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The ring-core technique is a stress relaxation-based method that is used to determine surface residual stresses in a material based on the linear elastic theory. However, material yielding that is due to ring creation on a highly stressed body would cause some errors. In this article, plasticity effects on high-level uniform residual stresses calculated by the ring-core technique were examined via a numerical analysis. The plasticity error owing to yielding was obtained by comparing the applied stress and the calculated stress derived from finite element (FE) simulation. Moreover, using the prepared FE model, the effects of various parameters, such as state of loading, ring geometry, and tangent modulus, were investigated. The results showed a maximum 30% positive errors in the calculated residual stresses and the great impact of ring geometry on the plasticity error. Based on the results, the optimized ring diameter and depth for suitable precision were proposed. [ABSTRACT FROM AUTHOR]

In this study, the numerical simulation of the fluid flow and acoustic field of a supersonic jet is performed by using high-order discretization and the vorticity confinement (VC) method on coarse grids. The three-dimensional Navier-Stokes equations are considered in the generalized curvilinear coordinate system and the high-order compact finite-difference scheme is applied for the space discretization, and the time integration is performed by the fourth-order Runge-Kutta scheme. A low-pass high-order filter is applied to stabilize the numerical solution. The non-reflecting boundary conditions are adopted for all the free boundaries, and the Kirchhoff surface integration is utilized to obtain the far-field sound pressure levels in a number of observer locations. Comparisons of the jet mean flow and jet aeroacoustics results with the other numerical and experimental data at similar flow conditions are made and show a reasonable agreement. The study shows that the proposed solution methodology based on the high-order compact finite-difference scheme in conjunction with the VC method can reasonably predict the near-field flow and the far-field noise of high Reynolds number jets with a fairly coarser grid than that used in the large eddy simulations and, thus, the computational cost can be significantly decreased. [ABSTRACT FROM AUTHOR]

Abstract: The ring‐core method is a mechanical technique used to determine the residual stresses on the surface of materials by milling a narrow circular groove around the point of interest and monitoring the strain variation. Original stress can be evaluated by using the relaxed strain through the linear elasticity theory. In case of a highly stressed field, the yielding of the material around the groove and its bottom causes an error related to the hypothesis of the basic theory of the method. In this paper, the plasticity effect of calculated residual stresses was considered. For this purpose, the ring‐core development and stress relaxation in a generally stressed body were simulated using a 3D parametric finite element model and the stress calculation errors were obtained by comparing calculation stress with the actual one. According to the results, the error value was affected by some parameters such as ring depth, stress magnitude and state, and material behaviour. In general, for residual stresses above 65% of the local yield strength, the plasticity‐induced errors were significant, as an error close to 35% was found. Based on the result, a correction procedure was proposed for the evaluation of the high level residual stresses in steel materials by the ring‐core method. By the method, true stresses can be obtained with considering the calculated stresses state, material properties, ring geometry, and estimated plasticity‐induced errors. [ABSTRACT FROM AUTHOR]

In this work, the capability and performance of the vorticity confinement (VC) implemented in a high-order accurate flow solver in predicting two-dimensional (2D) compressible mixing layer flows on coarse grids are investigated. Here, the system of governing equations with incorporation of the VC in the formulation is numerically solved by the fourth-order compact finite difference scheme. To stabilize the numerical solution, a low-pass high-order filter is applied, and the nonreflective boundary conditions are used at the farfield and outflow boundaries to minimize the reflections. At first, the numerical results without applying the VC are validated by available direct numerical simulations (DNSs) for a low Reynolds number mixing layer. Then, the calculations using a range of VC levels are performed for a high Reynolds number mixing layer and the results are thoroughly compared with those of available large eddy simulations (LESs). The study shows that, with applying the vortex identification method, more accurate results are obtained in the slow laminar region of the mixing layer. A sensitivity study is also performed to examine the effect of different numerical parameters to reasonably provide more accurate results. It is shown that the local VC introduced based on the artificial viscosity coefficient and the vorticity thickness can improve the accuracy of the results in the turbulent region of the mixing layer compared with those of LESs. It is found that the solution methodology proposed can reasonably preserve the vortices in the flowfield and the results are comparable with those of LESs on fairly coarser grids and thus the computational costs can be considerably decreased. [ABSTRACT FROM AUTHOR]

The Ring-Core method is a mechanical technique used to calculate the surface residual stresses in a material. In this paper, plasticity effects on the calculated results of the Ring-Core technique were studied by FEM analysis. For this purpose, the coefficients were obtained from an elastic finite element modeling. Then, the execution of the Ring-Core technique using bilinear elasticplastic behavior for the material was simulated and finally the relaxed strains due to ring core milling were obtained. The plastic error due to yielding was calculated by comparing the applied stress and calculated stress from the FE simulation. Also, by using the prepared FE model, the effects of various parameters like state of loading, ring geometry and tangent modulus were investigated. Based on the obtained results, a suitable range for the ring diameter was proposed in order for achieves accurate results. [ABSTRACT FROM AUTHOR]

Gas injection is one of the methods used in enhanced oil recovery. A pump is usually used for injection of gas into a core in the laboratory. For precision of the experimental results, it is important to keep experimental errors at the minimum value. In this work, an approach for reduction of one of the most important and effective parameters in the generation of experimental errors during gas injection is presented. One of the main goals of this study is to increase the accuracy of gas injection into a core by using a pump at the experimental scale. In gas injection into a core, if the pump is adjusted to a constant rate, under some conditions, gas injection cannot be conducted with a constant rate and therefore deviation from the constant rate occurs. The value of deviation from the constant rate is different with respect to rock and fluid properties and operating conditions. In this investigation, experiments were carried out on a carbonate core with low permeability. Experimental data and effective parameters on the error in using a pump for gas injection with a constant rate were studied. [ABSTRACT FROM AUTHOR]

