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Introduction Singapore phased in standardized tobacco packaging on 1 July 2020 following a three-month grace period. This pre-post study evaluated its impacts on smoking-related behaviors and perceptions among adults who currently smoke. Methods Baseline and follow-up data were collected in a pre- and post-questionnaire from a cohort of 1873 Singaporean adults who were currently smoking at baseline. Baseline data were collected from December 2019 to May 2020, and followup data from July 2021 to September 2021. We used descriptive statistics and bivariate analyses to assess pre-post changes (Bhapkar’s test, Wilcoxon signed rank test) and to identify characteristics of participants who had quit or cut down smoking at follow-up (Pearson’s chi-squared, Fisher’s exact test). Results At follow-up, 11.7% (n=220) had quit smoking. There was a higher proportion of those smoking non-daily (pre: 13.1%, post: 16.9%; p

Abstract With the increase in the dependency on digital devices, the incidence of myopia, a precursor of various ocular diseases, has risen significantly. Because myopia and eyeball volume are related, myopia progression can be monitored through eyeball volume estimation. However, existing methods are limited because the eyeball shape is disregarded during estimation. We propose an automated eyeball volume estimation method from computed tomography images that incorporates prior knowledge of the actual eyeball shape. This study involves data preprocessing, image segmentation, and volume estimation steps, which include the truncated cone formula and integral equation. We obtained eyeball image masks using U-Net, HFCN, DeepLab v3 +, SegNet, and HardNet-MSEG. Data from 200 subjects were used for volume estimation, and manually extracted eyeball volumes were used for validation. U-Net outperformed among the segmentation models, and the proposed volume estimation method outperformed comparative methods on all evaluation metrics, with a correlation coefficient of 0.819, mean absolute error of 0.640, and mean squared error of 0.554. The proposed method surpasses existing methods, provides an accurate eyeball volume estimation for monitoring the progression of myopia, and could potentially aid in the diagnosis of ocular diseases. It could be extended to volume estimation of other ocular structures.

Abstract Intracellular membranes composing organelles of eukaryotes include membrane proteins playing crucial roles in physiological functions. However, a comprehensive understanding of the cellular responses triggered by intracellular membrane-focused oxidative stress remains elusive. Herein, we report an amphiphilic photocatalyst localised in intracellular membranes to damage membrane proteins oxidatively, resulting in non-canonical pyroptosis. Our developed photocatalysis generates hydroxyl radicals and hydrogen peroxides via water oxidation, which is accelerated under hypoxia. Single-molecule magnetic tweezers reveal that photocatalysis-induced oxidation markedly destabilised membrane protein folding. In cell environment, label-free quantification reveals that oxidative damage occurs primarily in membrane proteins related to protein quality control, thereby aggravating mitochondrial and endoplasmic reticulum stress and inducing lytic cell death. Notably, the photocatalysis activates non-canonical inflammasome caspases, resulting in gasdermin D cleavage to its pore-forming fragment and subsequent pyroptosis. These findings suggest that the oxidation of intracellular membrane proteins triggers non-canonical pyroptosis.

Objective We propose that cervical intrafacetal fusion (cIFF) using bone chip insertion into the facetal joint space additional to minimal PLF is a supplementary fusion method to conventional posterolateral fusion (PLF). Methods Patients who underwent posterior cervical fixation accompanied by cIFF with minimal PLF or conventional PLF for cervical myelopathy from 2012 to 2023 were investigated retrospectively. Radiological parameters including Cobb angle and C2–7 sagittal vertical axis (SVA) were compared between the 2 groups. In cIFF with minimal PLF group, cIFF location and PLF location were carefully divided, and the fusion rates of each location were analyzed by computed tomography scan. Results Among enrolled 46 patients, 31 patients were in cIFF group, 15 in PLF group. The postoperative change of Cobb angle in 1-year follow-up in cIFF with minimal PLF group and conventional PLF group were 0.1° ± 4.0° and -9.7° ± 8.4° respectively which was statistically lower in cIFF with minimal PLF group (p = 0.022). Regarding the fusion rate in cIFF with minimal PLF group in postoperative 6 months, the rates was achieved in 267 facets (98.1%) in cIFF location, and 244 facets (89.7%) in PLF location (p < 0.001). Conclusion Postoperative sagittal alignment was more preserved in cIFF with minimal PLF group compared with conventional PLF group. Additionally, in cIFF with minimal PLF group, the bone fusion rate of cIFF location was higher than PLF location. Considering the concerns of bone chip migration onto the spinal cord and relatively low fusion rate in PLF method, applying cIFF method using minimized PLF might be a beneficial alternative for posterior cervical decompression and fixation.

Abstract The synthesis of sequence-regulated oligosulfates has not yet been established due to the difficulties in precise reactivity control. In this work, we report an example of a multi-directional divergent iterative method to furnish oligosulfates based on a chain homologation approach, in which the fluorosulfate unit is regenerated. The oligosulfate sequences are determined by high resolution mass spectrometry of the hydrolyzed fragments, and polysulfate periodic copolymers are synthesized by using oligomeric bisfluorosulfates in a bi-directional fashion. The synthetic utility of this iterative ligation is demonstrated by preparing crosslinked network polymers as synthetic adhesive materials.

Introduction: Given the recent additions of immune checkpoint inhibitors (ICIs) to various cancer treatments, adverse effects, especially involving the eyes, have been on the rise. Here, we report an acute exacerbation of cancer-associated retinopathy (CAR) triggered by durvalumab treatment of small-cell lung cancer (SCLC). Case Presentation: An 81-year-old Asian male complained of a scotoma in the left eye after durvalumab administration, to treat SCLC. Humphrey visual field examination revealed a C-shaped temporal scotoma. Spectralis domain optical coherence tomography revealed outer retinal layer atrophy and progressive loss of the ellipsoid zone in the atrophic peripapillary area. Fundus autofluorescence (AF) images evidenced a large C-shaped hypo-AF with enhanced AF at the margin of the atrophic area, thus at the position of the scotoma. We prescribed subtenon triamcinolone injections under suspicion of CAR exacerbation, supported by positive Western blotting results for Rab6 and aldolase, and immunohistochemical staining of photoreceptor cells. The disrupted ellipsoid zone evident on OCT partially recovered, and a visual field test showed that the scotoma had improved. Conclusion: ICI-triggered exacerbation of CAR should be considered in SCLC patients before ICI treatment commences; an optimal treatment should preserve functional vision.

The thermal-hydraulic performance of lattice structures with different topologies and relative densities was investigated. AlSi7Mg sandwich panels cored with vertical fin, pyramidal, and tetrahedral lattices were fabricated using additive manufacturing. Four different relative densities (7.5 %, 10 %, 12.5 %, and 15 %) were considered for each lattice core. The experiment was conducted under constant heat flux and steady-state forced convection. Results showed that increasing relative density led to an increase in the average Nusselt number by 3.2–12.5 % in the vertical fin, 23.8–56.4 % in the pyramidal lattice, and 38.8–46.9 % in the tetrahedral lattice. To evaluate the efficiency of different topologies, the average Nusselt number was compared at a fixed pumping power. The pyramidal lattice exhibited the best performance among the test samples, followed by the tetrahedral lattice. The numerical analysis was performed to gain further insights into the heat transfer mechanisms involved. As the relative density increased, an increase in both the maximum fluid velocity and turbulent kinetic energy was observed in all test samples. The numerical results demonstrate that the observed improvement in thermal-hydraulic performance with increasing relative densities in experiments is attributable to the enhanced momentum of the fluid and turbulent mixing.

The taxonomic validity of Dolichovespula kuami, especially in relation to D. flora, has been the subject of a long-term debate. Herein, the valid specific status of the former was supported through an integrated analysis of morphological characters and DNA barcodes. The pronotal rugae and male genitalia of the two species are different, and partial mitochondrial genes (cytochrome oxidase subunit I, COI) indicate that they form significantly distinct lineages. The hitherto unknown male of D. kuami is described for the first time, and a brief discussion of the D. maculata species group is provided.

