritis and Patients’ Synovial Fluid Have Divergent Molecular Impact on Chondrocytes In Vitro
Authors: Ragni Enrico , De Luca Paola , Valli Federico , Zagra Luigi , de Girolamo Laura
Published: January 2023

Osteoarthritis (OA) is a chronic disease characterized by joint tissue disruption and inflammation with a paucity of therapeutic options. Chondrocyte in vitro models are commonly used as the first step in evaluating new approaches and rely on the stimulation of an OA-like phenotype with inflammation often the method of choice. Inflammatory priming is frequently based on cytokines used at concentrations very far from the reality in the patients’ synovial fluid (SF). The aim of this work was to compare the transcriptional response of chondrocytes to different inflammatory conditions: the high levels of IL1β that are used for standardized inflammation protocols, OA-SF, IL1β, IL6 and IFNγ at SF-like concentrations both individually and simultaneously to mimic a simplified “in vitro” SF. Both high IL1β and OA-SF strongly influenced chondrocytes, while SF-like concentrations of cytokines gave weak (IL1β alone or in combination) or no (IL6 and IFNγ alone) outcomes. Chondrocytes under the two most powerful polarizing conditions had a clearly distinct fingerprint, with only a shared albeit molecularly divergent effect on ECM stability, with IL1β mainly acting on ECM degrading enzymes and OA-SF accounting for a higher turnover in favor of fibrous collagens. Moreover, OA-SF did not induce the inflammatory response observed with IL1β. In conclusion, although partially similar in the endpoint phenotype, this work intends to encourage reflection on the robustness of inflammation-based in vitro OA models for molecular studies on chondrocytes.
Barriers to the Adoption of Digital Twin in the Construction Industry: A Literature Review
Authors: Opoku De-Graft Joe , Perera Srinath , Osei-Kyei Robert , Rashidi Maria , Bamdad Keivan , Famakinwa Tosin
Published: January 2023

Digital twin (DT) has gained significant recognition among researchers due to its potential across industries. With the prime goal of solving numerous challenges confronting the construction industry (CI), DT in recent years has witnessed several applications in the CI. Hence, researchers have been advocating for DT adoption to tackle the challenges of the CI. Notwithstanding, a distinguishable set of barriers that oppose the adoption of DT in the CI has not been determined. Therefore, this paper identifies the barriers and incorporates them into a classified framework to enhance the roadmap for adopting DT in the CI. This research conducts an extensive review of the literature and analyses the barriers whilst integrating the science mapping technique. Using Scopus, ScienceDirect, and Web of Science databases, 154 related bibliographic records were identified and analysed using science mapping, while 40 carefully selected relevant publications were systematically reviewed. From the review, the top five barriers identified include low level of knowledge, low level of technology acceptance, lack of clear DT value propositions, project complexities, and static nature of building data. The results show that the UK, China, the USA, and Germany are the countries spearheading the DT adoption in the CI, while only a small number of institutions from Australia, the UK, Algeria, and Greece have established institutional collaborations for DT research. A conceptual framework was developed on the basis of 30 identified barriers to support the DT adoption roadmap. The main categories of the framework comprise stakeholder-oriented, industry-related, construction-enterprise-related, and technology-related barriers. The identified barriers and the framework will guide and broaden the knowledge of DT, which is critical for successful adoption in the construction industry.
Seismic Analysis of Historical Urban Walls: Application to the Volterra Case Study
Authors: Concu Giovanna , Deligia Mariangela , Sassu Mauro
Published: January 2023

Several Italian cities are characterized by the presence of centuries-old historic walls, which have a cultural heritage value and, due to their structural role as a retaining wall, often influence the safety of adjacent buildings and infrastructure. Ancient urban walls are increasingly subject to instability and collapse phenomena, because the greater frequency of extreme meteoric events aggravates the static condition of the walls and of the wall–soil system. Since the seismic risk in the contexts in which the historical urban walls are located is often medium-high, it is advisable to evaluate the influence of soil moisture on the seismic response of the soil–structure system. In this paper, the seismic vulnerability of historical urban walls was examined through considering scenarios of both dry and wet soil, in order to evaluate the seismic response of the structure as a function of soil imbibition. Seismic vulnerability analyses were carried out on the case study of the historical urban masonry walls of Volterra (Italy), which have been affected by two major collapses in the last ten years. Seismic vulnerability was assessed by means of the limit equilibrium method and the finite element method, and through adopting proper soil imbibition models. The results highlight which sections of the walls are at greater seismic risk due to the presence of soil moisture, as well as the influence of soil imbibition on the structural safety and failure mechanism.
New Dual Inhibitors of SARS-CoV-2 Based on Metal Complexes with Schiff-Base 4-Chloro-3-Methyl Phenyl Hydrazine: Synthesis, DFT, Antibacterial Properties and Molecular Docking Studies
Authors: Al-Janabi Ahmed S. M. , Elzupir Amin O. , Abou-Krisha Mortaga M. , Yousef Tarek A.
Published: January 2023