In an anisotropic medium, the direction of the energy propagation is different from the plane-wave propagation. This difference will cause velocity variation in different angles. Therefore, velocity modelling in anisotropic media is different from that in an isotropic medium. In this paper, a conventional algorithm has been extended based on ray tracing through an anisotropic model. The velocity model for ray tracing is parametrized in terms of blocky trapezoid cells where the velocity values change inside the cells linearly. Thomsen's approximations in weakly anisotropic media were used to estimate anisotropic velocity vectors. Rays were traced along the group vector in vertical transversely isotropic (VTI) media so that the phase angle and phase velocities satisfy the anisotropic Snell's law across the interface. To compute seismic amplitudes in the anisotropic media, a new parameter was defined as a partitioning factor which controls the seismic energy propagation in each interface. The effect of geometrical spreading was calculated by using Ursin's procedure. Synthetic models are computed to demonstrate the new ray tracing algorithm and to verify correctness of the traveltimes and amplitude calculations. It is shown that the difference between isotropic and anisotropic traveltimes increases with offset, especially when the ratio offset/depth exceeds 1.5. To calculate amplitudes in VTI media, a new parameter was introduced and applied as the energy partitioning factor, which helps us obtaining a more accurate amplitude calculation. Ray tracing was also performed for the velocity model extracted from a large offset 2-D seismic line located on the southwest of Iran. Anisotropic parameters were estimated from seismic data under the elliptical anisotropic assumption. Reflected traveltimes were computed by ray tracing from top of the reservoir horizon (fifth reflector) in the anisotropic model. The calculated traveltimes once we explicitly included anisotropic velocities showed a much improved correlation with the seismic real data. [ABSTRACT FROM AUTHOR]

In a homogenous transversely isotropic medium, P-wave NMO velocity depends on anisotropic parameters. Based on the approximation of Alkhalifah, P-wave traveltime correction for any offset is done by NMO velocity through a zero-offset ray. However, in anisotropic media, the velocity changes with different directions related to symmetry axis. In this paper, we present a formula to estimate NMO correction based on ray velocity instead of zero offset NMO velocity. The ray velocity can be determined for any offset using anisotropic ray tracing based on an exploding reflector model. Also, a dimensionless parameter defined by semblance analysis is applied as a third term of non-elliptical traveltime equation. Model and field experiments were performed to demonstrate the feasibility of the method. The results show that moveout correction using ray velocity is more accurate than Alkhalifah's method for long offsets. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the relationship between radiological and functional results in patients with extra-articular fractures of the distal radius. We conducted a prospective study of radiological and functional assessment in 95 consecutively selected extra-articular distal radius fractures. There were two patient groups: more than 60 and less than 60 years of age. The final fracture union radiographs were analysed for their functional outcome using the Michigan Hand Outcomes Questionnaire (MHQ) and the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire. In patients with acceptable radiological results, 62% (MHQ group) and 72% (DASH group) of patients had satisfactory functional outcome. Analysing patients with satisfactory functional results, 56% (MHQ group) and 59% (DASH group) had satisfactory radiological results. There was a higher proportion of patients with better functional results, despite poor radiological results, in both of the age groups. There was a statistically significant correlation between satisfactory radial tilt and functional outcome in the younger patients. In the older age group, patients with satisfactory radiological results had satisfactory functional outcome (p<0.05). However, in the older age group, satisfactory functional results were achieved, despite unsatisfactory radiological results. [ABSTRACT FROM AUTHOR]

For the production of synthesis gas utilised in Midrex direct reduction plants, catalytic steam/CO2 hydrocarbon reforming in tubular reformer is the major process. Owing to the high heat input through the Midrex reformer tube wall, the endothermic nature of reforming reactions, low mass velocity of feed gas and large tube diameter, the catalyst bed is exposed to considerable axial and radial temperature gradients. These radial concentration and temperature gradients may create local areas with potential for carbon formation. To investigate this phenomenon, a rigorous two-dimensional model is developed for simulating the operation of a Midrex reformer which applies a dual catalyst loading profile. Both process side and furnace side have been included in this integrated model. Simulation results are in good agreement with available data from an actual plant. Using this model, a thermodynamic approach is applied to recognise zones in which the risk of carbon formation is high inside the reformer tubes. The results show that the first half of tubes, both in centre and near the wall, is critical from carbon forming point of view. Furthermore, the model shows that how a certain catalyst loading profile will affect the operation of the reformer. [ABSTRACT FROM AUTHOR]

Conclusion. A significant reduction in post-tonsillectomy secondary haemorrhage rate was observed after coblation tonsillectomy was abandoned in our department. Objective. Comparison of the postoperative haemorrhage rate following coblation tonsillectomy and routine dissection tonsillectomy. Patients and methods. This was a retrospective study. In the first audit period, 441 sequential tonsillectomies between January and September 2002 were reviewed. Coblation was compared with cold steel and diathermy dissection with either ties and/or diathermy used for haemostasis. Coblation tonsillectomy was subsequently abandoned in our unit and, in the second audit period, all tonsillectomies (n=416) between July 2003 and August 2004 were included. Statistical analysis was performed using the χ2 test. Results. The overall primary haemorrhage rate in the first audit cycle was 1.8% (8/441). In the second cycle with no coblation procedures, 1.4% of patients (6/416) suffered from primary haemorrhage (c.f. 8/441 (1.8%) in the first cycle, p=0.666). Secondary haemorrhage, was seen among 15.4% of patients (68/441) in the first audit cycle. In the second cycle, after coblation was discontinued, the secondary haemorrhage rate fell significantly (p<0.001) to 5.8% (24/416). A breakdown of the results of cold steel/diathermy and coblation techniques in both adults and children is also presented. [ABSTRACT FROM AUTHOR]

In this study, the energy transference of a hybrid Al2O3-Cu-H2O nanosuspension within a lid-driven heated square chamber is simulated. The domain is affected by a horizontal magnetic field. The vertical sidewalls are insulated and the horizontal borders of the chamber are held at different fixed temperatures. A fourth-order accuracy compact method is applied to work out the vorticity-stream function view of incompressible Oberbeck–Boussinesq equations. The method used is validated against previous numerical and experimental works and good agreement is shown. The flow patterns, Nusselt numbers, and velocity profiles are studied for different Richardson numbers, Hartmann numbers, and the solid volume fraction of hybrid nanoparticles. Flow field and heat convection are highly affected by the magnetic field and volume fraction of each type of nanoparticles in a hybrid nanofluid. The results show an improvement of heat transfer using nanoparticles. To achieve a higher heat transmission rate by using the hybrid nanofluid, flow parameters like Richardson number and Hartmann number should be considered. [ABSTRACT FROM AUTHOR]

