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BackgroundIf there are people who do not want to use the internet despite having the circumstances and conditions for using it, another policy consideration will be needed. ObjectiveThe purpose of this study was to explore the factors related to the behavior of people who do not voluntarily use the internet. MethodsA cross-sectional survey was conducted in 2018. It used a proportional quota random sampling design to select a representative sample of Koreans. Accordingly, 6150 participants were included in the study. Multiple logistic regression methods were used to explore the predicting factors of the act of voluntarily not using the internet. ResultsAge, education level, bonding and bridging social capitals, and daily life satisfaction for health status were found to be factors related to the behavior of not voluntarily using the internet. However, gender, household income, occupation, family size, and community type were not related to voluntary nonuse of the internet. ConclusionsIt was found that sociodemographic factors, such as age and education level, which are difficult to modify, along with psychosocial factors located deeper than the visible living conditions, such as social capital and life satisfaction, are involved in voluntary internet nonuse. These results also suggest that it is not desirable to proceed with policies related to information and communications technology on a separate track, but rather that they should be comprehensively approached with other social policies that design various social interventions in order to enhance equity within the society.

BackgroundThe fact that patient satisfaction with primary care clinical practices and physician-patient communications has decreased gradually has brought a new opportunity to the online channel as a supplementary service to provide additional information. ObjectiveIn this study, our objectives were to examine the process of cognitive knowledge expectation-confirmation from eHealth users and to recommend the attributes of a “knowledge-intensive website.”. Knowledge expectation can be defined as users’ existing attitudes or beliefs regarding expected levels of knowledge they may gain by accessing the website. Knowledge confirmation is the extent to which user’s knowledge expectation of information systems use is realized during actual use. In our hypothesized research model, perceived information quality, presentation and attractiveness as well as knowledge expectation influence knowledge confirmation, which in turn influences perceived usefulness and end user satisfaction, which feeds back to knowledge expectation. MethodsAn empirical study was conducted at the National Cancer Center (NCC), Republic of Korea (South Korea), by evaluating its official website. A user survey was administered containing items to measure subjectively perceived website quality and expectation-confirmation attributes. A study sample of 198 usable responses was used for further analysis. We used the structural equation model to test the proposed research model. ResultsKnowledge expectation exhibited a positive effect on knowledge confirmation (beta = .27, P < .001). The paths from information quality, information presentation, and website attractiveness to knowledge confirmation were also positive and significant (beta = .24, P < .001; beta = .29, P < .001; beta = .18, P < .001, respectively). Moreover, the effect of knowledge confirmation on perceived usefulness was also positively significant (beta = .64, P < .001). Knowledge expectation together with knowledge confirmation and perceived usefulness also significantly affected end user satisfaction (beta = .22 P < .001; beta = .39, P < .001; beta = .25, P < .001, respectively). ConclusionsTheoretically, this study has (1) identified knowledge-intensive website attributes, (2) enhanced the theoretical foundation of eHealth from the information systems (IS) perspective by adopting the expectation-confirmation theory (ECT), and (3) examined the importance of information and knowledge attributes and explained their impact on user satisfaction. Practically, our empirical results suggest that perceived website quality (ie, information quality, information presentation, and website attractiveness) is a core requirement for knowledge building. In addition, our study has also shown that knowledge confirmation has a greater effect on satisfaction than both knowledge expectation and perceived usefulness.

Clinical Implications: Cough reflex hypersensitivity is increasingly recognized as a key treatable trait, and the Cough Hypersensitivity Questionnaire may serve as a reliable and responsive tool for measuring hypersensitivity symptoms in patients with chronic cough., (Copyright © 2025. Published by Elsevier Inc.)

Background: Suicide rates have significantly increased in South Korea, yet many individuals lack adequate support. Barriers such as reluctance to seek mental health help and fear of social stigma contribute to this gap. A mobile app focused on suicide risk awareness could provide accessible support, though none are currently available for public use in South Korea. This study conducted a usability test on a newly developed suicide risk awareness app using a mixed methods approach., Methods: Thirty-eight students from a large university in South Korea participated in the study, with 19 in a high-risk suicide group and 19 in a nonrisk suicide group. After using the app for 2 weeks, all participants completed an online usability survey, and 19 students took part in individual interviews., Results: Independent samples t-tests showed that participants, regardless of risk group, rated the app positively for ease of use, accessibility, design, perceived learning, and satisfaction. Regression analysis identified perceived learning as the strongest predictor of satisfaction, followed by ease of use. The qualitative analysis highlighted areas for improvement, including providing direct and guided feedback on suicide risk., Conclusion: The study demonstrated the potential of a mobile app to enhance suicide risk awareness among young adults in South Korea. Moreover, user engagement with the app can be improved by ensuring confidentiality and fostering perceived learning., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2025.)

Lipid emulsion has recently emerged as an effective agent for improving the cardiotoxicity of highly lipophilic drugs. However, its effect on cardiotoxicity induced by labetalol, a nonselective beta-blocker, remains unknown. In this study, we investigated the effects of lipid emulsion on the cardiotoxicity of labetalol in rat cardiomyoblasts and tried to decipher the underlying mechanisms. The effects of lipid emulsion on labetalol-induced changes in cell viability, expression of Bax/Bcl-2, cleaved caspase-3, and cleaved caspase-9, and phosphorylation of GSK-3β, Akt, and PI3K were examined. Lipid emulsion inhibited labetalol-induced decrease in cell viability, whereas LY294002, MK2206, and SB216763, the inhibitors of phosphoinositide 3-kinase (PI3K), Akt, glycogen synthase kinase-3β (GSK-3β), respectively, partially attenuated this restoration of cell viability. Lipid emulsion reversed the increase in expression of cleaved caspase-3, cleaved caspase-9, and Bax/Bcl-2 and decrease in the phosphorylation of GSK-3β, Akt, and PI3K by labetalol. Lipid emulsion and cyclosporin, a mitochondrial permeability transition pore (MPTP) inhibitor, reduced the labetalol-induced increase in the number of TUNEL-positive cells and promoted late-stage apoptosis. Overall, lipid emulsion inhibited apoptotic cell death caused by labetalol toxicity via the inhibition of intrinsic apoptotic pathway and MPTP in rat cardiomyoblasts, which appears to involve PI3K, Akt, and GSK-3β signaling pathways.