This paper explores a dual inhibition of main protease (Mpro) and nonstructural protein 10/nonstructural protein 16 (NSP16) methyltransferase complex as the key targets for COVID-19 therapy. These are based on the new Schiff-base ligand that was obtained from the condensation of (4-chloro-3-methyl phenyl) hydrazine with 2-pyridine-carboxaldehyde and its novel Schiff-base metal complexes. These include Ni(II), Pd(II), Pt(II), Zn(II), and Hg(II). The newly synthesized compounds have been characterized using FT-IR, 1H NMR, 13C NMR, and elemental analysis. The results suggested that the Schiff-base ligand is coordinated as a bidentate ligand through the nitrogen atoms of the azomethine group and pyridyl ring. In addition, the biological activity of the prepared complexes was examined against Pseudomonas aeruginosa and Staphylococcus aureus, and the results showed that the Zn(II) complex has the highest activity compared with other compounds. The active sites were found by looking at the molecular electrostatic potential (MEP) maps of the above ligands and complexes. The activity of the compound and its Ni(II) and Zn(II) complexes against Mpro and NSP10/ NSP16 was investigated using a molecular docking approach. They showed excellent binding energies ranging from −5.9 to −7.2 kcal/mol and −5.8 to −7.2 for Mpro and NSP16, respectively. All conformers of the metal complexes were docked with the active site of the NSP16 receptor, showing a binding affinity of 100%. According to our knowledge, this was the first report of these metal complexes as dual inhibitors for Mpro and NSP16 of SARS-CoV-2.
Interactions of an Artificial Zinc Finger Protein with Cd(II) and Hg(II): Competition and Metal and DNA Binding
Authors: Hajdu Bálint , Hunyadi-Gulyás Éva , Gyurcsik Béla
Published: January 2023

Cys2His2 zinc finger proteins are important for living organisms, as they—among other functions—specifically recognise DNA when Zn(II) is coordinated to the proteins, stabilising their ββα secondary structure. Therefore, competition with other metal ions may alter their original function. Toxic metal ions such as Cd(II) or Hg(II) might be especially dangerous because of their similar chemical properties to Zn(II). Most competition studies carried out so far have involved small zinc finger peptides. Therefore, we have investigated the interactions of toxic metal ions with a zinc finger proteins consisting of three finger units and the consequences on the DNA binding properties of the protein. Binding of one Cd(II) per finger subunit of the protein was shown by circular dichroism spectroscopy, fluorimetry and electrospray ionisation mass spectrometry. Cd(II) stabilised a similar secondary structure to that of the Zn(II)-bound protein but with a slightly lower affinity. In contrast, Hg(II) could displace Zn(II) quantitatively (logβ′ ≥ 16.7), demolishing the secondary structure, and further Hg(II) binding was also observed. Based on electrophoretic gel mobility shift assays, the Cd(II)-bound zinc finger protein could recognise the specific DNA target sequence similarly to the Zn(II)-loaded form but with a ~0.6 log units lower stability constant, while Hg(II) could destroy DNA binding completely.
A 2-DoF Kinematic Chain Analysis of a Magnetic Spring Excited by Vibration Generator Based on a Neural Network Design for Energy Harvesting Applications
Authors: Bijak Joanna , Lo Sciuto Grazia , Kowalik Zygmunt , Trawiński Tomasz , Szczygieł Marcin
Published: January 2023