The long-term behaviour of railway track has attracted increasing attention in recent years. Improvements in long-term structural performance reduce demands for maintenance and increase the continuous availability of railway lines. The focus of this paper is on the prediction of the sensitivity of a track design to long-term deterioration in terms of track geometry. According to the state of the art literature, degradation is often investigated using empirical models based on field measurement data. Although a rough maintenance forecast may be made employing empirical models, the predictions are not generic, and the physical processes which govern track degradation under train operation remain unclear. The first aim of this study is to present a mathematical model to elucidate the underlying physics of long-term degradation of railway tracks. The model consists of an infinitely long beam which is periodically supported by equidistantly discrete sleepers and a moving unsprung mass which represents a travelling train. The mechanical energy dissipated in the substructure is proposed to serve as a measure of the track degradation rate. Secondly, parametric studies on energy dissipation are conducted to identify effects of various track design parameters on the susceptibility of the track to degradation, as well as the effect of the train speed. It has been shown that the track/subgrade stiffness is the most influential parameter on degradation whereas other system parameters do influence the degradation rate but at lower magnitudes. The conclusions can be used to optimise the track design in the early stage for better long-term structural performance of railway tracks.

Tinea capities is the commonest dermatophytosis in children with diverse clinical presentations. The causative fungi of Tinea capitis vary with geographic area and time.This study was aimed to identify the etiologic agents and determine the related factors of Tinea capitis in Tehran, Iran. From clinically suspected cases of Tinea capitis, microscopy and culture were performed. Of 58patients 96% were children below 12 years of age with the male/ female ratio of 21, the common clinical manifestation was gray patch, followed by kerion, favus (scutula), black dot not seborrehic dermatitis- liker lesion, thrychophyton violaceum was the most common etiologic agent, responsible for 53.4% of infection, followed by T. shoepnleini (24.1%) Microsporum canis (5.5%) , T. mentagrophytes (3.4%) , T. tonsurans (1.7%) and M. gypseum (1.7%). T. violaceum was the predominat pathogen causing Tinea capitis in this region and gave rise to a varied clinical picture

Tinea corporis is a superficial fungal infection of the keratinized epithelial layer, presenting as erythematous scaling patches with central clearing. Sometimes it can resemble other skin disorders, so its misdiagnosis constitutes a problem of considerable practical importance. We describe a patient who presented with widespread Tinea corporis that morphology and distribution of the lesions mimicked lupus erythematosus and/or photodermatosis.

Abstract: External electric field effects on the optical rectification coefficient of an exciton confined in a spherical parabolic quantum dot are theoretically investigated. To this end, energy eigenvalues and eigenfunctions of the system are calculated, using the direct matrix diagonalization method. The compact-density matrix approach and an iterative method are used to find the optical rectification coefficient of a typical GaAs parabolic quantum dot. The results show that the optical rectification coefficient strongly depends on the confinement frequency and the magnitude of the electric field. Moreover, the peak value of this optical quantity is shifted to the aspect of high energy when the influence of the electric field is considered. [Copyright &y& Elsevier]

Human milk contains 2.2 ± 1.5×10 11 small extracellular vesicles (sEVs) per milliliter and human infants consume 1.7×10 14 milk sEVs (sMEVs) daily in 800 mL milk. Infant formula contains trace amounts of sMEVs. To date, eight adverse effects of milk depletion and five beneficial effects of sMEV supplementation have been reported including studies in infants and neonate mice. Formula-fed infants do not realize the benefits of sMEVs. Most of the phenotyping studies reported to date have the limitation that sMEV depletion and supplementation were initiated after mice were weaned. Here, we used a genetics approach for assessing effects of sMEV depletion on the development of suckling mice. Newborn C57BL/6J pups were fostered to Tumor Susceptibility Gene 101 (Tsg101) mammary-specific knockout (KO) dams or C57BL/6J dams (controls) in synchronized pregnancies. Tsg101 KO was associated with an 80% decrease of sMEVs. Postnatal weight gain and gut health (histology, morphology, and barrier function) were assessed until weaning at age three weeks. We observed a significant decrease in weight gain, length of small intestine, villi height, crypt depth, and intestinal barrier function in male and female pups fostered to Tsg101 dams compared to pups fostered to control dams. The effect size varied between 11 and 32 percent. Maternal Tsg101 KO did not affect the dams' health, content of macronutrients and dry mass of milk and had no effect on the amount of milk consumed by pups. We conclude that sMEVs are important for growth and gut health in neonate mice., Competing Interests: Declaration of competing interests The authors declare no conflict of interest. J. Zempleni serves as an editorial board member for the Journal of Nutritional Biochemistry and other scientific journals, and his research is currently funded by the National Institutes of Health, the National Institute of Food and Agriculture, and the Syngap Research Fund., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Regenerative medicine is revolutionizing oral and maxillofacial surgeries with stem cells, particularly mesenchymal stem cells, for tissue and bone regeneration. Despite promising in-vitro results, human trials are limited. A systematic review is needed to evaluate stem cell efficacy in maxillofacial issues, aiming to improve surgical outcomes and patient satisfaction., Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines, this review included peer-reviewed articles (2013-2023) on stem cells in oral surgery, excluding non-English publications, abstracts, reviews, and opinion pieces. Searches were conducted in PubMed, Web of Science, OVID, Cochrane, Dentistry & Oral Sciences Source-Ebscohost, and Scopus. Two authors independently screened titles and abstracts, resolving disagreements by consensus. Full-text analysis involved extracting key data, verified by a secondary reviewer and additional quality checks., Results: From 3540 initial articles, 2528 were screened after removing duplicates, and 7 met the inclusion criteria after excluding irrelevant studies. Key themes included the safety and efficacy of stem cell therapy, and bone regeneration and quality. Studies predominantly used mesenchymal stem cells. Findings showed positive outcomes in clinical safety and effectiveness and significant potential for bone regeneration., Conclusions: This systematic review highlights the potential of stem cell therapies in maxillofacial applications, supporting their safety, efficacy, and bone regeneration capabilities. Further research is needed to standardize protocols and confirm long-term benefits.