Cardiovascular disease is the leading cause of maternal mortality in the United States. Pregnancy is associated with increased risk of acute myocardial infarction (AMI) and outcomes of pregnancy-associated AMI (PAMI) are poor. Spontaneous coronary artery dissection is the most common cause of PAMI. Pregnancy is not a contraindication to invasive coronary angiography or percutaneous coronary intervention (PCI) when indicated. When coronary angiography or PCI is needed, measures should be taken to minimize procedural and anesthetic risks specific to pregnancy. Multidisciplinary collaboration is imperative to optimizing maternal and fetal outcomes associated with PAMI., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: This study aims to evaluate the readability, quality, and reliability of online resources about peripheral nerve surgeries to determine if they meet recommended literacy standards., Methods: We analyzed a total of 137 peripheral nerve surgery website by performing a Google search using the search terms "nerve transfer," "nerve repair," "nerve graft," "nerve decompression," "neurolysis," "targeted muscle reinnervation," "regenerative peripheral nerve interface," and "vascularized denervated muscle target." The reading level of the website text was assessed using Simple Measures of Gobbledygook, Flesch-Kincaid, and Gunning Fog. Quality was evaluated using the DISCERN Instrument. Reliability was determined using the Journal of American Medical Association Benchmark Criteria., Results: All the websites exceeded the sixth-grade reading level, with median readability scores corresponding to a high school reading level or above. Conceptually harder peripheral nerve surgeries such as targeted muscle reinnervation and regenerative peripheral nerve interface websites were generally written at a significantly higher reading level than conceptually easier surgeries such as nerve repair and nerve graft. The median quality of the websites was rated as poor, and the median reliability of the websites was rated as low., Conclusions: The findings indicate that the current peripheral nerve surgery websites texts do not adhere to recommended reading levels and are constructed with poor quality and low reliability. This potentially hinders patients understanding and utilization of peripheral nerve surgeries, suggesting a need for standardized guidelines to enhance the accessibility of medical information online., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Liver diseases are one of the leading causes of morbidity and mortality worldwide. Globally, liver diseases are responsible for approximately 2 million deaths annually (1 of every 25 deaths). Many of the patients with chronic liver diseases can benefit from organ transplantation. However, stringent criteria for placement on organ transplantation waitlist and chronic shortage of organs preclude access to patients. To bridge the shortfall, generation of chimeric human organs in pigs has long been considered as an alternative. Here, we report feasibility of the approach by generating chimeric livers in pigs using a conditional blastocyst complementation approach that creates a vacant niche in chimeric hosts, enabling the initiation of organogenesis through donor-derived pluripotent cells. Porcine fetal fibroblasts were sequentially targeted for knockin of CRE into the endogenous FOXA3 locus (FOXA3 CRE ) followed by floxing of exon 1 of HHEX (FOXA3 CRE HHEX loxP/loxP ) locus. The conditional HHEX knockout and constitutive GFP donor (COL1A CAG:LACZ 2A EGFP ) were used as nuclear donors to generate host embryos by somatic cell nuclear transfer, and complemented and transferred into estrus synchronized surrogates. In the resulting fetuses, donor EGFP blastomeres reconstituted hepatocytes as confirmed by immunohistochemistry. These results potentially pave the way for exogenous donor-derived hepatogenesis in large animal models., (© 2024 Federation of American Societies for Experimental Biology.)

Purpose: Severe postoperative edema after eyelid surgery can have negative clinical and psychological effects. In this study, the authors investigated whether surgical factors, including surgical techniques and suture type, were associated with clinically significant eyelid edema (CSEE)., Methods: A chart review was performed on 269 patients who underwent upper eyelid blepharoplasty with or without external levator advancement by 2 surgeons at a single institution between January 2021 and December 2022. Postoperative photos were graded by 2 physicians for eyelid edema using a standardized grading scale ranging from 0 (no edema) to 3 (severe edema). CSEE was defined either as having a grade of 3 at any point postoperatively or any grade that was 1 or greater after 90 days postoperatively. Logistic regression controlling for race was used for analysis; the statistical significance level was defined as p < 0.05., Results: Of 269 patients, 56 developed CSEE. Of those who underwent blepharoplasty with mini crease enhancement (closure with every other bite incorporating levator aponeurosis), 40.5% developed CSEE versus 12.5% of those without ( p < 0.001). Patients with lid crease formation using buried interrupted sutures had greater CSEE than those with externalized interrupted sutures removed at 1 week (43.8% versus 11.5%, p < 0.01). There was no increased risk of CSEE with additional procedures performed versus blepharoplasty alone., Conclusions: Patients who underwent blepharoplasty with mini crease enhancement, where more than 4 sutures are placed from skin to levator, and/or had buried suture lid crease formation had greater rates of CSEE., Competing Interests: The authors have no financial or conflicts of interest to disclose., (Copyright © 2024 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Background: Epinephrine (EPI) or norepinephrine (NOR) is widely used to treat cardiovascular collapse during lipid emulsion (LE) resuscitation for drug toxicity. However, the effect of LE on the vasoconstriction caused by EPI or NOR remains unknown. The purpose of this study was to examine the effect of an LE (Intralipid) on the vasoconstriction caused by EPI and NOR in isolated rat aorta., Methods: The effect of LE on the vasoconstriction caused by EPI or NOR in isolated rat aorta was examined. Additionally, the effect of LE on the calcium increase caused by EPI or NOR was investigated. The distribution constant (KD: lipid to aqueous phase) of EPI or NOR between a LE (1%) and an aqueous phase was determined., Results: LE (1 and 2%) did not significantly alter vasoconstriction caused by EPI or NOR in isolated endothelium-intact aorta. Moreover, the LE did not significantly alter the increased calcium level caused by EPI or NOR. The log KD of EPI in the LE (1%) was -0.71, -0.99, and -1.00 at 20, 50, and 100 mM ionic strength, respectively. The log KD of NOR in the LE (1%) was -1.22, -1.25, and -0.96 at 20, 50, and 100 mM ionic strength, respectively., Conclusions: Taken together, the Intralipid emulsion did not alter vasoconstriction induced by EPI or NOR that seems to be due to the hydrophilicity of EPI or NOR, leading to sustained hemodynamic support produced by EPI or NOR used during LE resuscitation.