In this paper, an original mathematical model and experimental results for the vibration generator and the magnetic spring prototype that converts mechanical energy to electrical energy are proposed. The magnetic spring model is developed by a robotic approach based on Denavit–Hartenberg’s notation and designed by the 2-degrees of freedom kinematic chain for determination of its motion and estimation of several resonance frequencies useful in many energy harvesting applications. The vibration generator that moves the magnetic spring is modeled by neural networks and the magnetic spring potential energy is calculated by the finite elements method (FEM). Furthermore, the magnetic spring and the vibration generator are designed by the Simulink block diagram. Testing results of the magnetic spring and vibration generator displacement conducted in laboratory have shown good agreement with simulation results.
Effect of Core Exercises on Motor Function Recovery in Stroke Survivors with Very Severe Motor Impairment
Authors: Bacho Zuliana , Khin Nyein Yin , Ag. Daud D Maryama
Published: January 2023

Paresis of the upper and lower limbs is a typical issue in stroke survivors. This study aims to determine whether core exercises help stroke survivors with very severe motor impairment recover their motor function. This study employed a within-subjects design. Eleven hemiparetic stroke patients with very severe motor impairment (FMA score < 35) and ages ranging from 24 to 52 years old were enrolled in this study. All participants engaged in supervised core exercise training twice a week for 12 weeks. The main outcome measures were Fugl-Meyer Assessment Lower Extremity (FMA-LE) and Fugl-Meyer Assessment Upper Extremity (FMA-UE), which were measured before training and at intervals of four weeks during training. Repeated measures ANOVA was used to analyze the effect of core exercises on motor function performance and lower extremity motor function and upper extremity motor function recovery. There were significant differences in the mean scores for motor function performance, lower extremity motor function, and upper extremity motor function throughout the four time points. A post-hoc pairwise comparison using the Bonferroni correction revealed that mean scores significantly increased and were statistically different between the initial assessment and follow-up assessments four, eight, and twelve weeks later. This study suggests that 12 weeks of core exercise training is effective for improving motor function recovery in patients with very severe motor impairment.
Use of Frogs as a Model to Study the Etiology of HLHS
Authors: Nie Shuyi
Published: January 2023

A frog is a classical model organism used to uncover processes and regulations of early vertebrate development, including heart development. Recently, we showed that a frog also represents a useful model to study a rare human congenital heart disease, hypoplastic left heart syndrome. In this review, we first summarized the cellular events and molecular regulations of vertebrate heart development, and the benefit of using a frog model to study congenital heart diseases. Next, we described the challenges in elucidating the etiology of hypoplastic left heart syndrome and discussed how a frog model may contribute to our understanding of the molecular and cellular bases of the disease. We concluded that a frog model offers its unique advantage in uncovering the cellular mechanisms of hypoplastic left heart syndrome; however, combining multiple model organisms, including frogs, is needed to gain a comprehensive understanding of the disease.
Target Balloon-Assisted Antegrade and Retrograde Use of Re-Entry Catheters in Complex Chronic Total Occlusions
Authors: Patrone Lorenzo , Theivacumar Nada Selva , Dharmarajah Brahman , Thulasidasan Narayanan , Diamantopoulos Athanasios , Palena Luis Mariano , Antaredja Muliadi , Tilemann Lisa , Blessing Erwin
Published: January 2023

Purpose, Retrograde recanalizations have gained increasing recognition in complex arterial occlusive disease. Re-entry devices are a well described adjunct for antegrade recanalizations. We present our experience with target balloon-assisted antegrade and retrograde recanalizations using re-entry devices in challenging chronic total occlusions. Materials and Methods: We report data from a retrospective multicenter registry. Eligibility criteria included either antegrade or retrograde use of the OutbackTM or GoBackTM re-entry catheter in combination with a balloon as a target to accomplish wire passage, when conventional antegrade and retrograde recanalization attempts had been unsuccessful. Procedural outcomes included technical success (defined as wire passage though the occlusion and delivery of adjunctive therapy with <30% residual stenosis at final angiogram), safety (periprocedural complications, e.g., bleeding, vessel injury, or occlusion of the artery at the re-entry site, and distal embolizations), and clinical outcome (amputation-free survival and freedom from target lesion revascularization after 12-months follow-up). Results: Thirty-six consecutive patients underwent target balloon-assisted recanalization attempts. Fourteen (39 %) patients had a history of open vascular surgery in the index limb. Fifteen patients were claudications (Rutherford Class 2 or 3, 21 presented with chronic limb threatening limb ischemia (Rutherford Class 4 to 6). The locations of the occlusive lesions were as follows: iliac arteries in 3 cases, femoropopliteal artery in 39 cases, and in below-the-knee arteries in 12 cases. In 15 cases, recanalization was attempted in multilevel occlusions. Retrograde access was attempted in 1 case in the common femoral artery, in the femoropopliteal segment in 10 cases, in below-the-knee arteries in 23 cases, and finally in 2 patients via the brachial artery. In 10 cases, the re-entry devices were inserted via the retrograde access site. Technical success was achieved in 34 (94 %) patients. There were 3 periprocedural complications, none directly related to the target balloon-assisted re-entry maneuver. Amputation-free survival was 87.8 % and freedom from clinically driven target lesion revascularization was 86.6 % after 12-months follow-up. Conclusion: Target balloon-assisted use of re-entry devices in chronic total occlusions provides an effective and safe endovascular adjunct, when conventional antegrade and retrograde recanalization attempts have failed.
Salivary Human β-Defensin 1-3 and Human α-Defensin-1 Levels in Relation to the Extent of Periodontal Disease and Tooth Loss in the Elderly
Authors: Gürsoy Ulvi Kahraman , Gürsoy Mervi , Liukkonen Anna , Suominen Anna Liisa , Könönen Eija
Published: January 2023