Immunotherapy has improved cancer treatment based on investigations of tumor immune escape. Manipulation of the immune system stimulates antitumor immune responses and blocks tumor immune escape routes. Genetically adoptive cell therapy, such as T cells, has yielded promising results for hematologic malignancies, but their application to solid tumors has been challenging. Macrophages have a wide broad of capabilities in regulating immune responses, homeostasis, and tissue development, as well as the ability to phagocyte, present antigens, and infiltrate the tumor microenvironment (TME). Given the importance of macrophages in cancer development, they could serve as novel tool for tumor treatment. Therefore, macrophages are used in different formats for direct and indirect targeting of tumor cells. This review summarized the available data on the various applications of macrophages in cancer immunotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Gastric cancer (GC) is a prominent cause of cancer-related mortality worldwide. Long noncoding RNA (lncRNA) maternal expression gene3 (MEG3) participates in numerous signaling pathways by targeting the miRNA-mRNA axis. Studies on human tumors have demonstrated that the antibiotic Ciprofloxacin induces cell cycle changes, programmed cell death, and growth suppression. In this study, we transfected MEG3 lncRNA and Ciprofloxacin into the MKN-45 GC cell line. qRT-PCR was employed to evaluate the effects on the specific microRNA and mRNA. The wound healing test, MTT assay, and flow cytometry were used to assess the impact of their administration on cell migration, viability, and apoptosis, respectively. Research showed that miR-147 expression fell even more after MEG3 lncRNA transfection, leading to an increase in B-cell lymphoma 2 (BCL-2) levels. Ciprofloxacin transfection did not significantly affect the axis, except for MEG3, which led to its slight upregulation. MEG3 lncRNA inhibited the migration of MKN-45 cells compared to the control group. When MEG3 lncRNA was coupled with Ciprofloxacin, there was a significant reduction in cell migration compared to untreated groups and controls. MTT assay and flow cytometry demonstrated that MEG3 lncRNA decreased cell viability and triggered apoptosis. Simultaneous administration of MEG3 lncRNA and Ciprofloxacin revealed a significant reduction in cell viability caused by increased apoptosis obtained from MTT or flow cytometry assays. Modulating the miR-147-BCL-2 axis decreases cell migration and survival while promoting cell death. In conclusion, combining MEG3 lncRNA with Ciprofloxacin may be an effective therapeutic approach for GC treatment by influencing the miR-14-BCl-2 axis, resulting in reduced cell viability, migration, and increased apoptosis., (© 2024 International Union of Biochemistry and Molecular Biology, Inc.)

Introduction: Most research examining vitamin D and dental caries focuses on children and younger adults. This study investigated the association between vitamin D levels and dental caries in older adults using data from the United States National Health and Nutrition Examination Survey from 2011 to 2016., Methods: Data were analyzed from 2723 participants aged 65 years and older who completed both dental examinations and serum 25(OH)D tests. Dental caries assessments included the decayed, missing, and filled teeth (DMFT) index and the presence of untreated dental caries. Vitamin D levels were measured as serum 25(OH)D concentrations and categorized as severely deficient (<25 nmol/L), deficient (25-49.9 nmol/L), insufficient (50-74.9 nmol/L), and normal (≥75 nmol/L). Logistic regression and Poisson regression models were used to assess the association between vitamin D levels and dental caries, adjusting for demographic factors., Results: The mean DMFT score was 17.73 ± 8.34, with 35.1% of participants having untreated dental caries. Vitamin D deficiency was associated with a 1.44 times higher likelihood of untreated caries (95% CI: 1.15, 1.81), which weakened after adjustment for demographic factors (adjusted OR: 1.23, 95% CI: 0.97, 1.55). Severe vitamin D deficiency correlated with a 1.13 times higher DMFT score (95% CI: 1.06, 1.20), with the association remaining similar after adjustment (adjusted RR: 1.12, 95% CI: 1.05, 1.20). Significant differences in vitamin D levels were observed across gender, race/ethnicity, and country of birth., Conclusions: This study suggests the potential importance of adequate vitamin D levels for maintaining dental health among older adults. Vitamin D deficiency is associated with a higher risk of poorer DMFT scores. Public health strategies that include vitamin D screening and supplementation, particularly for high-risk groups, may improve oral health outcomes in the older adult population. Further research is needed to elucidate the mechanisms by which vitamin D influences dental health and the potential for vitamin D supplementation to reduce the burden of dental caries in older adults.

Cancers of the kidney and renal pelvis are among the most prevalent types of urinary cancers. We aimed to outline the incidence trends of kidney and renal pelvis cancers by age, sex, race/ethnicity, and histology in the United States (US) from 2000 to 2020. The data was obtained from the Surveillance, Epidemiology, and End Results (SEER) 22 database. The identification of patients with kidney and renal pelvis cancers with morphologies of renal cell carcinoma, nephroblastoma, sarcoma, and neuroendocrine tumor was conducted utilizing the International Classification of Diseases for Oncology version 3. The average annual percent change (AAPC) were presented. All estimates were given in the form of counts and delayed age-standardized incidence rates (ASIRs) per 100,000 people. From 2000 to 2019, a total of 490,481 cases of kidney and renal pelvic cancer were recorded across all age groups in the US. The majority of them were among Non-Hispanic Whites (NHWs) (69.75%) and those aged 55-69 years (39.96%). The ASIRs per 100,000 for kidney and pelvis cancers were 22.03 for men and 11.14 for women. Non-Hispanic Black men had the highest ASIR (24.53 [24.24, 24.81]), and increase in ASIR over the 2000-2019 period (AAPC: 2.19% [1.84, 2.84]). There was a noticeable increase in incidence of kidney and renal pelvis cancers. Individuals aged 70-84 years had the highest ASIR for kidney and renal pelvis cancers. The COVID-19 era has resulted in a significant reduction in incidence rates across all demographics., (© 2024. The Author(s).)