Abstract We aimed to evaluate the feasibility of MR elastography (MRE) using a transpelvic approach. Thirty-one patients who underwent prostate MRE and had a pathological diagnosis were included in this study. MRE was obtained using a passive driver placed at the umbilicus and iliac crests. The shear stiffness, clinical data, and conventional imaging findings of prostate cancer and benign prostatic hyperplasia (BPH) were compared. Inter-reader agreements were evaluated using the intraclass coefficient class (ICC). Prostate MRE was successfully performed for all patients (100% technical success rate). Nineteen cancer and 10 BPH lesions were visualized on MRE. The mean shear stiffness of cancer was significantly higher than that of BPH (5.99 ± 1.46 kPa vs. 4.67 ± 1.54 kPa, p = 0.045). One cancer was detected on MRE but not on conventional sequences. Six tiny cancer lesions were not visualized on MRE. The mean size of cancers that were not detected on MRE was smaller than that of cancers that were visible on MRE (0.8 ± 0.3 cm vs. 2.3 ± 1.8 cm, p = 0.001). The inter-reader agreement for interpreting MRE was excellent (ICC = 0.95). Prostate MRE with transpelvic vibration is feasible without intracavitary actuators. Transpelvic prostate MRE is reliable for detecting focal lesions, including clinically significant prostate cancer and BPH.

Juyoung Khwarg,1 Soyoung Lee,1,2 In-Jin Jang,1 Won-Ho Kang,3 Hye Jung Lee,4 Kyu Yeon Kim,4 Ki-Sun Jeong,4 Chongho Won,4 Youn Woong Choi,5 Dae Chul Ha,5 RaeHoon Jung,5 Min-Gu Han,5 Won Tae Jung,6 Kyu-Yeol Nam,6 YeSeul Kim,6 Kyung-Sang Yu,1 Jaeseong Oh1,7 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Republic of Korea; 3R&D Center, Korea United Pharm. Inc., Seoul, Republic of Korea; 4Caleb Multilab, Inc., Seoul, Republic of Korea; 5R&D Center, Korea United Pharm.Inc., Sejong, Republic of Korea; 6Global R&D, Korea United Pharm. Inc., Seoul, Republic of Korea; 7Department of Pharmacology, Jeju National University College of Medicine, Jeju, Republic of KoreaCorrespondence: Jaeseong Oh, Department of Pharmacology, Jeju National University College of Medicine, 15, Aran 13-gil, Jeju-si, Jeju-do, 63241, Republic of Korea, Email jaeseong5@jejunu.ac.krPurpose: Statins are widely used in combination with omega-3 fatty acids for the treatment of patients with dyslipidemia. The aim of this study was to compare the pharmacokinetic (PK) profiles of atorvastatin and omega-3-acid ethyl esters between fixed-dose combination (FDC) and loose combination in healthy subjects.Methods: A randomized, open-label, single-dose, 2-sequence, 2-treatment, 4-period replicated crossover study was performed. Subjects were randomly assigned to one of the 2 sequences and alternately received four FDC soft capsules of atorvastatin/omega-3-acid ethyl esters (10/1000 mg) or a loose combination of atorvastatin tablets (10 mg × 4) and omega-3-acid ethyl ester soft capsules (1000 mg× 4) for four periods, each period accompanied by a high-fat meal. Serial blood samples were collected for PK analysis of atorvastatin, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). PK parameters were calculated by a non-compartmental analysis. The geometric mean ratio (GMR) and its 90% confidence interval (CI) of the FDC to the loose combination were calculated to compare PK parameters.Results: A total of 43 subjects completed the study as planned. The GMR (90% CI) of FDC to loose combination for maximum concentration (Cmax) and area under the time-concentration curve from zero to the last measurable point (AUClast) were 1.0931 (1.0054– 1.1883) and 0.9885 (0.9588– 1.0192) for atorvastatin, 0.9607 (0.9068– 1.0178) and 0.9770 (0.9239– 1.0331) for EPA, and 0.9961 (0.9127– 1.0871) and 0.9634 (0.8830– 1.0512) for DHA, respectively. The intra-subject variability for Cmax and AUClast of DHA was 30.8% and 37.5%, respectively, showing high variability. Both the FDC and the loose combination were safe and well tolerated.Conclusion: The FDC of atorvastatin and omega-3-acid ethyl esters showed comparable PK characteristics to the corresponding loose combination, offering a convenient therapeutic option for the treatment of dyslipidemia. Keywords: pharmacokinetics, cardiovascular disease

Graves’ orbitopathy is an inflammatory disorder that causes changes in different structures close to the eye. Accurate and consistent diagnoses are essential to improve the quality of life for Graves’ orbitopathy patients. To this end, a number of studies on Graves’ orbitopathy have been conducted based on neural networks recently. However, treatment decision methods based on neural networks have been much less addressed. This study aims to propose an effective deep neural network-based diagnosis method that makes treatment decisions for Graves’ orbitopathy patients. Specifically, the proposed method adopts a high-resolution feature enhancement and low-resolution feature preservation strategy focusing on the following points. First, the loss of detailed spatial information during the alignment of pixel spacing in computed tomography images leads to a decrease in performance. Thus, we preserve the detailed information of the images through high-resolution resampling. Second, existing studies lack sophistication in network design. The baseline network was improved by four modifications. Finally, resizing and coarse cropping cause learning instability. Thus, we adopt padding and fine-grained cropping. Our empirical study shows that the proposed method outperforms two existing neural network-based Graves’ orbitopathy diagnostic pipelines achieving an average area under the receiver operating characteristic curve of 0.793, accuracy of 0.699, F1 score of 0.416, sensitivity of 0.723, and specificity of 0.694 in five repetitive experiments. Furthermore, in-depth analysis provides several future research directions in computed tomography preprocessing and deep neural network design. The source code for the proposed model is available at https://github.com/tkdgur658/GOTDNet.

Thyroid-associated orbitopathy is an autoimmune disease that causes changes in various structures close to the eye. Medical images, such as three-dimensional computed tomography scans, can be used by medical experts to diagnose thyroid-associated orbitopathy. Meanwhile, image segmentation has been widely used in medical imaging owing to its significant impact on improving model performance by filtering out unnecessary pixel values. In this study, a neural network specialized in processing multiple segmented images was proposed to evaluate thyroid orbitopathy activity, focusing on the fact that multiple segmented images can be extracted from orbital computed tomography scans. The proposed neural network consists of multiple convolutional embedding heads, a group squeeze-and-excitation block, and a classifier stage. Our empirical study shows that the proposed model outperforms four baseline models on a thyroid-associated orbitopathy activity dataset obtained from a cohort of 1,068 patients at Chung-Ang University Hospital between January 2008 and October 2019. The proposed model achieved an average area under the receiver operating characteristic curve of 0.800, accuracy of 0.721, F1 score of 0.416, sensitivity of 0.728, and specificity of 0.720 across 50 replicate experiments. The source code for the proposed model is available at https://github.com/tkdgur658/MultiheadGroupSENet.

Abstract The purpose of this study was to assess the clinical utility and reliability of an automated eyelid measurement system utilizing neural network (NN) technology. Digital images of the eyelids were taken from a total of 300 subjects, comprising 100 patients with Graves’ orbitopathy (GO), 100 patients with ptosis, and 100 controls. An automated measurement system based on NNs was developed to measure margin–reflex distance 1 and 2 (MRD1 and MRD2), as well as the lengths of the upper and lower eyelids. The results were then compared with values measured using the manual technique. Automated measurements of MRD1, MRD2, upper eyelid length, and lower eyelid length yielded values of 3.2 ± 1.7 mm, 6.0 ± 1.4 mm, 32.9 ± 6.1 mm, and 29.0 ± 5.6 mm, respectively, showing a high level of agreement with manual measurements. To evaluate the morphometry of curved eyelids, the distance from the midpoint of the intercanthal line to the eyelid margin was measured. The minimum number of divisions for detecting eyelid abnormalities was determined to be 24 partitions (15-degree intervals). In conclusion, an automated NN-based measurement system could provide a straightforward and precise method for measuring MRD1 and MRD2, as well as detecting morphological abnormalities in the eyelids.