The oral innate immune response may diminish with aging. In the present study, the aim was to examine human β-defensin (hBD) 1-3 and human neutrophil peptide (HNP)-1 levels in the saliva of an elderly population to establish the extent of periodontal disease and tooth loss. A total of 175 individuals aged ≥ 65 years were divided into five groups based on the number of teeth with a pocket depth ≥ 4 mm as follows: 17 pocket-free individuals (Control), 55 individuals having 1–6 pocket teeth (PerioA), 33 individuals having 7–13 pocket teeth (PerioB), 29 individuals having at least 14 pocket teeth (PerioC), and 41 edentulous individuals. Their salivary defensin levels were measured with ELISA kits. The salivary HNP-1 levels were significantly higher in the Perio groups (PerioB: p < 0.001 and PerioC: p < 0.001) in comparison to the Control. The associations between salivary HNP-1 levels and the number of pocket teeth remained significant after adjustments for age, gender, level of education, and number of teeth. The salivary HNP and hBD levels differed in terms of their correlation to the extent of periodontal disease and tooth loss in the elderly.
A Cross-Sectional Analysis of Health Literacy and Compliance to Treatment in Organ Transplant Recipients
Authors: Bae Sun Hyoung , Lee Jung Jun , Son Sun Young , Kim Hee Young , Ju Man Ki
Published: January 2023

This study was conducted to determine the correlations between health literacy, transplant effects, and compliance to treatment in organ transplant recipients and to identify the factors influencing compliance to treatment. The participants (n = 130; males = 66.9%; mean age = 56.4 years) were organ transplant recipients visiting an organ transplantation center in Seoul, South Korea. The regression model explained 32% of the variance in participants’ compliance to treatment. Among the health literacy variables, “Scale 3: Actively managing my health” (β = 0.38, p = 0.001) and “Scale 4: Social support for health” (β = 0.25, p = 0.019) had a significant effect on compliance to treatment. In this study, health literacy was identified as a key factor influencing compliance to treatment. Therefore, patients’ health literacy should be assessed prior to transplantation to identify potential high-risk patients for treatment nonadherence. In addition, after transplantation surgery, patient-tailored interventions should be developed and provided for self-management that reflects the patient’s health literacy level to ultimately enhance patient outcomes.
Efficacy of Submicron Dispersible Free Phytosterols on Non-Alcoholic Fatty Liver Disease: A Pilot Study
Authors: Brañes María C. , Gillet Raimundo , Valenzuela Rodrigo
Published: January 2023

Background: No pharmacological treatment is yet approved for non-alcoholic fatty liver disease (NAFLD). Plant sterols have shown healthy properties beyond lowering LDL-cholesterol, including lowering triglycerides and lipoprotein plasma levels. Despite pre-clinical data suggesting their involvement in liver fat control, no clinical study has yet been successful. Aims: Testing a sub-micron, free, phytosterol dispersion efficacy on NAFLD. Methods: A prospective, uncontrolled pilot study was carried out on 26 patients with ≥17.4% liver steatosis quantified by magnetic resonance imaging. Subjects consumed daily a sub-micron dispersion providing 2 g of phytosterols. Liver fat, plasma lipids, lipoproteins, liver enzymes, glycemia, insulinemia, phytosterols, liposoluble vitamins and C-reactive protein were assessed at baseline and after one year of treatment. Results: Liver steatosis relative change was −19%, and 27% of patients reduced liver fat by more than 30%. Statistically and clinically significant improvements in plasma triglycerides, HDL-C, VLDL and HDL particle number and C-reactive protein were obtained, despite the rise of aspartate aminotransferase, glycemia and insulinemia. Though phytosterol plasma levels were raised by >30%, no adverse effects were presented, and even vitamin D increased by 23%. Conclusions: Our results are the first evidence in humans of the efficacy of submicron dispersible phytosterols for the treatment of liver steatosis, dyslipidemia and inflammatory status in NAFLD.
Factors Associated with Potentially Inappropriate Screening for Vitamin D Deficiency among Women in Medically Underserved Regions of West Texas
Authors: Appiah Duke , Kamrudin Samira , de Riese Cornelia
Published: January 2023