Schwann cells (SCs) undergo phenotypic transformation and then orchestrate nerve repair following PNS injury. The ligands and receptors that activate and sustain SC transformation remain incompletely understood. Proteins released by injured axons represent important candidates for activating the SC Repair Program. The low-density lipoprotein receptor-related protein-1 (LRP1) is acutely up-regulated in SCs in response to injury, activating c-Jun, and promoting SC survival. To identify novel LRP1 ligands released in PNS injury, we applied a discovery-based approach in which extracellular proteins in the injured nerve were captured using Fc-fusion proteins containing the ligand-binding motifs of LRP1 (CCR2 and CCR4). An intracellular neuron-specific protein, Protein Kinase C and Casein Kinase Substrate in Neurons (PACSIN1) was identified and validated as an LRP1 ligand. Recombinant PACSIN1 activated c-Jun and ERK1/2 in cultured SCs. Silencing Lrp1 or inhibiting the LRP1 cell-signaling co-receptor, the NMDA-R, blocked the effects of PACSIN1 on c-Jun and ERK1/2 phosphorylation. Intraneural injection of PACSIN1 into crush-injured sciatic nerves activated c-Jun in wild-type mice, but not in mice in which Lrp1 is conditionally deleted in SCs. Transcriptome profiling of SCs revealed that PACSIN1 mediates gene expression events consistent with transformation to the repair phenotype. PACSIN1 promoted SC migration and viability following the TNFα challenge. When Src family kinases were pharmacologically inhibited or the receptor tyrosine kinase, TrkC, was genetically silenced or pharmacologically inhibited, PACSIN1 failed to induce cell signaling and prevent SC death. Collectively, these studies demonstrate that PACSIN1 is a novel axon-derived LRP1 ligand that activates SC repair signaling by transactivating TrkC., (© 2024 The Authors. GLIA published by Wiley Periodicals LLC.)

Purpose: The present study sets out to investigate the effect of cyclopentolate-induced cycloplegia on distance and near deviation and the accommodative convergence/accommodation (AC/A) ratio., Methods: This prospective study was performed on 30 subjects. The inclusion criteria included a lack of any active ocular pathology and systemic diseases, no history of ocular surgery, and nonuse of various medications. Refraction, near and distance deviation were measured for all subjects, and the same examinations were repeated after the administration of two drops of cyclopentolate 1% to both eyes., Results: The obtained data from 30 subjects, including 19 males, with a mean age of 22.53 ± 1.74 years were analyzed. The mean ± SD of near deviation in dry and cycloplegic conditions were -6.9 ± 8.1 and +6.4 ± 9.1 prism diopters, respectively, which were statistically significant ( P < 0.001). Distance deviation in cycloplegic conditions demonstrated an average difference of 0.8 prism diopters, compared to dry conditions ( P < 0.001). AC/A ratios were 4.7 ± 2.5 and 9.7 ± 3.9 (Δ/D) in non-cycloplegic and cycloplegic conditions, respectively, which was a statistically significant difference ( P < 0.001). The multiple regression indicated that among all under study variables, refraction (B coefficient: -2.4; P < 0.001) and near pre-cycloplegic deviation (B coefficient: 0.56; P < 0.001) were significantly associated with post-cycloplegic near deviation., Conclusion: The results of this study indicated that cycloplegia causes a considerable esophoric shift in near deviation and a negligible esophoric shift in distance deviation. As a result, the AC/A ratio demonstrated a significant increase due to unequal changes in near and distance deviation., Competing Interests: None., (Copyright © 2024 Asharlous et al.)

Background: Vaccination is a primary prevention approach to preventing disease by disconnecting the transmission chain. The current study utilized a BASNEF model framework to identify factors influencing subsequent doses of COVID-19 vaccination among older adults., Methods: This cross-sectional study was performed in the west of Iran in May 2022. The participants were selected via multi-stage sampling. Finally, 1120 participants contributed to the present study. The questionnaire consisted of three sections: a) Socio-demographic characteristics, b) cognitive impairments tests, and c) Questionnaire about the subsequent dose of COVID-19 vaccine uptake based on the BASNEF model. Data were analyzed using the software IBM AMOS-20 and SPSS-23 via one-way analysis of variance (ANOVA) and independent sample T-tests were used, too. The significance level of statistical tests was regarded as less than 0.05., Results: The presented results of analyzing 50% of the variance of vaccination intention as the dependent variable (R square = 0.497) and 10% of the behavior variance as the dependent variable (R square = 0.104) can be explained based on the BASNEF model. The enabling factors (β = 0.636, p < 0.001) and the intention (β = 0.322, p < 0.001) were important factors for subsequent doses of COVID-19 vaccine uptake in older adults., Conclusion: So, planning and implementing promotional intervention programs for older people (over 65; 80), females, illiterate, widows and divorced, good economic status, and urban areas is essential. It seems that enabling factors such as free vaccinations, vaccination inaccessible places such as public social security agencies, social supports such as involvement of the government and physicians, and improving information by the medium or knowledge-sharing experience, which can be further used to enhance the acceptance of subsequent doses of COVID-19 uptake in older adults., (© 2023. The Author(s).)

Objectives: The present study was conducted to examine the relationship between smartphone dependency and its effect on clinical tasks of nurses in educational and medical centers of Hamadan, in western Iran., Method: In this cross-sectional study, 248 nurses were selected via the proportional allocation sampling method. The required data were collected using a self-report, reliable and validated questionnaire, covering patterns of smartphone use, smartphone dependency, effects of smartphone dependency, and influence of smartphone on the clinical performance of nurses. The collected data were analyzed through descriptive statistics and logistic regression analysis., Results: The average age of the participants was 30.43 (± 5.68) years. The average smartphone dependency, effects of smartphone dependency, and clinical performance of the examined nurses were, respectively, 38.65 (20.93), 20.78 (13.90), and 29.48 (10.03). Clinical performance of nurses decreased with age ( P = 0.02) and increase of smartphone dependency ( P = 0.02), effects of smartphone dependency ( P ≤ 0.001), and smartphone use while working ( P ≤ 0.001). Higher work experience ( P = 0.02) and the application of smartphone multiple capabilities ( P = 0.02) had positive effects on the clinical performance of the examined nurses., Conclusions: The results of this study indicated that using smartphones affects the clinical performance of nurses, and if not well managed, it can lead to some physical, psychological, and social problems for the individual nurse, patients, and society. Thus, training nurses and developing regulations for the use of smartphones in the workplace must be considered by the relevant authorities., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Indian Journal of Occupational and Environmental Medicine.)