Purpose: This study analyzed changes in body composition and physical fitness in men with testosterone deficiency (TD) after testosterone treatment (TT) and examined the correlations of body composition and physical fitness with serum testosterone levels and hypogonadal symptoms. Materials and Methods: Seventy patients with TD were divided into control (group I, n=23) and experimental (group II, n=47) groups. Patients in the experimental group were administered intramuscular testosterone enanthate (250 mg) for six months. The aging males symptom scale (AMS) score, international prostate symptom score (IPSS), body mass index, waist circumference, and serum laboratory values were measured at baseline and at the end of the study. Bioelectrical impedance analysis was used to assess the patients’ body composition. Seven types of basic exercise tests were used to evaluate the patients’ physical fitness. Results: After six months, there were no significant differences in group I, while group II had significantly improved IPSS and AMS scores; increased hemoglobin, hematocrit, prostate-specific antigen, and testosterone levels and skeletal muscle mass; and waist circumference, and body fat mass. All elements of the physical fitness test were significantly improved in group II, with the exceptions of flexibility and endurance. Decreased waist circumference was correlated with changes in testosterone levels in group II, and the IPSS, cardiorespiratory fitness, and agility were correlated with improved hypogonadal symptoms. Conclusions: TT improved the hypogonadal and lower urinary tract symptoms in patients with TD and improved body composition, physical fitness, and metabolic syndrome parameters. Increased testosterone and improved hypogonadal symptoms were correlated with a decrease in waist circumference and an improvement in cardiorespiratory fitness and agility. As such, when implementing TT, we should consider whether these areas may be improved, as this can help to predict the effect.

Background: Hypoxia-regulated proteins (HIF-1α and GLUT-1) have been identified as prognostic markers in various cancers; however, their role in endometrial cancer remains unclear. This study aimed to evaluate HIF-1α and GLUT-1 expression in endometrial cancer and correlate their expression with clinicopathological features. Materials and Methods: A tissue microarray (TMA) was constructed using specimens from a retrospective cohort of 51 endometrial cancer patients who underwent hysterectomy at the Gyeongsang National University Hospital between 2002 and 2009. Clinicopathologic data were collected from electronic medical records, and HIF-1α and GLUT-1 expressions were assessed in the tumor tissue. Results: GLUT-1 expression in endometrial cancer was categorized as mosaic, central, or diffuse. Most patients (56.0%) exhibited a central pattern, followed by diffuse (32.0%) and mosaic (12.0%) patterns. GLUT-1 expression was not significantly associated with histologic grade (p = 0.365). HIF-1α expression in immune cells, but not tumor cells, was significantly associated with a higher histologic grade. A higher proportion of HIF-1α-positive immune cells, using both thresholds (≤1% vs. >1% and ≤5% vs. >5%), was significantly associated with higher histologic grade (p = 0.032 and p = 0.048, respectively). In addition, a higher proportion of HIF-1α-positive immune cells was significantly associated with a diffuse GLUT-1 expression pattern using >5% as a threshold. There were no significant differences in the proportion of HIF-1α-positive immune cells between groups stratified by age, tumor size, or invasion depth, regardless of whether the 1% or 5% threshold for HIF-1α positivity was used. Conclusions: A higher proportion of HIF-1α-positive immune cells is associated with endometrial cancers with higher histologic grade and diffuse GLUT1 expression patterns. These findings suggest a potential role for HIF-1α as a prognostic marker and highlight the need for further studies into the role of HIF-1α in the tumor microenvironment.

BackgroundContact tracing technology has been adopted in many countries to aid in identifying, evaluating, and handling individuals who have had contact with those infected with COVID-19. Singapore was among the countries that actively implemented the government-led contact tracing program known as TraceTogether. Despite the benefits the contact tracing program could provide to individuals and the community, privacy issues were a significant barrier to individuals’ acceptance of the program. ObjectiveBuilding on the privacy calculus model, this study investigates how the perceptions of the 2 key groups (ie, government and community members) involved in the digital contact tracing factor into individuals’ privacy calculus of digital contact tracing. MethodsUsing a mixed method approach, we conducted (1) a 2-wave survey (n=674) and (2) in-depth interviews (n=12) with TraceTogether users in Singapore. Using structural equation modeling, this study investigated how trust in the government and the sense of community exhibited by individuals during the early stage of implementation (time 1) predicted privacy concerns, perceived benefits, and future use intentions, measured after the program was fully implemented (time 2). Expanding on the survey results, this study conducted one-on-one interviews to gain in-depth insights into the privacy considerations involved in digital contact tracing. ResultsThe results from the survey showed that trust in the government increased perceived benefits while decreasing privacy concerns regarding the use of TraceTogether. Furthermore, individuals who felt a connection to community members by participating in the program (ie, the sense of community) were more inclined to believe in its benefits. The sense of community also played a moderating role in the influence of government trust on perceived benefits. Follow-up in-depth interviews highlighted that having a sense of control over information and transparency in the government’s data management were crucial factors in privacy considerations. The interviews also highlighted surveillance as the most prevalent aspect of privacy concerns regarding TraceTogether use. In addition, our findings revealed that trust in the government, particularly the perceived transparency of government actions, was most strongly associated with concerns regarding the secondary use of data. ConclusionsUsing a mixed method approach involving a 2-wave survey and in-depth interview data, we expanded our understanding of privacy decisions and the privacy calculus in the context of digital contact tracing. The opposite influences of privacy concerns and perceived benefit on use intention suggest that the privacy calculus in TraceTogether might be viewed as a rational process of weighing between privacy risks and use benefits to make an uptake decision. However, our study demonstrated that existing perceptions toward the provider and the government in the contact tracing context, as well as the perception of the community triggered by TraceTogether use, may bias user appraisals of privacy risks and the benefits of contact tracing.

With the growing demand for high‐speed electronic devices with low energy consumption, spin–orbit torque (SOT) has become a significant focus. SOT can switch the magnetization direction in a material system with broken inversion symmetry, such as a normal metal (NM)/ferromagnet (FM) heterojunction. The SOT consists of two mutually orthogonal vector components along with the injected current direction: the transverse damping‐like torque (DLT) and the longitudinal field‐like torque (FLT). Numerous studies have mainly centered on the DLT for the SOT switching mechanism. However, DLT and FLT are essential to enhance SOT efficiency because FLT boosts the magnetization precession motion. Herein, heterojunctions consisting of NM 1 (Ta, W, or Pt)/NM 2 (Nb)/FM (CoFeB) are devised to manipulate the FLT‐to‐DLT ratio (η) through the change in Nb thickness. Furthermore, experimental confirmation exists for reducing threshold current as η increases. The SOT devices with substantial η generate random numbers. The National Institute of Standards and Technology Special Publication 800‐90B test verifies randomness and confirms that the SOT devices are beneficial sources for true random number generators (TRNGs). These findings indicate the crucial role of FLT in the SOT switching process and underscore its significance in developing SOT‐based TRNG devices.

Background Availability of long-term psychological interventions for personality disorders is limited because of their high intensity and cost. Research in evidence-based, low-intensity interventions is needed. Aims This study aimed to examine the feasibility, acceptability and potential impact of a low-intensity, digital guided self-help (GSH) intervention that is focused on emotion regulation, recovery-oriented and provides in-the-moment delivery for patients with personality disorders. Method We conducted a single-blind feasibility trial. A total of 43 patients with a personality disorder were recruited and randomly assigned to either a GSH arm (n = 22) or a treatment-as-usual arm (n = 21). The GSH intervention included a series of short videos offering psychoeducation and support, personalised feedback using text messages, and supportive telephone calls, for 4 weeks in addition to treatment as usual. Outcomes of emotional disturbance, emotion dysregulation, self-harm behaviours and decentring ability were measured at baseline, 4 weeks (end of intervention) and 8 weeks (follow-up). Results All patients who attended the first session continued until the last session. There was an interaction effect between time and group on anxiety (P = 0.027, Δη2 = 0.10), where the GSH group showed a significant reduction in anxiety at follow-up (P = 0.003, d = 0.25). The GSH group increased in decentring ability at the end of intervention (P = 0.007, d = −0.65), and the decrease in self-harm behaviours continued until follow-up (P = 0.02, d = 0.57). Conclusions The results suggest that a personalised digital GSH with a focus on recovery could reduce anxiety and self-harm behaviours at short-term follow-up.