Lipid emulsions are used as adjuvant drugs to alleviate intractable cardiovascular collapse induced by drug toxicity. We aimed to examine the effect of lipid emulsions on labetalol-induced vasodilation and the underlying mechanism in the isolated rat aorta. We studied the effects of endothelial denudation, N W -nitro-l-arginine methyl ester (l-NAME), calmidazolium, methylene blue, 1 H -[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one (ODQ), and lipid emulsions on labetalol-induced vasodilation. We also evaluated the effects of lipid emulsions on cyclic guanosine monophosphate (cGMP) formation, endothelial nitric oxide synthase (eNOS) phosphorylation, and endothelial calcium levels induced by labetalol. Labetalol-induced vasodilation was higher in endothelium-intact aortas than that in endothelium-denuded aortas. l-NAME, calmidazolium, methylene blue, and ODQ inhibited labetalol-induced vasodilation in endothelium-intact aortas. Lipid emulsions inhibited labetalol-induced vasodilation in endothelium-intact and endothelium-denuded aortas. l-NAME, ODQ, and lipid emulsions inhibited labetalol-induced cGMP formation in endothelium-intact aortas. Lipid emulsions reversed the stimulatory and inhibitory eNOS (Ser1177 and Thr495) phosphorylation induced by labetalol in human umbilical vein endothelial cells and inhibited the labetalol-induced endothelial calcium increase. Moreover, it decreased labetalol concentration. These results suggest that lipid emulsions inhibit vasodilation induced by toxic doses of labetalol, which is mediated by the inhibition of endothelial nitric oxide release and reduction of labetalol concentration.

This study aimed to investigate the effects of high-dose inhaled corticosteroids (ICS) on chronic cough patients with elevated fractional exhaled nitric oxide (FeNO) levels. In a prospective study, adults with chronic cough and FeNO ≥ 25 ppb, without any other apparent etiology, received fluticasone furoate (200 mcg) for three weeks. Outcomes were evaluated using FeNO levels, cough severity, and Leicester Cough Questionnaire (LCQ) before and after treatment. Of the fifty participants (average age: 58.4 years; 58% female), the treatment responder rate (≥ 1.3-point increase in LCQ) was 68%, with a significant improvement in cough and LCQ scores and FeNO levels post-treatment. However, improvements in cough did not significantly correlate with changes in FeNO levels. These findings support the guideline recommendations for a short-term ICS trial in adults with chronic cough and elevated FeNO levels, but the lack of correlations between FeNO levels and cough raises questions about their direct mechanistic link., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Vasoconstriction induced by levobupivacaine, a local anesthetic, is mediated by increased levels of calcium, tyrosine kinase, c-Jun NH 2 -terminal kinase (JNK), and phospholipase D, which are associated with prolonged local anesthesia. Epidermal growth factor receptor (EGFR) phosphorylation is associated with vasoconstriction. However, its role in levobupivacaine-induced contractions remains unknown. We determined whether EGFR phosphorylation is associated with levobupivacaine-induced contractions in isolated rat thoracic aortas and identified the underlying cellular signaling pathways. The effects of various inhibitors and a calcium-free solution alone or in combination on levobupivacaine-induced contractions were then assessed. Furthermore, we examined the effects of various inhibitors on levobupivacaine-induced EGFR and JNK phosphorylation and calcium levels in vascular smooth muscle cells (VSMCs) of rat aortas. The EGFR tyrosine kinase inhibitor AG1478, matrix metalloproteinase (MMP) inhibitor GM6001, Src kinase inhibitors PP1 and PP2, and JNK inhibitor SP600125 attenuated levobupivacaine-induced contractions. Moreover, although the calcium-free solution abolished levobupivacaine-induced contractions, calcium reversed this inhibitory effect. The magnitude of the calcium-mediated reversal of abolished levobupivacaine-induced contractions was lower in the combination treatment with calcium-free solution and AG1478 than in the treatment with calcium-free solution alone. Levobupivacaine induced EGFR and JNK phosphorylation. However, AG1478, GM6001, and PP2 attenuated levobupivacaine-induced EGFR and JNK phosphorylation. Moreover, although levobupivacaine induced JNK phosphorylation in control siRNA-transfected VSMCs, EGFR siRNA inhibited levobupivacaine-induced JNK phosphorylation. Furthermore, AG1478 inhibited levobupivacaine-induced calcium increases in VSMCs. Collectively, these findings suggest that levobupivacaine-induced EGFR phosphorylation, which may occur via the Src kinase-MMP pathway, contributes to vasoconstriction via JNK phosphorylation and increased calcium levels., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Dexmedetomidine is widely used to induce sedation in the perioperative period. This study examined the effect of hypothermia (33 and 25 °C) on dexmedetomidine-induced contraction in an endothelium-intact aorta with or without the nitric oxide synthase inhibitor N W -nitro-L-arginine methyl ester (L-NAME). In addition, the effect of hypothermia on the contraction induced by dexmedetomidine in an endothelium-denuded aorta with or without a calcium-free Krebs solution was examined. The effects of hypothermia on the protein kinase C (PKC), myosin light chain (MLC 20 ) phosphorylation, and Rho-kinase membrane translocation induced by dexmedetomidine were examined. Hypothermia inhibited dexmedetomidine-induced contraction in the endothelium-intact aorta with L-NAME or endothelium-denuded aorta. Hypothermia had almost no effect on the dexmedetomidine-induced contraction in the endothelium-denuded aorta with the calcium-free Krebs solution; however, the subsequent contraction induced by the addition of calcium was inhibited by hypothermia. Conversely, the transition from profound hypothermia back to normothermia reversed the hypothermia-induced inhibition of subsequent calcium-induced contractions. Hypothermia inhibited any contraction induced by KCl, PDBu, and NaF, as well as PKC and MLC 20 phosphorylation and Rho-kinase membrane translocation induced by dexmedetomidine. These results suggest that hypothermia inhibits dexmedetomidine-induced contraction, which is mediated mainly by the impediment of calcium influx and partially by the attenuation of pathways involving PKC and Rho-kinase activation.