Researchers have tried to find novel strategies for cancer treatment in the past decades. Among the utilized methods, administering oncolytic viruses (OVs) alone or combined with other anticancer therapeutic approaches has had promising outcomes, especially in solid tumors. Infecting the tumor cells by these viruses can lead to direct lysis or induction of immune responses. However, the immunosuppressive tumor microenvironment (TME) is considered a significant challenge for oncolytic virotherapy in treating cancer. Based on OV type, hypoxic conditions in the TME can accelerate or repress virus replication. Therefore, genetic manipulation of OVs or other molecular modifications to reduce hypoxia can induce antitumor responses. Moreover, using OVs with tumor lysis capability in the hypoxic TME may be an attractive strategy to overcome the limitations of the therapy. This review summarizes the latest information available in the field of cancer virotherapy and discusses the dual effect of hypoxia on different types of OVs to optimize available related therapeutic methods., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The Arias-Stella reaction is a hormone-related atypical endometrial change characterized by cytomegaly, nuclear enlargement, and hyperchromasia of endometrial glands; typically associated with intrauterine or extrauterine pregnancies or with gestational trophoblastic disease. Although differentiating the Arias-Stella reaction (ASR) from clear cell carcinoma (CCC) of the endometrium is usually straightforward, but differentiating ASR might be difficult if it occurs outside the setting of pregnancy, in extra-uterine sites or in older patients. The aim of this study was to determine whether P504S/Alpha Methyacyl CoA racemase (AMACR) immunohistochemical (IHC) staining can be used to differentiate ASR from CCC., Methods: Fifty endometrial ASR and 57 CCC samples were assessed by IHC staining with antibody for AMACR. The immunoreactive score (IRS) was based on total intensity score (no staining to strong scored as 0-3) + percentage score (0-100% categorized as 0-3) ranged from 0 to 6. Positive expression was considered as a total IRS exceeding 2., Results: The mean age of the patients in the ASR was significantly lower than that of CCC (33.34 ± 6.36 and 57.81 ± 11.64 years old, respectively, p < 0.001). The overall AMACR staining score was significantly higher among CCC compared to ASR groups (p = 0.003). The positive and negative predictive values for AMACR expression in detecting CCC from ASR were 81.1% and 57%, respectively., Conclusion: IHC staining for AMACR can be helpful and a member of discriminatory IHC panel when clinical or histologic features cannot facilitate the differential diagnosis between ASR versus CCC., (© 2023. The Author(s).)

Research Question: What is the effect of vitamin D3 (1,25(OH) 2 D 3 ) on proliferation, cell cycle and apoptosis of endometrial stromal cells (ESC) in endometriotic patients?, Design: ESC isolated from 10 women with endometriosis and 10 healthy controls were treated with 1,25(OH) 2 D 3 . The proliferation of control endometrial stromal cells (CESC), eutopic endometrial stromal cells (EuESC) and ectopic endometrial stromal cells (EESC) was analysed 72 h after the treatment using methyl thiazolyl tetrazolium assay. Propidium iodide staining and flow cytometry were used to determine the cell cycle distribution in ESC. Annexin V/propidium iodide double staining was used to evaluate apoptosis in ESC., Results: In the presence of oestrogen, 1,25(OH) 2 D 3 treatment inhibited the proliferation of ESC from all three origins (P = 0.009 for CESC, P = 0.005 for EuESC and P < 0.001 for EESC). The percentage of S phase cells in EESC was higher than in EuESC and CESC (P = 0.002 and P = 0.001, respectively). The percentage of S phase cells in EuESC was higher than in CESC (P = 0.005). The percentage of G1 phase cells in EESC was lower than that of EuESC and CESC (P = 0.003 and P = 0.002, respectively) and the percentage of G1 phase cells in EuESC was lower than that of CESC (P = 0.007). Moreover, 1,25(OH) 2 D 3 inhibited cell cycle regardless of cell type (P = 0.002 in EESC, P = 0.001 in EuESC and P = 0.014 in CESC), but in the absence of oestrogen, inhibited cell cycle only in EuESC (P = 0.012)., Conclusions: Although 1,25(OH) 2 D 3 increased apoptotic and necrotic cells and decreased live cells in the EuESC and EESC, it did not affect apoptosis in CESC and only increased necrotic cells. These findings indicate that 1,25(OH) 2 D 3 potentially has a growth-inhibiting and pro-apoptotic effect on ESC from endometriotic patients., (Copyright © 2022 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: This study aimed to assess the effect of laser irradiation and Tooth Mousse on tooth hypersensitivity (TH) after office bleaching (OB)., Materials and Methods: This clinical trial, parallel-design split-mouth nonrandomized was conducted on 30 patients requiring OB. After scaling and fabrication of a custom tray, 35% hydrogen peroxide was applied on all teeth, and 940 nm diode laser (10 W, Class IV, 110-240 V) was irradiated to the upper and lower right quadrants. Laser in off mode was used for the left quadrants. Bleaching agent was then reapplied. After completion of bleaching, a custom tray containing tooth Mousse was placed on the maxillary arch while the tray was used without the paste for the mandibular arch. A visual analog scale was used to assess the degree of TH at 15 min and 24 h after OB. Data were compared using t -test, paired t -test, and analysis of variance. Significance level was set at α = 0.05., Results: Comparison of TH at 15 min and 24 h after OB showed a significantly lower TH score in the left upper quadrant (tooth Mousse alone) than right upper quadrant (both laser and Tooth Mousse) ( P < 0.05). The TH score in the right upper quadrant was significantly lower than that in the right lower quadrant (laser only) ( P < 0.05). The mean TH score in the left upper quadrant was insignificantly lower than that in the left lower quadrant (no intervention) ( P > 0.05)., Conclusion: The use of 940 nm diode laser for OB increases the postoperative TH. The application of Tooth Mousse can effectively decrease TH after OB with/without laser irradiation., Competing Interests: The authors of this manuscript declare that they have no conflicts of interest, real or perceived, financial or nonfinancial in this article., (Copyright: © 2023 Dental Research Journal.)