This paper provides a comparison between the conventional Electromagnetic Forming (EMF) technique and the novel Electromagnetic Hydraulic Forming (EMHF) approach. The EMHF involves the use of finite element analysis coupled with the EM and arbitrary Lagrangian–Eulerian techniques analyzed through LS-DYNA. In the free-bulge configuration, EMF is influenced by the forming coil, resulting in a dead zone and uneven forming. Additionally, EMF can only be used to shape materials with high electrical conductivity. In contrast, EMHF, driven by induced hydraulic pressure from the electromagnetic field-affected drive sheet, is independent of the electrical conductivity of the material and produces dome-shaped workpieces. For rectangular die shapes, EMF is prone to collision owing to the acceleration of the blank, which results in a reduced quality owing to bouncing. However, EMHF exhibits no bouncing effect and successfully achieves the target shape in most cases. The two techniques differ in the strain rate, with EMF at 4850/s, whereas EMHF operates at approximately 1250/s. Despite being slower, EMHF is still a high-speed forming technique. In conclusion, EMHF is a promising technique capable of addressing the shortcomings of conventional EMF and achieving improvements in forming processes.

As an escalating global concern for environmentally sustainable marine fuels, liquefied petroleum gas (LPG) is attracting attention as an eco-friendly and economical alternative. This study explored LPG utilization in small marine vessels, focusing on its eco-friendliness and economic feasibility. To assess its environmental implications, the AVL FIRE simulation program was used to compare CO2, CO, NO, and soot emissions from LPG engines with those from conventional gasoline and diesel engines. The LPG engine model relied on data from a pioneering type-approved experimental LPG engine designed for small South Korean marine vessels, while parameters for gasoline and diesel engines were adjusted to suit their distinctive features. Regarding long-term economic feasibility, assuming a 30-year ship lifespan, incorporating 2022 annual average prices, average annual price growth rates, and annual fuel consumption data of each fuel, results indicate that LPG engines exhibited lower CO2, CO, NO, and soot emissions than conventional engines, except that NO emissions were higher than gasoline engines. Evaluating LPG’s economic feasibility over a 30-year ship life cycle for an individual vessel revealed varying fuel cost savings, with the greatest savings observed in gasoline–other (KRW 2220.7 million) and the least in gasoline–coastal (KRW 1152.5 million). These findings offer vital insights for ship operators and policymakers seeking a balance between eco-friendliness and cost-effectiveness, as well as LPG engine technology emerging as pivotal for a sustainable future, harmonizing environmental protection and economic viability.

Atopic dermatitis (AD), a chronic inflammatory disease, severely interferes with patient life. Human placenta extract (HPH; also known as human placenta hydrolysate) is a rich source of various bioactive substances and has widely been used to dampen inflammation, improve fatigue, exert anti-aging effects, and promote wound healing. However, information regarding HPH's incorporation in AD therapies is limited. Therefore, this study aimed to evaluate HPH's effective potential in treating AD using tumor necrosis factor (TNF)-α/interferon (IFN)-γ-stimulated human keratinocytes (HaCaT), immunized splenocytes, and a 2,4-dinitrochlorobenzene (DNCB)-induced AD mouse model. In TNF-α /IFN-γ-stimulated HaCaT cells, HPH markedly reduced the production of reactive oxygen species (ROS) and restored the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), superoxide dismutase 1(SOD1), catalase, and filaggrin (FLG). HPH reduced interleukin (IL)-6; thymus- and activation-regulated chemokine (TARC); thymic stromal lymphopoietin (TSLP); and regulated upon activation, normal T cell expressed and presumably secreted (RANTES) levels and inhibited nuclear factor kappa B phosphorylation. Additionally, HPH suppressed the T helper 2 (Th2) immune response in immunized splenocytes. In the AD-like mouse model, it significantly mitigated the DNCB-induced elevation in infiltrating mast cells and macrophages, epidermal thickness, and AD symptoms. HPH also reduced TSLP levels and prevented FLG downregulation. Furthermore, it decreased the expression levels of IL-4, IL-5, IL-13, TARC, RANTES, and immunoglobulin E (IgE) in serum and AD-like skin lesion. Overall, our findings demonstrate that HPH effectively inhibits AD development and is a potentially useful therapeutic agent for AD-like skin disease.

Objective: Sleep is a potential risk factor for metabolic syndrome. We investigated the associations of various sleep characteristics with the status and incidence of metabolic syndrome in middle-aged Koreans., Methods: Using data from a community-based Korean Medicine Daejeon Citizen Cohort study on participants aged 30-50years, cross-sectional (n = 1984) and longitudinal (n = 1216, median follow-up: 2.1years) analyses were performed. To study the association of metabolic syndrome and five components with various sleep characteristics, measured using the Pittsburgh Sleep Quality Index, we used Poisson and logistic regression and Cox proportional hazard regression analyses, adjusting for covariates., Results: Of 1984 participants, 66%, 19%, and 15% belonged to the non-metabolic syndrome, pre-metabolic syndrome, and metabolic syndrome groups, respectively. After covariate adjustments, the pre-metabolic syndrome group was associated with late mid-sleep time (≥5:00; prevalence ratios 1.61, 95% confidence interval 1.01-2.54) and late bedtime (≥2:00; prevalence ratios 1.55, 95% confidence interval 1.03-2.34), and the metabolic syndrome group was associated with long sleep latency (prevalence ratios 1.33, 95% confidence interval 1.03-1.73), poor sleep quality (prevalence ratios 1.38, 95% confidence interval 1.07-1.78), and early wake time (<6:00; prevalence ratios 1.29, 95% confidence interval 1.01-1.63). Longitudinal analysis of participants without metabolic syndrome at baseline indicated a significant increase in metabolic syndrome risk associated with very short sleep duration (<6 hours; hazard ratio 1.72, 95% confidence interval 1.06-2.79), long sleep latency (>30 minutes; hazard ratio 1.86, 95% confidence interval 1.1-3.12), and early wake time (<6:00 o'clock; hazard ratio 1.73, 95% confidence interval 1.01-2.97)., Conclusion: Sleep characteristics, such as short duration, long latency, and early wake time, were associated with an increased risk of metabolic syndrome in middle-aged adults., Competing Interests: Declaration of conflicts of 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 Inc. All rights reserved.)

The oxidation of the cellular membrane through lipid peroxidation (LPO) is linked to aging and disease. Despite the physiological importance, the chemical mechanisms underlying LPO and oxidative reactions in membranes in general remain incompletely understood, and challenges exist in translating LPO inhibitor efficacies from in vitro to in vivo. The complexity of LPO, including multiple oxidation reactions in complex membrane environments and the difficulty in quantifying reaction kinetics, underlies these difficulties. In this work, we developed a robust and straightforward method for quantifying the oxidation rate kinetics of fluorescent molecules and determined the oxidation kinetics of widely fluorophores used as indicators of membrane LPO, diphenylhexatriene (DPH), BODIPY-C11, and Liperfluo. The measurement is initiated by lipoxygenase, which provides chemical specificity and enables a straightforward interpretation of oxidation kinetics. Our results reveal that the membrane composition significantly impacts the observed kinetics oxidation in DPH and BODIPY-C11 but not Liperfluo. Reaction mechanisms for their lipid peroxide-induced oxidation are proposed. This work provides a foundation for the quantitative analysis of LPO with fluorescence and extricating the complexity of oxidation reactions within membranes.

The development of greener and more sustainable synthesis processes for manufacturing commodity chemicals is of great importance. The majority of current phenol production methods involve harsh reaction conditions with high energy consumption, causing severe environmental pollution. In this study, we present a novel approach for the decarboxylation of hydroxybenzoic acids (HBAs) to phenol using a choline chloride-urea (ChCl-urea) deep eutectic solvent (DES). Our study reveals the remarkable dual performance of ChCl-urea both as a catalyst and solvent for the decarboxylation of HBA, resulting in a high phenol yield (94 mol%) under mild reaction conditions. The proposed reaction pathway, established through a combination of experiments and computational simulations, enhances our understanding of this process. The recyclability of the DES system during decarboxylation was also assessed. Our findings demonstrate that the integration of DES into conventional chemical processes can pave the way for sustainable manufacturing, exemplifying a novel approach for producing phenol from abundant natural resources using designer solvents., (© 2024 Wiley‐VCH GmbH.)

Migrasomes, the newly discovered cellular organelles that form large vesicle-like structures on the retraction fibers of migrating cells, are thought to be involved in communication between neighboring cells, cellular content transfer, unwanted material shedding, and information integration. Although their formation has been described previously, the molecular mechanisms of migrasome biogenesis are largely unknown. Here, we developed a cell line that overexpresses GFP-tetraspanin4, enabling observation of migrasomes. To identify compounds that regulate migrasome activity in retinal pigment epithelial (RPE) cells, we screened a fecal chemical library and identified cadaverine, a biogenic amine, as a potent migrasome formation inducer. Compared with normal migrating cells, those treated with cadaverine had significantly more migrasomes. Putrescine, another biogenic amine, also increased migrasome formation. Trace amine-associated receptor 8 (TAAR8) depletion inhibited migrasome increase in cadaverine-treated RPE cells, and cadaverine also inhibited protein kinase A phosphorylation. In RPE cells, cadaverine triggers migrasome formation via a TAAR8-mediated protein kinase A signaling pathway.