Background  Increasing concerns regarding the safety of textured surface implants have resulted in surgeons transitioning from textured tissue expanders (TEs) to smooth TEs. Given this change has only recently occurred, this study evaluated outcomes between smooth and textured TEs. Methods  Women who underwent two-stage breast reconstruction using TEs from 2013 to 2022 were included. TE-specific variables, perioperative information, pain scores, and complications were collected. Chi-squared, t -test, and linear regression analyses were performed. Results  A total of 320 patients received a total of 384 textured and 152 smooth TEs. Note that 216 patients received bilateral reconstruction. TEs were removed in 9 cases. No significant differences existed between groups regarding comorbidities. Smooth TEs had a higher proportion of prepectoral placement ( p  < 0.001). Smooth TEs had less fills (3 ± 1 vs. 4 ± 2, p  < 0.001), shorter expansion periods (60 ± 44 vs. 90 ± 77 days, p  < 0.001), smaller expander fill volumes (390 ± 168 vs. 478 ± 177 mL, p  < 0.001), and shorter time to exchange (80 ± 43 vs. 104 ± 39 days, p  < 0.001). Complication rates between textured and smooth TEs were comparable. Smooth TE had a greater proportion of TE replacements ( p  = 0.030). On regression analysis, pain scores were more closely associated with age ( p  = 0.018) and TE texture ( p  = 0.046). Additional procedures at time of TE exchange ( p  < 0.001) and textured TE ( p  = 0.017) led to longer operative times. Conclusion  As many surgeons have transitioned away from textured implants, our study shows that smooth TEs have similar outcomes to the textured alternatives., Competing Interests: Conflict of Interest M.A. receives funding from CTSA Grant Number KL2 TR001862 from the National Center for Advancing Translational Science (NCATS), a component of the National Institutes of Health (NIH) and consults for Johnson & Johnson and LifeNet Health. The manuscript contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Introduction: Point-of-care ultrasound is becoming increasingly popular, and we sought to examine its role in evaluating ocular and periocular structures and facial vasculature. With the large number of point-of-care ultrasound devices available, it is difficult to determine which devices may be best suited for ophthalmic and facial aesthetic applications. This study compares five popular handheld point-of-care ultrasound devices to help guide clinicians in choosing the device best suited for their needs., Methods: We compared five point-of-care ultrasound devices: Butterfly IQ+ (Butterfly, Burlington, MA), L15 (Clarius Mobile Health, Vancouver, British Columbia, Canada), L20 (Clarius Mobile Health, Vancouver, British Columbia, Canada), Lumify (Philips, Amsterdam, Netherlands) and Vscan Air (GE, Boston, MA). Three ophthalmologists obtained the following views on three volunteers: eight arteries, four ocular and periocular structures and areas of filler injections. The image quality of each view was graded on a four-point Likert-type scale. In addition, graders filled out a survey. The data were analysed using analysis of variance tests with the significance level set to p  < 0.05., Results: In terms of overall image quality, the L20 received the highest mean rating, followed by the L15, Vscan Air, Butterfly IQ+ and the Lumify ( p  < 0.05). With further stratification for structure type, the L20 was ranked first for filler, artery and orbital imaging ( p  < 0.05)., Conclusions: The L20 received the highest image quality rankings. While image quality is an important aspect of point-of-care ultrasound device selection, other factors such as cost, wireless capabilities, range of presets and battery life should also be considered., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Disease resistance genes in livestock provide health benefits to animals and opportunities for farmers to meet the growing demand for affordable, high-quality protein. Previously, researchers used gene editing to modify the porcine CD163 gene and demonstrated resistance to a harmful virus that causes porcine reproductive and respiratory syndrome (PRRS). To maximize potential benefits, this disease resistance trait needs to be present in commercially relevant breeding populations for multiplication and distribution of pigs. Toward this goal, a first-of-its-kind, scaled gene editing program was established to introduce a single modified CD163 allele into four genetically diverse, elite porcine lines. This effort produced healthy pigs that resisted PRRS virus infection as determined by macrophage and animal challenges. This founder population will be used for additional disease and trait testing, multiplication, and commercial distribution upon regulatory approval. Applying CRISPR-Cas to eliminate a viral disease represents a major step toward improving animal health.