Testing for vitamin D deficiency (VDD) has been on the increase due to its association with several diseases. However, inappropriate testing for VDD, defined as screening for VDD among individuals with a low risk, has been reported. The aim of this study was to evaluate the prevalence and factors associated with potentially inappropriate screening for VDD among medically underserved populations in West Texas. Data were from 21,407 women who were hospitalized from 2016 to 2018 at a large regional health system. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). The median age of patients was 40 years. While the proportion of patients tested for VDD reduced from 8.9% to 7.6% (p = 0.013) from 2016 to 2018, the prevalence of inappropriate testing increased from 32.3% to 46.8% (p < 0.001), with the 3-year prevalence of VDD being 27.6%. White race (OR = 2.71, CI: 1.95–3.78), an age ≥ 65 years (OR = 3.07, CI: 2.05–4.59), the use of public-sponsored insurance (OR = 1.62, CI: 1.20–2.17), cardiovascular disease (OR = 0.75, CI: 0.63–0.90), and vitamin D supplement use (OR = 7.05, CI: 5.82–8.54) were associated with inappropriate testing for VDD. In this study, an increasing prevalence of potentially inappropriate testing for VDD was observed. Sociodemographic and health-related conditions were associated with potentially inappropriate testing for VDD.
The Therapeutic Intensity Score as Predictor of Clinical Outcomes after Total and Partial Adrenalectomy for Unilateral Primary Aldosteronism: Results of a Multicentric Series
Authors: Anceschi Umberto , Mormando Marilda , Flammia Rocco Simone , Fiori Cristian , Zappalà Orazio , De Concilio Bernardino , Brassetti Aldo , Carrara Alessandro , Ferriero Maria Consiglia , Tuderti Gabriele , Misuraca Leonardo , Prata Francesco , Tufano Antonio , Bove Alfredo Maria , Mastroianni Riccardo , Appetecchia Marialuisa , Tirone Giuseppe , Porpiglia Francesco , Celia Antonio , Simone Giuseppe
Published: January 2023

Background: To evaluate the ability of therapeutic intensity score (TIS) in predicting the clinical outcomes of partial (PA) and total adrenalectomy (TA) for UPA. Methods: Between 2011 and 2022, a four-center adrenalectomy dataset was queried for “unilateral adrenal mass” and “UPA” (n = 90). Preoperative TIS of each antihypertensive medication were individually calculated and merged to create a single, cumulative variable. Probability of complete clinical, partial, and absent pooled success rates according to TIS were assessed for the overall cohort by Kaplan–Meier. Cox analyses were used to identify predictors of complete clinical and partial/absent success, respectively. For all analyses, a two-sided p < 0.05 was considered significant. Results: At a median follow-up of 42 months (IQR 27–54) complete partial, and absent clinical success were observed in 60%, 17.7%, and 22.3%, respectively. On Kaplan–Meier analysis, TIS < 1 predicted higher complete success rates (p < 0.001), while TIS ≥ 1 was predictor of either partial and absent clinical success (p = 0.008). On multivariable analysis, TIS < 1 (HR 0.25; 95% CI 0.11–0.57; p = 0.001) and adenoma size (HR 1.11; 95% CI 1–1.23; p = 0.0049) were independent predictors of complete clinical success, while TIS ≥ 1 (HR 2.84; 95% CI 1.32–6.1; p = 0.007) was the only independent predictor of absent clinical success. Conclusions: TIS score and adenoma size may help to identify patients who are likely to be at risk of persistent hypertension after surgery.
GLI1 Deficiency Impairs the Tendon–Bone Healing after Anterior Cruciate Ligament Reconstruction: In Vivo Study Using Gli1-Transgenic Mice
Authors: Liu Yake , Liu Shaohua , Song Zhe , Chen Daoyun , Album Zoe , Green Samuel , Deng Xianghua , Rodeo Scott
Published: January 2023