Dysfunction of the lymphatic system following injury, disease, or cancer treatment can lead to lymphedema, a debilitating condition with no cure. Advances in targeted therapy have shown promise for treating diseases where conventional therapies have been ineffective and lymphatic vessels have recently emerged as a new therapeutic target. Lipid nanoparticles (LNPs) have emerged as a promising strategy for tissue specific delivery of nucleic acids. Currently, there are no approaches to target LNPs to lymphatic endothelial cells, although it is well established that intradermal (ID) injection of nanoparticles will drain to lymphatics with remarkable efficiency. To design an LNP that would effectively deliver mRNA to LEC after ID delivery, we screened a library of 150 LNPs loaded with a reporter mRNA, for both self-assembly and delivery in vivo to lymphatic endothelial cells (LECs). We identified and validated several LNP formulations optimized for high LEC uptake when administered ID and compared their efficacy for delivery of functional mRNA with that of free mRNA and mRNA delivered with a commercially available MC3-based LNP (Onpattro ™ ). The lead LEC-specific LNP was then loaded with VEGFC mRNA to test the therapeutic advantage of the LEC-specific LNP (namely, LNP7) for treating a mouse tail lymphatic injury model. A single dose of VEGFC mRNA delivered via LNP7 resulted in enhanced LEC proliferation at the site of injury, and an increase in lymphatic function up to 14-days post-surgery. Our results suggest a therapeutic potential of VEGFC mRNA lymphatic-specific targeted delivery in alleviating lymphatic dysfunction observed during lymphatic injury and could provide a promising approach for targeted, transient lymphangiogenic therapy., Competing Interests: Competing interests: Dahlman, Dixon, Michalaki, and Tamburini are authors on a patent application associated with this work.

This study aims to figure out the worldwide prevalence of anticancer therapy-associated acute kidney injury (AKI) and tubulointerstitial nephritis (TIN) and the relative risk of each cancer drug. We conducted an analysis of VigiBase, the World Health Organization pharmacovigilance database, 1967-2023 via disproportionate Bayesian reporting method. We further categorized the anticancer drugs into four groups: cytotoxic therapy, hormone therapy, immunotherapy, and targeted therapy. Reporting odds ratio (ROR) and information component (IC) compares observed and expected values to investigate the associations of each category of anticancer drugs with AKI and TIN. We identified 32,722 and 2056 reports (male, n = 17,829 and 1,293) of anticancer therapy-associated AKI and TIN, respectively, among 4,592,036 reports of all-drug caused AKI and TIN. There has been a significant increase in reports since 2010, primarily due to increased reports of targeted therapy and immunotherapy. Immunotherapy exhibited a significant association with both AKI (ROR: 8.92; IC 0.25 : 3.06) and TIN (21.74; 4.24), followed by cytotoxic therapy (7.14; 2.68), targeted therapy (5.83; 2.40), and hormone therapy (2.59; 1.24) for AKI, and by cytotoxic therapy (2.60; 1.21) and targeted therapy (1.54; 0.61) for TIN. AKI and TIN were more prevalent among individuals under 45 years of age, with a female preponderance for AKI and males for TIN. These events were reported in close temporal relationship after initiation of the respective drug (16.53 days for AKI and 27.97 days for TIN), and exhibited a high fatality rate, with 23.6% for AKI and 16.3% for TIN. These findings underscore that kidney-related adverse drug reactions are of prognostic significance and strategies to mitigate such side effects are required to optimize anticancer therapy., (© 2024. The Author(s).)

The objective was to evaluate the performance of exploratory models containing routinely available on-farm data, behavior data, and the combination of both to predict metritis self-cure (SC) and treatment failure (TF). Holstein cows (n = 1,061) were fitted with a collar-mounted automated-health monitoring device (AHMD) from -21 ± 3 to 60 ± 3 d relative to calving to monitor rumination time and activity. Cows were examined for diagnosis of metritis at 4 ± 1, 7 ± 1, and 9 ± 1 d in milk (DIM). Cows diagnosed with metritis (n = 132), characterized by watery, fetid, reddish/brownish vaginal discharge (VD), were randomly allocated to 1 of 2 treatments: control (CON; n = 62), no treatment at the time of metritis diagnosis (d 0); or ceftiofur (CEF; n = 70), subcutaneous injection of 6.6 mg/kg of ceftiofur crystalline-free acid on d 0 and 3 relative to diagnosis. Cure was determined 12 d after diagnosis and was considered when VD became mucoid and not fetid. Cows in CON were used to determine SC, and cows in CEF were used to determine TF. Univariable analyses were performed using farm-collected data (parity, calving season, calving-related disorders, body condition score, rectal temperature, and DIM at metritis diagnosis) and behavior data (i.e., daily averages of rumination time, activity generated by AHMD, and derived variables) to assess their association with metritis SC or TF. Variables with P-values ≤0.20 were included in the multivariable logistic regression exploratory models. To predict SC, the area under the curve (AUC) for the exploratory model containing only data routinely available on-farm was 0.75. The final exploratory model to predict SC combining routinely available on-farm data and behavior data increased the AUC to 0.87, with sensitivity (Se) of 89% and specificity (Sp) of 77%. To predict TF, the AUC for the exploratory model containing only data routinely available on-farm was 0.90. The final exploratory model combining routinely available on-farm data and behavior data increased the AUC to 0.93, with Se of 93% and Sp of 87%. Cross-validation analysis revealed that generalizability of the exploratory models was poor, which indicates that the findings are applicable to the conditions of the present exploratory study. In summary, the addition of behavior data contributed to increasing the prediction of SC and TF. Developing and validating accurate prediction models for SC could lead to a reduction in antimicrobial use, whereas accurate prediction of cows that would have TF may allow for better management decisions., (The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Purpose: Limited knowledge exists regarding the psychosocial characteristics of young Asian children affected by food allergies (FAs) and their caregivers. This study aims to assess the usefulness of the Food Allergy Severity Score (FASS) system in evaluating the risk of emotional impacts on young children and caregivers who are dealing with severe FA., Methods: Children between 2 and 10 years of age who were diagnosed with FA and following an elimination diet were enrolled in the study. The FASS, Korean Parenting Stress Index, and Korean Behavior Assessment System for Children-2 were used for evaluating the above mentioned risk., Results: Among the 75 participants, 64.0% had a history of anaphylaxis, and 56.0% reported multiple FAs. A total of 160 cases of FASS was documented across 21 types of food and classified as mild (n = 5, 1.07), moderate (n = 100, 2.01-4.01), or severe (n = 55, 4.24-6.84). The concordance of calculated- and stakeholder interpreted-FASS was moderate (kappa 0.587). Children with severe FASS (sFASS) showed increased risk for functional communication (relative risk [RR], 1.57; 95% confidence interval [CI], 0.99-2.48) and increased parental reinforcement (RR, 1.40; 95% CI, 0.91-2.14). Their caregivers exhibited reduced levels of demandingness (RR, 0.59; 95% CI, 0.37-0.94) and role restriction (RR, 0.62; 95% CI, 0.39-0.98). Receiver operating characteristic curves suggested that functional communication (numeric FASS cutoff, 3.47; area under the curve [AUC], 0.695), withdrawal (cutoff, 3.40; AUC, 0.657), developmental social disorders (cutoff, 3.96; AUC, 0.648), and reinforces parent (cutoff, 3.15; AUC, 0.646) were possibly be affected., Conclusions: The FASS provides an objective tool to assess pediatric FA severity. Early psychosocial intervention for young children with severe FASS and their caregivers may improve prognosis by identifying possible adaptive skill deficiencies and excessive parenting stresses., Competing Interests: There are no financial or other issues that might lead to conflict of interest., (Copyright © 2024 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease.)