Background: One benefit of hyaluronic acid fillers is the ability to dissolve them using hyaluronidase. With the increasing number of fillers entering the market, it is crucial to understand each of these fillers' responsiveness to hyaluronidase., Methods: Twenty-one hyaluronic acid fillers of 0.2 mL aliquots each were placed on slides. Twenty units of recombinant human hyaluronidase were injected into the aliquots every 30 minutes for a total of 120 units recombinant human hyaluronidase injected over 3 hours. With each injection, videos and photographs were taken from bird's eye and lateral views to measure aliquot height. Stirring videos were graded by three oculoplastic surgeons, and these grades were used to categorize each filler's responsiveness., Results: Restylane Lyft, Restylane-L/Eyelight, and Resilient Hyaluronic Acid (RHA) 1/Redensity were the least resistant. The moderately resistant group comprised of Restylane Silk, Juvéderm Volbella, Revanesse Versa/Lips, and Belotero Balance on the less resistant side to Juvéderm Vollure, RHA 2, Restylane Contour, Juvéderm Ultra, Restylane Refyne, Belotero Intense, Restylane Kysse, RHA 3, Juvéderm Ultra Plus, and Restylane Defyne on the more resistant side. The most resistant were RHA 4, Juvéderm Voluma, Belotero Volume, and Juvéderm Volux. The most resistant fillers required 120 units of hyaluronidase per 0.2 mL filler to dissolve., Conclusions: With the increasing popularity of fillers comes the increasing need to dissolve them for both ischemic and nonischemic complications. The majority of hyaluronic acid fillers available on the market are very resistant to hyaluronidase, which must be considered when determining the amount of hyaluronidase to dissolve a particular filler., Competing Interests: Dr. Woodward: Allergan (speaker and consultant), Galderma (speaker and consultant), Prollenium (speaker and consultant), Merz (speaker and consultant), SkinCenticals (consultant). Dr. Lee: Allergan, Galderma, Revance, Evolus, RoC, Tarsus, RVL, Horizon, NovaBay. Dr. Kherani: Abbvie, Horizon, Santen, SunPharma, Tarsus. Dr. Foster: Horizon, Tarsus. Dr. Zhang-Nunes: Horizon Therapeutics, Tarsus Pharmaceuticals, Bruder, Sciton. Drs. Park and Mehta have nothing to disclose., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Our primary objective is to verify or refute a 2013 study by Connolly et al. which showed that in early pregnancy, a gestational sac was visualized 99% of the time on transvaginal ultrasound when the HCG level reached 3510 mIU/mL. Our secondary objective was to make clinical correlations by assessing the relationship between human chorionic gonadotropin (HCG) level in early pregnancy when a gestational sac is not seen and pregnancy outcomes of live birth, spontaneous abortion, and ectopic pregnancy. This retrospective study includes 144 pregnancies with an outcome of live birth, 87 pregnancies with an outcome of spontaneous abortion, and 59 ectopic pregnancies. Logistic regression is used to determine the probability of visualizing a gestational sac and/or yolk sac based on the HCG level. A gestational sac is predicted to be visualized 50% of the time at an HCG level of 979 mIU/mL, 90% at 2421 mIU/mL, and 99% of the time at 3994 mIU/mL. A yolk sac was predicted to be visualized 50% of the time at an HCG level of 4626 mIU/mL, 90% at 12,892 mIU/mL, and 99% at 39,454 mIU/mL. A total of 90% of ectopic pregnancies presented with an HCG level below 3994 mIU/mL. These results are in agreement with the study by Connolly et al. Since most early ectopic pregnancies had an HCG value below the discriminatory level for gestational sac visualization, other methods for the evaluation of pregnancy of unknown location such as repeat HCG values are clinically important., (© 2023. The Author(s).)

This study aimed to examine the endothelial dependence of vasodilation induced by the phosphodiesterase inhibitor theophylline in isolated rat thoracic aortas and elucidate the underlying mechanism, with emphasis on endothelial nitric oxide (NO). The effects of various inhibitors and endothelial denudation on theophylline-induced vasodilation, and the effect of theophylline on vasodilation induced by NO donor sodium nitroprusside, cyclic guanosine monophosphate (cGMP) analog bromo-cGMP, and β-agonist isoproterenol in endothelium-denuded aorta were examined. The effects of theophylline and sodium nitroprusside on cGMP formation were also examined. We examined the effect of theophylline on endothelial nitric oxide synthase (eNOS) phosphorylation and intracellular calcium levels. Theophylline-induced vasodilation was greater in endothelium-intact aortas than that in endothelium-denuded aortas. The NOS inhibitor, NW-nitro-L-arginine methyl ester; non-specific guanylate cyclase (GC) inhibitor, methylene blue; and NO-sensitive GC inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one inhibited theophylline-induced vasodilation in endothelium-intact aortas. Theophylline increased the vasodilation induced by sodium nitroprusside, bromo-cGMP, and isoproterenol. Theophylline increased cGMP formation in endothelium-intact aortas, and sodium nitroprusside-induced cGMP formation in endothelium-denuded aortas. Moreover, theophylline increased stimulatory eNOS (Ser1177) phosphorylation and endothelial calcium levels, but decreased the phosphorylation of inhibitory eNOS (Thr495). These results suggested that theophylline-induced endothelium-dependent vasodilation was mediated by increased endothelial NO release and phosphodiesterase inhibition.