Background: Endothelin-1 (ET-1) is a peptide overexpressed in gastric cancer (GC) and linked to carcinogenesis and resistance to chemotherapy. Applying microRNAs (miRNAs/miRs) to downregulate ET-1 and reverse resistance to commonly used chemotherapy drugs such as 5-fluorouracil (5-FU) is practical., Methods: The current study sought to evaluate the miR-648 expression in GC and any plausibility of its replacement, either with or without the combination of chemo agents to downregulate ET-1 expression through interaction with its target gene. To this end, miR-648 and ET-1 expression levels were assessed in GC tissues and adjacent non-tumor tissues driven from 65 patients who had already undergone surgery, fifteen of which had received 5-FU before surgery. The impact of miR-648 and chemo agents on ET-1 expression was measured using qPCR and Western blotting. Further, an MTT assay was conducted to assess its association with cell viability. Ultimately, the association of miR-648 and ET-1 with clinicopathological characteristics was evaluated., Results: The current study revealed that miR-648 was considerably down-regulated, while ET-1 was substantially up-regulated in patients with GC. The 5-FU caused a significant increase in miR-648 and reduced ET-1 expression. It was also determined that overexpression of miR-648 suppressed ET-1 production, notably when combined with 5-FU, leading to survival reduction. These results further showed that miR-648 replacement could sensitize chemoresistant GC cells. Besides, a significant association between ET-1 and miR-648 with clinicopathological features was discovered CONCLUSIONS: miR-648 replacement may serve as a potential oncosuppressive therapeutic approach that warrants further investigation to translate into an effective GC treatment., Competing Interests: Competing interests None., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Tumor-infiltrating lymphocytes (TILs), frontline soldiers of the adaptive immune system, are recruited into the tumor site to fight against tumors. However, their small number and reduced activity limit their ability to overcome the tumor. Enhancement of TILs number and activity against tumors has been of interest for a long time. A lack of knowledge about the tumor microenvironment (TME) has limited success in primary TIL therapies. Although the advent of engineered T cells has revolutionized the immunotherapy methods of hematologic cancers, the heterogeneity of solid tumors warrants the application of TILs with a wide range of specificity. Recent advances in understanding TME, immune exhaustion, and immune checkpoints have paved the way for TIL therapy regimens. Nowadays, TIL therapy has regained attention as a safe personalized immunotherapy, and currently, several clinical trials are evaluating the efficacy of TIL therapy in patients who have failed conventional immunotherapies. Gaining favorable outcomes following TIL therapy of patients with metastatic melanoma, cervical cancer, ovarian cancer, and breast cancer has raised hope in patients with refractory solid tumors, too. Nevertheless, TIL therapy procedures face several challenges, such as high cost, timely expansion, and technical challenges in selecting and activating the cells. Herein, we reviewed the recent advances in the TIL therapy of solid tumors and discussed the challenges and perspectives., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kazemi, Sadri, Najafi, Rahimi, Baghernejadan, Khorramdelazad and Falak.)

Background: This study aimed to identify the predictors of the intention to receive the COVID-19 vaccine among Iranian health care workers (HCWs) based on the Theory of Planned Behavior (TPB)., Methods: The study was a descriptive cross-sectional study that was conducted on 473 personnel working in hospitals of Hamadan, in May 2021 and before COVID-19 vaccination on hospital staff. The multi-stage sampling method was used for choosing participants. The survey included socio-demographic, questions related to TPB dimensions, and intention to receive a COVID-19 vaccine. Qualitative and quantitative data analyses were performed using the Chi-square test and T-test, respectively. Predictors of COVID-19 vaccination intention were determined using the logistic regression model., Results: Seventy percent of 361 eligible respondents stated their willingness to receive COVID-19 vaccine. The participants with the intention to receive COVID-19 vaccine had higher scores of attitude (7.25 ± 3.92 vs. 4.40 ± 5.14) and norm (3.04 ± 2.92 vs. -0.5 ± 3.18) ( P < 0.001). Having an underlying disease and being married were significantly associated with the intention to receive COVID-19 vaccine ( P < 0.05). Higher attitude and norm scores as a construct of the TPB were associated with an increase in intention to receive COVID-19 vaccine., Conclusions: The results of this study showed that the vaccination intention was affected by social, demographic, health, and behavioral features, such as age, marital status, underlying diseases, subjective norms, and attitude. Therefore, age groups below 50, single people, and those with no underlying diseases were eligible to be the target of interventional programs., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Indian Journal of Occupational and Environmental Medicine.)

Hypoxia is a common characteristic of the tumor microenvironment. In response to hypoxia, expression of the hypoxia-inducible factor (HIF) can lead to activation of downstream molecular events such as epithelial-mesenchymal transition (EMT), invasion, and angiogenesis. In this study, CoCl2 was used to simulate hypoxia in SKBR3 and HEK293T cell lines to investigate whether this treatment can induce hypoxia-associated EMT and invasion in the studied cells. SKBR3 and HEK293T cells were treated with different concentrations of CoCl2 at different exposure times and their viability was analyzed. To confirm successful hypoxia induction, the expression levels of HIF1α and vascular endothelial growth factor A (VEGFA) mRNA were assessed. Additionally, the expression of EMT-associated markers including snail, E-cadherin, N-cadherin, and vimentin, as well as invasion-related genes including matrix metalloproteinase-2 (MMP2) and MMP9 was measured. We found that cell viability in CoCl2-treated cells was concentration-dependent and was not affected at low doses. While the expression of HIF and VEGFA genes was upregulated following hypoxia induction. E-cadherin expression was significantly downregulated in HEK293T cells; while, N-cadherin and snail were upregulated in both cell lines. Moreover, an increment of MMP expression was only observed in SKBR3 cells. Taken together, the findings indicated that CoCl2 can mimic hypoxia in both cell lines, but EMT was triggered in SKBR3 cells more effectively than in HEK293T cells, and invasion was only stimulated in SKBR3 cells. In conclusion, SKBR3 cancer cells can be used as an EMT model to better understand its control and manipulation mechanisms and to investigate new therapeutic targets for the suppression of tumor metastasis.