Background: Cognitive-behavioral therapy (CBT) is an evidence-supported treatment for adolescents with binge-eating disorder (BED). Executive dysfunctions, which are associated with binge eating and elevated body weight in youth, may undermine CBT outcomes by making it difficult for youth to engage with or adhere to treatment, including recalling and/or implementing intervention strategies in real-world contexts., Methods: We assessed 73 adolescents [82.2% female; M age  = 15.0 ± 2.5 year; M baseline standardized body mass index (zBMI) = 1.9 ± 1.0 kg/m 2 ] with BED at baseline, posttreatment, 6-, 12-, and 24-month follow-up. Linear mixed models examined the effects of baseline executive functioning (EF) on loss of control (LOC) eating and weight change following CBT. Linear and logistic regressions probed associations between EF, attendance, and attrition., Results: More impulsive decision-making, as reflected in higher baseline scores on the Iowa Gambling Task, predicted better attendance (β = .07; p = .019) and more frequent LOC eating following treatment (β = .12; p = .017). Lower cognitive flexibility, as reflected in lower baseline T-scores on the Comprehensive Trail Making Test complex sequencing index, predicted higher zBMI following treatment (β = -.03; p = .003). Inhibition, concentration, attention, and parent-reported EF behavior symptoms were not associated with outcome, attendance, or attrition., Conclusions: More impulsive decision-making and lower cognitive flexibility were associated with suboptimal response to CBT for BED, although findings should be interpreted with caution in light of the sample size and waitlist control design. Future research should examine whether strengthening EF could improve eating and weight outcomes among adolescents with BED who have lower pre-treatment EF., (© 2024 The Author(s). Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Purpose: ( 2S,4R )-4-[ 18 F]fluoroglutamine ([ 18 F]FGln) is a promising metabolic imaging marker in cancer. Based on the fact that major inflammatory cells are heavily dependent on glutamine metabolism like cancer cells, we explored the potential utility of [ 18 F]FGln as a metabolic imaging marker for inflammation in two rat models: carrageenan-induced paw edema (CIPE) and collagen-induced arthritis (CIA)., Procedures: The CIPE model (n = 4) was generated by injecting 200 μL of 3% carrageenan solution into the left hind paw three hours before the PET. The CIA model (n = 4) was generated by injecting 200 μg of collagen emulsion subcutaneously at the tail base 3-4 weeks before the PET. A qualitative scoring system was used to assess the severity of paw inflammation. After a CT scan, 15.7 ± 4.9 MBq of [ 18 F]FGln was injected via the tail vein, followed by a dynamic micro-PET scan for 90 minutes under anesthesia with isoflurane. The standard uptake value of [ 18 F]FGln was measured by placing a volume of interest in each paw. The non-injected right hind paws of the CIPE model rats served as controls for both models. The paws with CIA were pathologically examined after PET., Results: In CIPE models, uptake in the injected paw was higher compared to the non-injected paw by 52-83%. In CIA models, uptake in the paws with severe inflammation was higher than the averaged controls by 54-173%, while that with mild and no inflammation was slightly higher (33%) and lower (-7%), respectively. Combined overall, the [ 18 F]FGln uptake in CIA showed a significant positive correlation with inflammation severity ( r = 0.88, P = 0.009). The pathological findings confirmed profound inflammation in CIA., Conclusions: [ 18 F]FGln uptake was increased in both acute and chronic inflammation, and the uptake level was significantly correlated with the severity, suggesting its potential utility as a novel metabolic imaging marker for inflammation., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest.

Alzheimer's disease (AD) and related tauopathies are associated with pathological tau protein aggregation, which plays an important role in neurofibrillary degeneration and dementia. Targeted immunotherapy to eliminate pathological tau aggregates is known to improve cognitive deficits in AD animal models. The tau repeat domain (TauRD) plays a pivotal role in tau-microtubule interactions and is critically involved in the aggregation of hyperphosphorylated tau proteins. Because TauRD forms the structural core of tau aggregates, the development of immunotherapies that selectively target TauRD-induced pathological aggregates holds great promise for the modulation of tauopathies. In this study, we generated recombinant TauRD polypeptide that form neurofibrillary tangle-like structures and evaluated TauRD-specific immune responses following intranasal immunization in combination with the mucosal adjuvant FlaB. In BALB/C mice, repeated immunizations at one-week intervals induced robust TauRD-specific antibody responses in a TLR5-dependent manner. Notably, the resulting antiserum recognized only the aggregated form of TauRD, while ignoring monomeric TauRD. The antiserum effectively inhibited TauRD filament formation and promoted the phagocytic degradation of TauRD aggregate fragments by microglia. The antiserum also specifically recognized pathological tau conformers in the human AD brain. Based on these results, we engineered a built-in flagellin-adjuvanted TauRD (FlaB-TauRD) vaccine and tested its efficacy in a P301S transgenic mouse model. Mucosal immunization with FlaB-TauRD improved quality of life, as indicated by the amelioration of memory deficits, and alleviated tauopathy progression. Notably, the survival of the vaccinated mice was dramatically extended. In conclusion, we developed a mucosal vaccine that exclusively targets pathological tau conformers and prevents disease progression., (© 2024. The Author(s).)

Here, we show that insulin induces palmitoylation turnover of Caveolin-2 (Cav-2) in adipocytes. Acyl protein thioesterases-1 (APT1) catalyzes Cav-2 depalmitoylation, and zinc finger DHHC domain-containing protein palmitoyltransferase 21 (ZDHHC21) repalmitoylation of the depalmitoylated Cav-2 for the turnover, thereby controlling insulin receptor (IR)-Cav-2-insulin receptor substrate-1 (IRS-1)-Akt-driven signaling. Insulin-induced palmitoylation turnover of Cav-2 facilitated glucose uptake and fat storage through induction of lipogenic genes. Cav-2-, APT1-, and ZDHHC21-deficient adipocytes, however, showed increased induction of lipolytic genes and glycerol release. In addition, white adipose tissues from insulin sensitive and resistant obese patients exhibited augmented expression of LYPLA1 (APT1) and ZDHHC20 (ZDHHC20). Our study identifies the specific enzymes regulating Cav-2 palmitoylation turnover, and reveals a new mechanism by which insulin-mediated lipid metabolism is controlled in adipocytes., Competing Interests: Declaration of competing interest All 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 Elsevier B.V. All rights reserved.)

This study assesses the need for education in forensic medicine and forensic radiology among radiographers by investigating the perceptions and experiences of Korean radiographers working in medical institutions. A structured questionnaire was administered to participants, collected, and analyzed. The results showed that despite receiving frequent forensic cases, Korean radiographers face difficulties in taking appropriate measures about forensic radiology due to a lack of awareness and knowledge of its forensic aspects. The participants indicated that university education in forensic medicine and forensic radiology is necessary. Therefore, it is imperative to develop and implement policies for forensic education programs to enhance radiographers' forensic knowledge and capabilities. Universities should conduct courses on forensic radiology and provide continuing education for radiographers working in this field., Competing Interests: 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., (© 2024 The Authors. Published by Elsevier Ltd.)

Introduction: Stenotic thoracic ligamentum flavum hypertrophy can cause leg and/or low back pain similar to that caused by lumbar spinal stenosis. However, the thoracic spine may occasionally be overlooked in patients with leg and/or low back pain. An accurate understanding of the prevalence of stenotic thoracic ligamentum flavum hypertrophy and its associated factors is necessary., Methods: In this prevalence study, we reviewed whole-spine MRI scans of patients who visited the pain clinic complaining of leg and/or low back pain between 2010 and 2019. We analyzed the overall prevalence and prevalence according to the age group, sex, grade of lumbar disc degeneration, and thoracic level. In addition, we identified factors independently associated with stenotic thoracic ligamentum flavum hypertrophy occurrence., Results: Among 1896 patients, the overall prevalence of stenotic thoracic ligamentum flavum hypertrophy was 9.8% (185/1896), with the highest prevalence observed in the ≥80-year-old age group among all age groups (15.9%, 14/88). The region with the highest prevalence was the T10/11 level (3.0%, 57/1896). Multivariable logistic regression analysis revealed that when compared with the <50-year-old age group, all other age groups were significantly associated with stenotic thoracic ligamentum flavum hypertrophy (p<0.01). In addition, grade 5 of lumbar disc degeneration was significantly associated with stenotic thoracic ligamentum flavum hypertrophy (p=0.03)., Conclusions: Given the possibility for missed stenotic thoracic ligamentum flavum hypertrophy to potentially result in neurological complications, extending lumbar spine MRI covering the lower thoracic region may be considered for patients over 50 years of age with suspected severe lumbar disc degeneration., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Molecular analysis of advanced tumors can increase tumor heterogeneity and selection bias. We developed a robust prognostic signature for gastric cancer by comparing RNA expression between very rare early gastric cancers invading only mucosal layer (mEGCs) with lymph node metastasis (Npos) and those without metastasis (Nneg)., Methods: Out of 1003 mEGCs, all Npos were matched to Nneg using propensity scores. Machine learning approach comparing Npos and Nneg was used to develop prognostic signature. The function and robustness of prognostic signature was validated using cell lines and external datasets., Results: Extensive machine learning with cross-validation identified the prognostic classifier consisting of four overexpressed genes (HDAC5, NPM1, DTX3, and PPP3R1) and two downregulated genes (MED12 and TP53), and enabled us to develop the risk score predicting poor prognosis. Cell lines engineered to high-risk score showed increased invasion, migration, and resistance to 5-FU and Oxaliplatin but maintained sensitivity to an HDAC inhibitor. Mouse models after tail vein injection of cell lines with high-risk score revealed increased metastasis. In three external cohorts, our risk score was identified as the independent prognostic factor for overall and recurrence-free survival., Conclusion: The risk score from the 6-gene classifier can successfully predict the prognosis of gastric cancer., (© 2024. The Author(s).)