The United States has the highest maternal mortality in the developed world with cardiovascular disease as the leading cause of pregnancy-related deaths. In response to this, the emerging subspecialty of cardio-obstetrics has been growing over the past decade. Cardiologists with training and expertise in caring for patients with cardiovascular disease in pregnancy are essential to provide effective, comprehensive, multidisciplinary, and high-quality care for this vulnerable population. This document provides a blueprint on incorporation of cardio-obstetrics training into cardiovascular disease fellowship programs to improve knowledge, skill, and expertise among cardiologists caring for these patients, with the goal of improving maternal and fetal outcomes., Competing Interests: Funding Support and Author Disclosures Supported by Bello- NIH/NHLBI (K23 HL136853, R01 HL153382). Dr Harrington has received support from AllWays Health Partners and QuidelOrtho. Dr Park has received support from Abbott Vascular. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The neurodevelopmental effects of skull asymmetry and orthotic helmet therapy for deformational plagiocephaly (DP) have had limited investigation. This study assessed the long-term neurocognitive outcomes in patients with DP and their association with orthotic helmet therapy and head shape abnormality., Methods: A total of 138 school-age children with a history of DP, 108 of whom received helmet therapy, were tested with a neurocognitive battery assessing academic achievement, intelligence quotient, and visual-motor function. Severity of presenting plagiocephaly was calculated using anthropometric and photometric measurements. Analysis of covariance was used to compare outcomes between helmeted and nonhelmeted cohorts, unilateral plagiocephaly and concomitant brachycephaly, and left-sided and right-sided plagiocephaly. The association between severity of plagiocephaly and neurocognitive outcome was assessed through a residualized change approach., Results: There were no significant differences in neurocognitive outcomes between the helmeted and nonhelmeted DP cohorts or the unilateral plagiocephaly and brachycephaly cohorts. Participants with left-sided DP had significantly lower motor coordination scores than participants with right-sided DP (84.8 versus 92.7; effect size = -0.50; P = 0.03). There was a significant laterality by cephalic index interaction, with a negative association between cephalic index and reading comprehension and spelling for participants with left-sided DP. No significant associations were found between severity of presenting or posttreatment deformity and neurocognitive outcome., Conclusions: Pretreatment and posttreatment severity of plagiocephaly were not correlated with neurocognitive function at school age. Helmet therapy was not associated with better or worse long-term neurocognitive function. However, participants with left-sided DP demonstrated worse neurocognitive outcomes than participants with right-sided DP in the domains of motor coordination and some types of academic achievement., Clinical Question/level of Evidence: Therapeutic, III., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Background: Diffuse coronary artery disease may need multiple overlapping stents, associated with less favorable outcomes than those of a single stent. The availability of longer stents can circumvent the need for overlapping stents in long lesions. This prospective, single-arm, SPIRIT 48 trial evaluated the safety and effectiveness of Abbott's next-generation drug-eluting stent, XIENCE Skypoint 48, in patients with coronary artery disease with long de novo native coronary lesions., Methods: SPIRIT 48 enrolled 107 patients at 25 sites in 3 countries. Patients were required to have 1 target lesion treated with XIENCE Skypoint 48 (lesion length of >32.0 mm and ≤44.0 mm). The primary end point was target lesion failure (TLF; composite of cardiac death, target vessel-related myocardial infarction, or clinically indicated target lesion revascularization) at the 1-year compared with a prespecified performance goal of 20%, established through historical control data. This study recently completed its 1-year follow-up., Results: XIENCE Skypoint 48 was implanted in 105 patients with a device success rate of 97.2%. SPIRIT 48 met its primary end point, with a TLF rate of 5.7%, and the upper bound of 95% CI at 9.5% (

This study aimed to examine the effect of lipid emulsion on the vasodilation induced by a toxic dose of amlodipine in isolated rat aorta and elucidate its mechanism, with a particular focus on nitric oxide. The effects of endothelial denudation, N W -nitro-L-arginvine methyl ester (L-NAME), methylene blue, lipid emulsion, and linolenic acid on the amlodipine-induced vasodilation and amlodipine-induced cyclic guanosine monophosphate (cGMP) production were examined. Furthermore, the effects of lipid emulsion, amlodipine, and PP2, either alone or combined, on endothelial nitric oxide synthase (eNOS), caveolin-1, and Src-kinase phosphorylation were examined. Amlodipine-induced vasodilation was higher in endothelium-intact aorta than in endothelium-denuded aorta. L-NAME, methylene blue, lipid emulsion, and linolenic acid inhibited amlodipine-induced vasodilation and amlodipine-induced cGMP production in the endothelium-intact aorta. Lipid emulsion reversed the increased stimulatory eNOS (Ser1177) phosphorylation and decreased inhibitory eNOS (Thr495) phosphorylation induced via amlodipine. PP2 inhibited stimulatory eNOS, caveolin-1, and Src-kinase phosphorylation induced via amlodipine. Lipid emulsion inhibited amlodipine-induced endothelial intracellular calcium increase. These results suggest that lipid emulsion attenuated the vasodilation induced via amlodipine through inhibiting nitric oxide release in isolated rat aorta, which seems to be mediated via reversal of stimulatory eNOS (Ser1177) phosphorylation and inhibitory eNOS (Thr495) dephosphorylation, which are also induced via amlodipine.

Background: High-deductible health plans (HDHPs) are becoming increasingly common, but their financial implications for enrollees with and without chronic conditions and the mitigating effects of health savings accounts (HSAs) are relatively unknown., Objective: Our aim was to compare financial hardship between non-HDHPs and HDHPs with and without HSAs, stratified by enrollees' number of chronic conditions., Design: We used data from 2015 to 2018 Medical Expenditure Panels Surveys (MEPS) to compare rates of financial hardship across individuals with HDHPs and non-HDHPs using linear and logistic regression models., Participants: A nationally representative sample of 30,981 adults aged 18-64 enrolled in HDHPs and non-HDHPs., Main Measures: We examined several measures of financial hardship, including total yearly out-of-pocket medical spending as well as rates of delaying medical care or prescriptions in the past year due to cost, forgoing medical care or prescriptions in the past year due to cost, paying medical bills over time, or having problems paying medical bills. We compared rates using the non-HDHP as the control., Key Results: On most measures, HDHPs are associated with greater financial hardship compared to non-HDHPs, including average annual out-of-pocket spending of $637 for non-HDHPs, $939 for HDHPs with HSAs, and $825 for HDHPs without HSAs (p < 0.01). However, for HDHP enrollees with multiple chronic conditions, having an HSA was associated with less financial hardship (p < 0.05)., Conclusions: Our findings suggest that HSAs may be most beneficial for those with chronic conditions, in part due to the tax benefits they offer as well as the fact that those with chronic conditions are more likely to take advantage of their HSAs than their younger, healthier counterparts. However, as HDHPs are more likely to be correlated with worse financial outcomes regardless of health status, recent trends of increasing participation may be a reason for concern., (© 2022. The Author(s), under exclusive licence to Society of General Internal Medicine.)