Objective: The goal of treatment in palindromic rheumatism (PR) is to control the attacks and prevent disease evolution to chronic arthritis. Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) including antimalarial and methotrexate cannot control attacks in all patients., Methods: In this retrospective study, we assessed the efficacy of leflunomide in patients with PR who had an inadequate response to DMARDs. In this study, patients who had a diagnosis of PR and were treated with leflunomide because of active disease despite treatment with csDMARDs for at least 6 months were included. Remission was defined as no attacks for 3 months and prednisolone dose ≤5 mg/d. Leflunomide treatment failure was defined as failure to achieve remission, the need to add other DMARDs for controlling attacks and disease progression to chronic arthritis during treatment with leflunomide., Results: Ten cases with active disease despite treatment with hydroxychloroquine and methotrexate and low-dose prednisolone treated with leflunomide were included in the study. During the 12.6 ± 7.5 months of treatment with leflunomide, the frequency of attacks significantly decreased. Complete and partial remission were achieved in 90% of patients., Conclusion: Our results indicate that leflunomide controls PR attacks and it might be a new option for patients with PR., (© 2022 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Holocarboxylase synthetase (HLCS) catalyzes the biotinylation of five distinct biotin-dependent carboxylases and perhaps chromatin proteins. HLCS deficiency causes multiple carboxylase deficiency which results in fatal consequences unless patients are diagnosed early and treated with pharmacological doses of biotin. The objective of this study was to develop an HLCS conditional knockout (KO) mouse and assess effects of HLCS knockout on embryo survival. In the mouse, exon 8 is flanked by LoxP sites, thereby removing a catalytically important region upon recombination by Cre. HLCS conditional KO mice were backcrossed for 14 generations with C57BL/6J mice to yield Hlcstm1Jze. Fertility and weight gain were normal and no frank disease phenotypes and abnormal feeding behavior were observed in the absence of Cre. HLCS knockout was embryonic lethal when dams homozygous for both the floxed Hlcs gene and tamoxifen-inducible Cre recombinase (denoted Hlcstm1.1Jze) were injected with tamoxifen on gestational days 2.5 and 10.5. This is the first report of an HLCS conditional KO mouse, which enables studies of the roles of HLCS and biotin in intermediary metabolism., Competing Interests: The authors have declared that no competing interests exist. J.Z. serves as consultant for PureTech Health, Inc. (Boston, MA) for work not related to this paper.

Schwann cells (SCs) are known to produce extracellular vesicles (EV) that participate in cell-cell communication by transferring cargo to target cells, including mRNAs, microRNAs, and biologically active proteins. Herein, we report a novel mechanism whereby SC EVs may regulate PNS physiology, especially in injury, by controlling the activity of TNFα. SCs actively sequester tumor necrosis factor receptor-1 (TNFR1) into EVs at high density, accounting for about 2% of the total protein in SC EVs (~1000 copies TNFR1/EV). Although TNFR2 was robustly expressed by SCs in culture, TNFR2 was excluded from SC EVs. SC EV TNFR1 bound TNFα, decreasing the concentration of free TNFα available to bind to cells and thus served as a TNFα decoy. SC EV TNFR1 significantly inhibited TNFα-induced p38 MAPK phosphorylation in cultured SCs. When TNFR1 was proteolytically removed from SC EVs using tumor necrosis factor-α converting enzyme (TACE) or neutralized with antibody, the ability of TNFα to activate p38 MAPK in the presence of these EVs was restored. As further evidence of its decoy activity, SC EV TNFR1 modified TNFα activities in vitro including: (1) regulation of expression of other cytokines; (2) effects on SC morphology; and (3) effects on SC viability. SC EVs also modified the effects of TNFα on sciatic nerve morphology and neuropathic pain-related behavior in vivo. By sequestering TNFR1 in EVs, SCs may buffer against the potentially toxic effects of TNFα. SC EVs provide a novel mechanism for the spatial and temporal regulation of neuro-inflammation., (© 2021 Wiley Periodicals LLC.)

The COVID-19 pandemic has accelerated neurological, mental health disorders, and neurocognitive issues. However, there is a lack of inexpensive and efficient brain evaluation and screening systems. As a result, a considerable fraction of patients with neurocognitive or psychobehavioral predicaments either do not get timely diagnosed or fail to receive personalized treatment plans. This is especially true in the elderly populations, wherein only 16% of seniors say they receive regular cognitive evaluations. Therefore, there is a great need for development of an optimized clinical brain screening workflow methodology like what is already in existence for prostate and breast exams. Such a methodology should be designed to facilitate objective early detection and cost-effective treatment of such disorders. In this paper we have reviewed the existing clinical protocols, recent technological advances and suggested reliable clinical workflows for brain screening. Such protocols range from questionnaires and smartphone apps to multi-modality brain mapping and advanced imaging where applicable. To that end, the Society for Brain Mapping and Therapeutics (SBMT) proposes the Brain, Spine and Mental Health Screening (NEUROSCREEN) as a multi-faceted approach. Beside other assessment tools, NEUROSCREEN employs smartphone guided cognitive assessments and quantitative electroencephalography (qEEG) as well as potential genetic testing for cognitive decline risk as inexpensive and effective screening tools to facilitate objective diagnosis, monitor disease progression, and guide personalized treatment interventions. Operationalizing NEUROSCREEN is expected to result in reduced healthcare costs and improving quality of life at national and later, global scales.

Endometriosis is a chronic inflammatory disease that has been reported to be associated with immune system dysfunction. On the other hand, the effect of Vitamin D as an immune modulator and its relation with several autoimmune and inflammatory diseases has been previously investigated. Moreover, several studies have reported the polymorphisms of VDR and VDBP genes can change the functions of these molecules. Therefore, these polymorphisms may be influential on endometriosis pathogenesis. In this study, we aimed at evaluating the association between VDR gene (FokI (F/f), BsmI (B/b), ApaI (A/a), TaqI (T/t)), and VDBP gene (GC*1S, GC*1F, and GC*2) polymorphisms with endometriosis in Iranian women population. This case-control study was performed on 120 women with endometriosis and 110 healthy women. ARMS-PCR and PCR-RFLP methods were used to inspect polymorphisms in VDR and VDBP genes, respectively. Based on the results, there was no statistically significant difference between the cases with endometriosis and control subjects in terms of genotypes and allele frequencies of VDR and VDBP gene polymorphisms. These data suggest that VDR and VDBP gene polymorphisms may have no role in endometriosis susceptibility in Iranian women., (© 2021. Society for Reproductive Investigation.)