High-grade neuroendocrine cervical cancers (NETc) are exceedingly rare, highly aggressive tumors. We analyzed 64 NETc tumor samples by whole-exome sequencing (WES). Human papillomavirus DNA was detected in 65.6% (42/64) of the tumors. Recurrent mutations were identified in PIK3CA, KMT2D/MLL2, K-RAS, ARID1A, NOTCH2, and RPL10. The top mutated genes included RB1, ARID1A, PTEN, KMT2D / MLL2, and WDFY3, a gene not yet implicated in NETc. Somatic CNV analysis identified two copy number gains (3q27.1 and 19q13.12) and five copy number losses (1p36.21/5q31.3/6p22.2/9q21.11/11p15.5). Also, gene fusions affecting the ACLY-CRHR1 and PVT1-MYC genes were identified in one of the eight samples subjected to RNA sequencing. To resolve evolutionary history, multiregion WES in NETc admixed with adenocarcinoma cells was performed (i.e., mixed-NETc). Phylogenetic analysis of mixed-NETc demonstrated that adenocarcinoma and neuroendocrine elements derive from a common precursor with mutations typical of adenocarcinomas. Over one-third (22/64) of NETc demonstrated a mutator phenotype of C > T at CpG consistent with deficiencies in MBD4 , a member of the base excision repair (BER) pathway. Mutations in the PI3K/AMPK pathways were identified in 49/64 samples. We used two patient-derived-xenografts (PDX) (i.e., NET19 and NET21) to evaluate the activity of pan-HER (afatinib), PIK3CA (copanlisib), and ATR (elimusertib) inhibitors, alone and in combination. PDXs harboring alterations in the ERBB2/PI3K/AKT/mTOR/ATR pathway were sensitive to afatinib, copanlisib, and elimusertib ( P < 0.001 vs. controls). However, combinations of copanlisib/afatinib and copanlisib/elimusertib were significantly more effective in controlling NETc tumor growth. These findings define the genetic landscape of NETc and suggest that a large subset of these highly lethal malignancies might benefit from existing targeted therapies., Competing Interests: Competing interests statement:A.D.S. is listed as author in a paper (i.e., N. Engl. J. Med. 2022; 386:437–448, DOI: 10.1056/NEJMoa2108330) where G.E.K. is listed as group author. A.D.S. had no interactions with G.E.K. (or any other of the 309-KEYNOTE-775 multicenter clinical trial Investigators) over the course of the research and writing of this paper.

Background: IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis, although the definitive markers are unknown. We aimed to investigate the clinical significance of urinary cytokines in patients with IgAN., Methods: From 2009 to 2018, the patients were divided into three groups: IgAN (n = 191), disease control (n = 53), and normal control (n = 76). We used a multiplex enzyme-linked immunosorbent assay to measure 16 selected urinary inflammatory cytokines, evaluated the correlation between clinical and pathological features following regression analysis on progression., Results: The IgAN group exhibited significantly different levels of urinary cytokines compared to the normal control and disease control groups. Urinary levels of B-cell-activating factor, vascular endothelial growth factor receptor-2, monocyte chemoattractant protein-1, C-X-C motif chemokine 10, C-X-C motif ligand 16, epidermal growth factor (EGF), endocan, endostatin, growth/differentiation factor-15 (GDF-15), interleukin-6 (IL-6), mannose-binding lectin, transferrin receptor, and kidney injury molecule-1 were significantly correlated with both the estimated glomerular filtration rate and urine protein-creatinine ratio. In a multivariate Cox regression analysis, urinary EGF (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.17-0.95, P = 0.04), GDF-15 (HR 2.45, 95% CI 1.01-5.94, P = 0.048), and IL-6 (HR 3.02, 95% CI 1.05-8.64, P = 0.04) were associated with progression in IgAN., Conclusions: Urinary inflammatory biomarkers may serve as alternative predictive biomarkers in patients with IgAN. Further studies are needed to elucidate the physiological mechanisms and confirm the results., (© 2024. The Author(s).)

Background: Atherosclerosis preferentially occurs in arterial regions of disturbed blood flow, and stable flow (s-flow) protects against atherosclerosis by incompletely understood mechanisms., Methods: Our single-cell RNA-sequencing data using the mouse partial carotid ligation model was reanalyzed, which identified Heart-of-glass 1 (HEG1) as an s-flow-induced gene. HEG1 expression was studied by immunostaining, quantitive polymerase chain reaction, hybridization chain reaction, and Western blot in mouse arteries, human aortic endothelial cells (HAECs), and human coronary arteries. A small interfering RNA-mediated knockdown of HEG1 was used to study its function and signaling mechanisms in HAECs under various flow conditions using a cone-and-plate shear device. We generated endothelial-targeted, tamoxifen-inducible HEG1 knockout (HEG1 iECKO ) mice. To determine the role of HEG1 in atherosclerosis, HEG1 iECKO and littermate-control mice were injected with an adeno-associated virus-PCSK9 [proprotein convertase subtilisin/kexin type 9] and fed a Western diet to induce hypercholesterolemia either for 2 weeks with partial carotid ligation or 2 months without the surgery., Results: S-flow induced HEG1 expression at the mRNA and protein levels in vivo and in vitro. S-flow stimulated HEG1 protein translocation to the downstream side of HAECs and release into the media, followed by increased messenger RNA and protein expression. HEG1 knockdown prevented s-flow-induced endothelial responses, including monocyte adhesion, permeability, and migration. Mechanistically, HEG1 knockdown prevented s-flow-induced KLF2/4 (Kruppel-like factor 2/4) expression by regulating its intracellular binding partner KRIT1 (Krev interaction trapped protein 1) and the MEKK3-MEK5-ERK5-MEF2 pathway in HAECs. Compared with littermate controls, HEG1 iECKO mice exposed to hypercholesterolemia for 2 weeks and partial carotid ligation developed advanced atherosclerotic plaques, featuring increased necrotic core area, thin-capped fibroatheroma, inflammation, and intraplaque hemorrhage. In a conventional Western diet model for 2 months, HEG1 iECKO mice also showed an exacerbated atherosclerosis development in the arterial tree in both sexes and the aortic sinus in males but not in females. Moreover, endothelial HEG1 expression was reduced in human coronary arteries with advanced atherosclerotic plaques., Conclusions: Our findings indicate that HEG1 is a novel mediator of atheroprotective endothelial responses to flow and a potential therapeutic target., Competing Interests: Disclosures Dr Jo is the founder of Flokines Pharma. The other authors report no conflicts.