This study examined the effect of chloroquine on vasodilation induced by levcromakalim in isolated endothelium-denuded rat aortas and clarified the underlying mechanisms. We examined the effects of chloroquine, hydroxychloroquine, lipid emulsion, reactive oxygen species (ROS) scavenger N-acetyl-ʟ-cysteine (NAC), and KATP channel inhibitor glibenclamide on levcromakaliminduced vasodilation. The effects of chloroquine, hydroxychloroquine, NAC, and levcromakalim on membrane hyperpolarization and ROS production were examined in aortic vascular smooth muscle cells (VSMCs). Chloroquine inhibited levcromakalim-induced vasodilation more than hydroxychloroquine. NAC attenuated chloroquine-mediated inhibition of levcromakalim-induced vasodilation, while lipid emulsion had no effect. Glibenclamide eliminated levcromakalim-induced vasodilation in aortas pretreated with chloroquine. Chloroquine and hydroxychloroquine inhibited levcromakalim-induced membrane hyperpolarization in VSMCs. Chloroquine and hydroxychloroquine both produced ROS, but chloroquine produced more. NAC inhibited chloroquine-induced ROS production in VSMCs. Collectively, these results suggest that, partially through ROS production, chloroquine inhibits levcromakalim-induced vasodilation. In addition, chloroquine-induced KATP channel-induced vasodilation impairment was not restored by lipid emulsion.

Objectives: The aim of this study was to examine the association between changes in oral health related quality of life (OHRQoL) and depressive symptoms in the elderly South Koreans. Methods: We used the 2018 and 2020 Korean Longitudinal Study of Ageing data. Our study population was a total of 3,604 participants aged over 65 in 2018. The independent variable of interest was the changes in the Geriatric Oral Health Assessment Index as OHRQoL between 2018 and 2020. The dependent variable was depressive symptoms in 2020. Multivariable logistic regression analyzed the associations between changes in OHRQoL and depressive symptoms. Results: Participants with improvement in OHRQoL over 2-year period were likely to have fewer depressive symptoms in 2020. Especially, changes in the oral pain and discomfort dimension score was associated with depressive symptoms. A decline in oral physical function, such as difficulty in chewing and speaking, was also associated with depressive symptoms. Conclusion: Negative change in OHRQoL is a risk factor for depression in elderly. This results suggest the importance of maintaining good oral health in later life, as a protective factor against depression., Competing Interests: The authors declare that they do not have any conflicts of interest., (Copyright © 2023 Park, Lee, Kwon and Kim.)

Objective: Childhood sexual abuse is associated with compulsive sexual behavior, depression, and anxiety in men. Furthermore, both depression and anxiety have been linked to compulsive sexual behaviors. However, whether anxiety and depression mediate the relationship between childhood sexual abuse and compulsive sexual behaviors has yet to be tested. We investigated whether symptoms of depression and anxiety mediate the relationship between childhood sexual abuse and compulsive sexual behaviors in 222 men seeking treatment for such behaviors., Methods: Participants completed the Sexual Compulsivity Scale, Childhood Trauma Questionnaire, Beck Depression Inventory, and Beck Anxiety Inventory. A cross-sectional parallel mediation analysis was conducted., Results: The prevalence of childhood sexual abuse in our sample was 57%. Significant correlations were found between childhood sexual abuse and compulsive sexual behaviors, depression, and anxiety. The results of the mediation analyses suggested that depression (B = 0.07, standard error [SE] = 0.03, 95%CI 0.02 to 0.15), but not anxiety (B = 0.02, SE = 0.02, 95%CI -0.2 to 0.07), mediated the link between childhood sexual abuse and compulsive sexual behaviors. The pattern of our results remained the same when controlling for other types of childhood trauma., Conclusions: Depression, not anxiety, appears to mediate the relationship between childhood sexual abuse and compulsive sexual behaviors in men. Future research that tests our mediation analyses using a prospective longitudinal study would be highly informative., Competing Interests: The authors report no conflicts of interest.

Background: Guidelines recommend maximal antianginal medical therapy before attempted coronary artery chronic total occlusion (CTO) percutaneous coronary intervention (PCI). The degree to which this occurs in contemporary practice is unknown. We aimed to characterize the frequency and variability of preprocedural use of antianginal therapy and stress testing within 3 months before PCI of CTO (CTO PCI) across a nationally integrated health care system., Methods: We identified patients who underwent attempted CTO PCI from January 2012 to September 2018 within the Veterans Affairs Healthcare System. Patients were categorized by management before CTO PCI: presence of ≥2 antianginals, stress testing, and ≥2 antianginals and stress testing within 3 months of PCI attempt. Multivariable logistic regression and inverse propensity weighting were used for adjustment before trimming, with median odds ratios calculated for variability estimates., Results: Among 4250 patients undergoing attempted CTO PCI, 40% received ≥2 antianginal medications and 24% underwent preprocedural stress testing. The odds of antianginal therapy with more than one medication before CTO PCI did not change over the years of the study (odds ratio [OR], 1.0 [95% CI, 0.97-1.04]), whereas the odds of undergoing preprocedural stress testing decreased (OR, 0.97 [95% CI, 0.93-0.99]), and the odds of antianginal therapy with ≥2 antianginals and stress testing did not change (OR, 0.98 [95% CI, 0.93-1.04]). Median odds ratios (MOR) showed substantial variability in antianginal therapy across hospital sites (MOR, 1.3 [95% CI, 1.26-1.42]) and operators (MOR, 1.35 [95% CI, 1.26-1.63]). Similarly, preprocedural stress testing varied significantly by site (MOR, 1.68 [95% CI, 1.58-1.81]) and operator (MOR, 1.80 [95% CI, 1.56-2.38])., Conclusions: Just under half of patients received guideline-recommended management before CTO PCI, with significant site and operator variability. These findings suggest an opportunity to reduce variability in management before CTO PCI.