Hedgehog (Hh) signaling plays a fundamental role in the enthesis formation process and GLI-Kruppel family member GLI1 (Gli1) is a key downstream mediator. However, the role of Gli1 in tendon–bone healing after anterior cruciate ligament reconstruction (ACLR) is unknown. To evaluate the tendon–bone healing after ACLR in Gli1LacZ/LacZ (GLI1-NULL) mice, and compare Gli1LacZ/WT (GLI1-HET) and Gli1WT/WT wild type (WT) mice, a total of 45 mice, 15 mice each of GLI1-NULL, GLI1-HET and WT were used in this study. All mice underwent microsurgical ACLR at 12 weeks of age. Mice were euthanized at 4 weeks after surgery and were used for biomechanical testing, histological evaluation, and micro-CT analysis. The GLI1-NULL group had significantly lower biomechanical failure force, poorer histological healing, and lower BV/TV when compared with the WT and GLI1-HET groups. These significant differences were only observed at the femoral tunnel. Immunohistology staining showed positive expression of Indian hedgehog (IHH) and Patched 1(PTCH1) in all three groups, which indicated the activation of the Hh signal pathway. The GLI1 was negative in the GLI1-NULL group, validating the absence of GLI1 protein in these mice. These results proved that activation of the Hh signaling pathway occurs during ACL graft healing, and the function of Gli1 was necessary for tendon–bone healing. Healing in the femoral tunnel is more obviously impaired by Gli1 deficiency. Our findings provide further insight into the molecular mechanism of tendon–bone healing and suggest that Gli1 might represent a novel therapeutic target to improve tendon–bone healing after ACLR.
Comparison of Hemodynamic Response between Patients with Systolic Heart Failure Differing in Serum Aldosterone Concentrations during and after a 6-Minute Walk Test
Authors: Miętkiewska-Szwacka Kamila , Krauze Tomasz , Barecka Katarzyna , Różańska-Kirschke Anna , Przymuszała-Staszak Dagmara , Schneider Agata , Dziarmaga Miłosz , Tarchalski Jacek Lech , Nowak Aneta , Bryl Mateusz , Kaczmarek Jolanta , Piskorski Jarosław , Wykrętowicz Andrzej , Guzik Przemysław
Published: January 2023

Aldosterone regulates hemodynamics, including blood pressure (BP), and is involved in the development and progression of cardiovascular diseases, including systolic heart failure (HF). While exercise intolerance is typical for HF, neither BP nor heart rate (HR) have specific characteristics in HF patients. This study compares BP and HR profiles during and after standardized exercise between patients with systolic HF with either lower or higher aldosterone concentrations. We measured BP and HR in 306 ambulatory adults with systolic HF (left ventricular ejection fraction (LVEF) <50%) during and after a 6 min walk test (6MWT). All patients underwent a resting transthoracic echocardiography, and venous blood samples were collected for biochemical analyses. The patients were also divided into tertiles of serum aldosterone concentration: T1 (<106 pg/mL), T2 (106 and 263 pg/mL) and T3 (>263 pg/mL), respectively. Individuals from T1 and T2 were combined into T1–T2 as the reference group for comparisons with patients from T3. The individuals from T3 had significantly lower systolic, mean and diastolic BPs at rest, at the end and at 1 and 3 min post-6MWT recovery, as well as a more dilated left atrium and right ventricle alongside a higher concentration of N-terminal pro-B-type natriuretic peptide (NT-proBNP). Higher serum aldosterone concentration in HF patients with an LVEF < 50% is associated with a lower 6MWT BP but not an HR profile.
Advanced Paternal Age Does Not Affect Medically-Relevant Obstetrical and Perinatal Outcomes following IVF or ICSI in Humans with Donated Oocytes
Authors: Navarro-Gomezlechon Ana , Gil Juliá María , Hervás Irene , Mossetti Laura , Rivera-Egea Rocío , Garrido Nicolás
Published: January 2023