The primary constituents of honeybee venom, melittin and phospholipase A 2 (PLA 2 ), display toxin synergism in which the PLA 2 activity is significantly enhanced by the presence of melittin. It has been shown previously that this is accomplished by the disruption in lipid packing, which allows PLA 2 to become processive on the membrane surface. In this work, we show that melittin is capable of driving miscibility phase transition in giant unilamellar vesicles (GUVs) and that it raises the miscibility transition temperature ( T misc ) in a concentration-dependent manner. The induced phase separation enhances the processivity of PLA 2 , particularly at its boundaries, where a substantial difference in domain thickness creates a membrane discontinuity. The catalytic action of PLA 2 , in response, induces changes in the membrane, rendering it more conducive to melittin binding. This, in turn, facilitates further lipid phase separation and eventual vesicle lysis. Overall, our results show that melittin has powerful membrane-altering capabilities that activate PLA 2 in various membrane contexts. More broadly, they exemplify how this biochemical system actively modulates and capitalizes on the spatial distribution of membrane lipids to efficiently achieve its objectives.

Herein, we conducted a comprehensive statistical assessment of the ultrasonic pulse velocity (UPV) method's effectiveness in predicting concrete strength under diverse conditions, specifically early age, middle age, and high-temperature exposure. The concrete mixtures, with water-to-cement (W/C) ratios of 0.33 and 0.28, were classified as granite aggregate or coal-ash aggregate mixes. Compressive strength and UPV measurements were performed under these conditions, and subsequent statistical analyses treated the identified factors as distinct groups. The results revealed a substantial difference in compressive strength between specimens at early age (average of 13.01) and those at middle age (average of 41.96) and after high-temperature exposure (average of 48.08). Conversely, UPV analysis showed an insignificant difference between the early-age specimens and those after high-temperature exposure. The analysis of the W/C ratio and coarse aggregate demonstrated significant differences ( p -value < 0.05) in compressive strength between specimens in middle age and those exposed to high temperatures, excluding the early-age specimens. However, UPV analysis revealed insignificant differences, with p -values of 0.67 and 0.38 between specimens at an early age and post-high-temperature exposure, respectively. Regression analysis identified suitable functions for each scenario, emphasizing the importance of a strength prediction model for concrete after high-temperature exposure, particularly considering the W/C ratio. Since concrete showed statistically different compressive strength, UPV, and strength prediction models in three conditions (early age, middle age, and high temperature), different strength prediction models must be used for the purpose of accurately predicting the strength of concrete.

Background: Recently, the target systolic blood pressure (BP) <120 mm Hg was suggested in the population with chronic kidney disease. We aimed to determine the applicability of intensified BP and to assess the incidence of cardiovascular disease (CVD) in the population with chronic kidney disease., Methods and Results: Participants who were >20 years old and had estimated glomerular filtration rate 15 to 60 mL/min per 1.73 m 2 during 2009 to 2011 were included from the database of Korean National Health Insurance Service and were followed up to 2018. Participants were categorized by BP as <120/80 mm Hg; 120 to 129/<80 mm Hg; 130 to 139/80 to 89 mm Hg; ≥140/90 mm Hg. The primary outcome was CVD risk and the secondary outcomes were all-cause mortality and progression to end-stage renal disease followed by subgroup analysis. Among the 45 263 adults with chronic kidney disease, 5196 CVD events were noted. In Cox regression analysis, higher BP was associated with a higher risk for CVD (hazard ratio [HR], 1.15 [95% CI, 1.12-1.19]; P for trend <0.001), end-stage renal disease (HR, 1.29 [95% CI, 1.22-1.37]; P for trend <0.001), and all-cause mortality (HR, 1.09 [95% CI, 1.06-1.13]; P for trend <0.001) than BP <120/80 mm Hg. In subgroup analysis, the association between BP and CVD showed a different trend in participants taking antihypertensives compared with those not using antihypertensive drugs. When comparing BP-treated individuals to untreated individuals, a significant interaction in the association between BP categories and end-stage renal disease was observed., Conclusions: The new intensive BP target proposed by 2021 Kidney Disease: Improving Global Outcomes should be applied to patients with chronic kidney disease in a personalized and advisory manner.

Vascular smooth muscle cells (VSMCs) are crucial components of the arterial wall, controlling blood flow and pressure by contracting and relaxing the artery walls. VSMCs can switch from a contractile to a synthetic state, leading to increased proliferation and migratory potential. Epigenetic pathways, including DNA methylation, play a crucial role in regulating VSMC differentiation and phenotypic flexibility. DNA methylation involves attaching a methyl group to the 5' carbon of a cytosine base, which regulates gene expression by interacting with transcription factors. Understanding the key factors influencing VSMC plasticity may help to identify new target molecules for the development of innovative drugs to treat various vascular diseases. This review focuses on DNA methylation pathways in VSMCs, summarizing mechanisms involved in controlling vascular remodeling, which can significantly enhance our understanding of related mechanisms and provide promising therapeutic approaches for complex and multifactorial diseases.

Rare diseases are underrepresented in biomedical research, leading to insufficient awareness. Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare disease caused by genetic alterations that result in heterozygous loss of function of SON. While patients with ZTTK syndrome live with numerous symptoms, the lack of model organisms hampers our understanding of SON and this complex syndrome. Here, we developed Son haploinsufficiency (Son+/-) mice as a model of ZTTK syndrome and identified the indispensable roles of Son in organ development and hematopoiesis. Son+/- mice recapitulated clinical symptoms of ZTTK syndrome, including growth retardation, cognitive impairment, skeletal abnormalities, and kidney agenesis. Furthermore, we identified hematopoietic abnormalities in Son+/- mice, including leukopenia and immunoglobulin deficiency, similar to those observed in human patients. Surface marker analyses and single-cell transcriptome profiling of hematopoietic stem and progenitor cells revealed that Son haploinsufficiency shifted cell fate more toward the myeloid lineage but compromised lymphoid lineage development by reducing genes required for lymphoid and B cell lineage specification. Additionally, Son haploinsufficiency caused inappropriate activation of erythroid genes and impaired erythropoiesis. These findings highlight the importance of the full gene expression of Son in multiple organs. Our model serves as an invaluable research tool for this rare disease and related disorders associated with SON dysfunction.

Topological insulators have recently received attention in optoelectronic devices because of their high mobility and broadband absorption resulting from their topological surface states. In particular, theoretical and experimental studies have emerged that can improve the spin generation efficiency in a topological insulator-based p-n junction structure called a TPNJ, drawing attention in optospintronics. Recently, research on implementing the TPNJ structure is conducted; however, studies on the device characteristics of the TPNJ structure are still insufficient. In this study, the TPNJ structure is effectively implemented without intermixing by controlling the annealing temperature, and the photocharacteristics appearing in the TPNJ structure are investigated using a cross-pattern that can compare the characteristics in a single device. Enhanced photo characteristics are observed for the TPNJ structure. An optical pump Terahertz probe and a physical property measurement system are used to confirm the cause of improved photoresponsivity. Consequently, the photocharacteristics are improved owing to the change in the absorption mechanism and surface transport channel caused by the Fermi level shift in the TPNJ structure., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Purpose: Despite the risk of anaphylaxis, oral food challenges (OFCs) are performed clinically for various indications, particularly to confirm tolerance development. This study aimed to assess OFCs by relevant indications and build an outcome prediction model to help determine when to perform OFCs in children who are likely to have developed immune tolerance., Methods: In total, 432 pediatric OFCs were retrospectively analyzed according to indications. Clinical characteristics, serum total immunoglobulin (Ig) E, blood eosinophils, and specific IgE and IgG4 levels for food allergens were noted and compared. Machine learning was utilized to select the most important variables in determining the passage of the OFCs, and prediction models were constructed using the selected variables., Results: OFCs were most commonly performed to confirm tolerance development (number, %; 267, 61.8%). The most common food allergens tested were egg (191, 44.2%) and milk (135, 31.3%). Children who passed the egg challenges for confirming tolerance acquisition had significantly lower egg white-specific IgE level ( P = 0.008). Similarly, those who passed milk challenges had significantly lower cow's milk-specific IgE ( P = 0.002) and casein-specific IgE levels ( P = 0.005). We developed a nomogram to predict the outcome of OFCs to determine the tolerance acquisition with the selected variables; lower food-specific IgE, higher total IgE, and younger age indicated a higher probability of passage. The area under the curve (95% confidence interval) was 0.623 (0.503-0.743) for egg and 0.734 (0.628-0.840) for milk., Conclusions: Serum total IgE and food-specific IgE combined with age showed trends toward passing OFCs for confirming tolerance development. The constructed model may be used by clinicians as a practical guide for minimizing the risks of OFCs and a timely reintroduction for children with food allergies., Competing Interests: There are no financial or other issues that might lead to conflict of interest., (Copyright © 2024 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease.)