Competing Interests: The authors have no conflicts of interest to disclose.

Physostigmine (Phs) is a reversible inhibitor of acetylcholinesterase (AChE) that penetrates the blood-brain barrier (BBB) and could be used to protect the central nervous system (CNS) against the effects of nerve agents. For prophylactic effectiveness, long, steady, and adequate inhibition of AChE activity by Phs is needed to broadly protect against the CNS effects of nerve agents. Here, we evaluated the efficacy of transdermal patches containing Phs and procyclidine (PC) as prophylactic agents. Patches (25 cm 2 ) containing 4.4 mg Phs and 17.8 mg PC had a protective ratio of approximately 78.6-fold in rhesus monkeys challenged with VX nerve agent and given an antidote. Physiologically based pharmacokinetic model in conjunction with an indirect pharmacodynamic (PBPK/PD) was developed for Phs and scaled to rhesus monkeys. The model was able to reproduce the concentration profile and inhibitory effect on AChE of Phs in monkeys, as evidenced by correlation coefficients of 0.994 and 0.992 for 25 cm 2 and 49 cm 2 patches, respectively (i.e., kinetic data), and 0.989 and 0.968 for 25 cm 2 and 49 cm 2 patches, respectively (i.e., dynamic data). By extending the monkey PBPK/ PD model to humans, the effective human dose was predicted to be five applications of a 25 cm 2 patch (i.e., 22 mg Phs), and two applications of a 49 cm 2 patch (i.e., 17.4 mg Phs). Therefore, given that patch application of Phs in rhesus monkeys has a prolonged effect (namely, AChE inhibition of 19.6% for the 25 cm 2 patch and 23.0% for the 49 cm 2 patch) for up to 216 h, patch formulation of Phs may provide similar protection against nerve agent intoxication in humans., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Several severity metrics have been developed for metopic craniosynostosis, including a recent machine learning-derived algorithm. This study assessed the diagnostic concordance between machine learning and previously published severity indices., Design: Preoperative computed tomography (CT) scans of patients who underwent surgical correction of metopic craniosynostosis were quantitatively analyzed for severity. Each scan was manually measured to derive manual severity scores and also received a scaled metopic severity score (MSS) assigned by the machine learning algorithm. Regression analysis was used to correlate manually captured measurements to MSS. ROC analysis was performed for each severity metric and were compared to how accurately they distinguished cases of metopic synostosis from controls., Results: In total, 194 CT scans were analyzed, 167 with metopic synostosis and 27 controls. The mean scaled MSS for the patients with metopic was 6.18 ± 2.53 compared to 0.60 ± 1.25 for controls. Multivariable regression analyses yielded an R-square of 0.66, with significant manual measurements of endocranial bifrontal angle (EBA) (P = 0.023), posterior angle of the anterior cranial fossa (p < 0.001), temporal depression angle (P = 0.042), age (P < 0.001), biparietal distance (P < 0.001), interdacryon distance (P = 0.033), and orbital width (P < 0.001). ROC analysis demonstrated a high diagnostic value of the MSS (AUC = 0.96, P < 0.001), which was comparable to other validated indices including the adjusted EBA (AUC = 0.98), EBA (AUC = 0.97), and biparietal/bitemporal ratio (AUC = 0.95)., Conclusions: The machine learning algorithm offers an objective assessment of morphologic severity that provides a reliable composite impression of severity. The generated score is comparable to other severity indices in ability to distinguish cases of metopic synostosis from controls.

Competing Interests: None disclosed.

Hydrogen peroxide (H 2 O 2 ) has been a fascinating target in various chemical, biological, clinical, and industrial fields. Several types of fluorescent protein-stabilized gold nanoclusters (protein-AuNCs) have been developed for sensitive and easy detection of H 2 O 2 . However, its low sensitivity makes is difficult to measure negligible concentrations of H 2 O 2 . Therefore, to overcome this limitation, we developed a horseradish peroxidase-encapsulated fluorescent bio-nanoparticle (HEFBNP), comprising bovine serum albumin-stabilized gold nanoclusters (BSA-AuNCs) and horseradish peroxidase-stabilized gold nanoclusters (HRP-AuNCs). The fabricated HEFBNP can sensitively detect H 2 O 2 owing to its two properties. The first is that HEFBNPs have a continuous two-step fluorescence quenching mechanism, which comes from the heterogenous fluorescence quenching mechanism of HRP-AuNCs and BSA-AuNCs. Second, the proximity of two protein-AuNCs in a single HEFBNP allows a reaction intermediate (•OH) to rapidly reach the adjacent protein-AuNCs. As a result, HEFBNP can improve the overall reaction event and decrease the loss of intermediate in the solution. Due to the continuous quenching mechanism and effective reaction event, a HEFBNP-based sensing system can measure very low concentrations of H 2 O 2 up to 0.5 nM and show good selectivity. Furthermore, we design a glass-based microfluidic device to make it easier use HEFBNP, which allowed us to detect H 2 O 2 with the naked eye. Overall, the proposed H 2 O 2 sensing system is expected to be an easy and highly sensitive on-site detection tool in chemistry, biology, clinics, and industry fields.