Background: Concomitant with delays in childbearing, concerns have been raised of whether advanced paternal age is associated with adverse reproductive outcomes, but the evidence is controversial in part due to the uncertain threshold in which to consider advanced paternal age and confounding maternal factors. This retrospective study aimed to evaluate the effect of paternal age on reproductive outcomes related to the pregnancy and perinatal health of the offspring. Methods: We retrospectively evaluated 16,268 cases of patients who underwent IVF or ICSI (using autologous sperm and donated oocytes, between January 2008 and March 2020, at Spanish IVIRMA clinics. Patients were divided based on paternal age at conception [≤30 (n = 204), 31–40 (n = 5752), and >40 years (n = 10,312)], and the differences in obstetrical and perinatal outcomes were analyzed by descriptive analysis, followed by univariate and multivariate analysis. Results: Fathers 31–40 and >40 years old were associated with lower odds of caesarean delivery [AOR 0.63 (95% CI, 0.44–0.90; p = 0.012) and AOR 0.61 (95% CI, 0.41–0.91; p = 0.017), respectively] and longer pregnancies [ARC 5.09 (95% CI, 2.39–7.79; p < 0.001) and ARC 4.54 (95% CI, 1.51–7.58; p = 0.003), respectively] with respect to fathers ≤30 years old. Furthermore, fathers aged 31–40 years old had lower odds of having a female infant (AOR, 0.70; 95% CI, 0.49–0.99; p = 0.045) than those ≤30. The rest of obstetrical and perinatal outcomes, which we deemed more medically-relevant as they were considered serious for health, were comparable between groups with our adjusted model. Conclusions: Despite this hopeful message to fathers of advanced paternal age, future studies should consider the short- and long-term outcomes of the offspring and try to better elucidate the associations of advanced paternal age with reproductive outcomes and the molecular mechanisms underlying the observed associations.
Pathophysiology of Early Brain Injury and Its Association with Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage: A Review of Current Literature
Authors: Alsbrook Diana L. , Di Napoli Mario , Bhatia Kunal , Desai Masoom , Hinduja Archana , Rubinos Clio A. , Mansueto Gelsomina , Singh Puneetpal , Domeniconi Gustavo G. , Ikram Asad , Sabbagh Sara Y. , Divani Afshin A.
Published: January 2023

Background: Delayed cerebral ischemia (DCI) is a common and serious complication of aneurysmal subarachnoid hemorrhage (aSAH). Though many clinical trials have looked at therapies for DCI and vasospasm in aSAH, along with reducing rebleeding risks, none have led to improving outcomes in this patient population. We present an up-to-date review of the pathophysiology of DCI and its association with early brain injury (EBI). Recent Findings: Recent studies have demonstrated that EBI, as opposed to delayed brain injury, is the main contributor to downstream pathophysiological mechanisms that play a role in the development of DCI. New predictive models, including advanced monitoring and neuroimaging techniques, can help detect EBI and improve the clinical management of aSAH patients. Summary: EBI, the severity of subarachnoid hemorrhage, and physiological/imaging markers can serve as indicators for potential early therapeutics in aSAH. The microcellular milieu and hemodynamic pathomechanisms should remain a focus of researchers and clinicians. With the advancement in understanding the pathophysiology of DCI, we are hopeful that we will make strides toward better outcomes for this unique patient population.
Neuroimaging Studies of the Neural Correlates of Heart Rate Variability: A Systematic Review
Authors: Matusik Patrycja S. , Zhong Chuwen , Matusik Paweł T. , Alomar Omar , Stein Phyllis K.
Published: January 2023

Direct and indirect links between brain regions and cardiac function have been reported. We performed a systematic literature review to summarize current knowledge regarding the associations of heart rate variability (HRV) and brain region morphology, activity and connectivity involved in autonomic control at rest in healthy subjects. Both positive and negative correlations of cortical thickness and gray matter volumes of brain structures with HRV were observed. The strongest were found for a cluster located within the cingulate cortex. A decline in HRV, as well as cortical thickness with increasing age, especially in the orbitofrontal cortex were noted. When associations of region-specific brain activity with HRV were examined, HRV correlated most strongly with activity in the insula, cingulate cortex, frontal and prefrontal cortices, hippocampus, thalamus, striatum and amygdala. Furthermore, significant correlations, largely positive, between HRV and brain region connectivity (in the amygdala, cingulate cortex and prefrontal cortex) were observed. Notably, right-sided neural structures may be preferentially involved in heart rate and HRV control. However, the evidence for left hemispheric control of cardiac vagal function has also been reported. Our findings provide support for the premise that the brain and the heart are interconnected by both structural and functional networks and indicate complex multi-level interactions. Further studies of brain–heart associations promise to yield insights into their relationship to health and disease.
Clinically Manifest Infections Do Not Increase the Relapse Risk in People with Multiple Sclerosis Treated with Disease-Modifying Therapies: A Prospective Study
Authors: Miele Giuseppina , Cepparulo Simone , Abbadessa Gianmarco , Lavorgna Luigi , Sparaco Maddalena , Simeon Vittorio , Guizzaro Lorenzo , Bonavita Simona
Published: January 2023

Background: Many factors are believed to be positively associated with the incidence of relapses in people with multiple sclerosis (MS), including infections. However, their role is still controversial. We aimed to investigate whether symptomatic infections in people with MS increase the risk of relapse in the short, medium, or long term. Materials and Methods: We enrolled consecutive patients with relapsing MS (RMS) from October to December 2018. From enrolment up to September 2020, an online questionnaire investigating the occurrence of infections was sent via WhatsApp® monthly to the enrolled patients, while in-person visits were performed every six months. When patients complained of symptoms compatible with relapses, they attended an extra in-person visit. Results: We enrolled 155 patients with RMS, and 88.38% of patients were treated with disease-modifying therapies. In the dataset, 126,381 total patient days, 78 relapses, and 1202 infections were recorded over a period of about 2 years. No increased risk of relapse after clinically manifest infections was found in the short-, medium-, or long-term period. No correlation was found between all infections and the number of relapses (p = 0.212). The main analyses were repeated considering only those infections that had at least two of the following characteristics: duration of infection ≥ 4 days, body temperature > 37° Celsius, and the use of drugs (antibiotics and/or antivirals), and no significant associations were observed. Conclusions: No associations between infections and relapses were observed, likely suggesting that disease-modifying therapies may protect against the risk of relapse potentially triggered by infections.
Clinical Evaluation of Patients with Genetically Confirmed Familial Hypercholesterolemia
Authors: Aparicio Andrea , Villazón Francisco , Suárez-Gutiérrez Lorena , Gómez Juan , Martínez-Faedo Ceferino , Méndez-Torre Edelmiro , Avanzas Pablo , Álvarez-Velasco Rut , Cuesta-Llavona Elías , García-Lago Claudia , Neuhalfen David , Coto Eliecer , Lorca Rebeca
Published: January 2023

Familial hypercholesterolemia (FH) is the most common genetic disorder associated with premature atherosclerotic cardiovascular (CV) disease (ASCVD). However, it still is severely underdiagnosed. Initiating lipid-lowering therapy (LLT) in FH patients early in life can substantially reduce their ASCVD risk. As a result, identifying FH is of the utmost importance. The increasing availability of genetic testing may be useful in this regard. We aimed to evaluate the genetic profiles, clinical characteristics, and gender differences between the first consecutive patients referred for genetic testing with FH clinical suspicion in our institution (a Spanish cohort). Clinical information was reviewed, and all participants were sequenced for the main known genes related to FH: LDLR, APOB, PCSK9 (heterozygous FH), LDLRAP1 (autosomal recessive FH), and two other genes related to hyperlipidaemia (APOE and LIPA). The genetic yield was 32%. Their highest recorded LDLc levels were 294 ± 65 SD mg. However, most patients (79%) were under > 1 LLT medication, and their last mean LDLc levels were 135 ± 51 SD. LDLR c.2389+4A>G was one of the most frequent pathogenic/likely pathogenic variants and its carriers had significantly worse LDLc highest recorded levels (348 ± 61 SD vs. 282 ± 60 SD mg/dL, p = 0.002). Moreover, we identified an homozygous carrier of the pathogenic variant LDLRAP1 c.207delC (autosomal recessive FH). Both clinical and genetic hypercholesterolemia diagnosis was significantly established earlier in men than in women (25 years old ± 15 SD vs. 35 years old ± 19 SD, p = 0.02; and 43 ± 17 SD vs. 54 ± 19 SD, p = 0.02, respectively). Other important CV risk factors were found in 44% of the cohort. The prevalence of family history of premature ASCVD was high, whereas personal history was exceptional. Our finding reaffirms the importance of early detection of FH to initiate primary prevention strategies from a young age. Genetic testing can be very useful. As it enables familial cascade genetic testing, early prevention strategies can be extended to all available relatives at concealed high CV risk.