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Introduction: Depression has emerged as a modifiable risk factor for cardiovascular disease (CVD). However, evidence on whether depressive symptoms measured using a self-report questionnaire are associated with CVD incidence is scarce. Therefore, we aimed to investigate the association between depressive symptoms and CVD risk using data from national health examinations and insurance claim records., Methods: This retrospective cohort study included participants who underwent the Korean National Screening Program for Transitional Ages at age 66 years between 2007 and 2017. The presence of depressive symptoms was defined as affirmative responses to any of three questions (loss of activities and interests, worthlessness, and hopelessness) selected from the Geriatric Depression Scale. Incident composite CVD event included myocardial infarction, stroke, heart failure, and CVD death. The association between depressive symptoms and CVD risk was evaluated using hazard ratios (HRs) and 95 % confidence intervals (CIs) estimated with Cox proportional hazards models., Results: Among 88,765 participants (48.5 % women) aged 66 years, 4036 incident CVD events occurred during a mean follow-up of 6.8 years. Participants with depressive symptoms had a significantly higher risk of CVD than those without depressive symptoms (adjusted HR = 1.16 [95 % CI: 1.07-1.24]). The three individual depressive symptoms showed similar associations with CVD risk (loss of activities and interests, adjusted HR = 1.17 [95 % CI: 1.08-1.26]; worthlessness, 1.15 [1.03-1.29]; hopelessness, 1.13 [1.01-1.26])., Limitations: The study was limited to participants aged 66 years. Despite extensive adjustment for potential confounders and multiple sensitivity analyses, residual confounding and reverse causality could not be ruled out., Conclusion: The presence of depressive symptoms was associated with an increased risk of CVD. Screening for depressive symptoms in the general population may effectively mitigate the burden of CVD., Competing Interests: Declaration of competing interest The authors declare no competing interests related to this study., (Copyright © 2024. Published by Elsevier B.V.)

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

Objective: This study aimed to assess the efficacy and safety of intravenous ramosetron for pain relief in patients with fibromyalgia (FM) unresponsive to conventional treatments., Methods: In this prospective, double-blind, placebo-controlled trial, 80 FM patients were randomly allocated to receive either placebo (n = 40) or ramosetron (n = 40) at a dosage of 0.3 mg/day intravenously for five consecutive days. The primary outcome was the reduction in pain intensity at the end of the treatment period, evaluated using a visual analogue scale (VAS). Secondary outcome measures included the FM Impact Questionnaire, Beck Depression Inventory (BDI), Multi-Dimensional Health Assessment Questionnaire (MDHAQ), EQ-5D and State-Trait Anxiety Inventory on days 5 (end of treatment), 7, 10 and 28. Safety was continuously monitored throughout the study., Results: At the end of the treatment phase, the ramosetron group demonstrated a significantly greater reduction in VAS pain scores compared with the placebo group (1.18 ± 1.60 vs 0.54 ± 1.59, P < 0.05). Additionally, the ramosetron group exhibited significant improvements in BDI (4.42 ± 5.18 vs 1.33 ± 4.87, P < 0.05) and MDHAQ pain scale (0.37 ± 0.74 vs 0.04 ± 0.52, P < 0.05) scores. However, these improvements in pain VAS and BDI scores were not sustained through day 28. The safety profile of ramosetron was favorable, with gastrointestinal symptoms, particularly constipation, being the most commonly reported adverse events., Conclusions: Intravenous administration of ramosetron provided safe and effective short-term relief of pain intensity in FM patients with inadequate response to standard treatments., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: This study aimed to evaluate the expression of microRNAs (miRNAs) and inflammasomes in diabetes-induced retinal cells and to determine their role in the pathogenesis of diabetic retinopathy (DR)., Methods: To establish diabetes-induced cell models, ARPE-19 cells were treated with high glucose. The expression levels of five miRNAs (miR-185, miR-17, miR-20a, miR-15a, and miR-15b) were measured in high glucose-treated ARPE-19 cells using real-time quantitative polymerase chain reaction. Western blotting was performed to measure inflammasome expression in cellular models. miR-17 was selected as the target miRNA, and inflammasome expression was measured following the transfection of an miR-17 mimic into high glucose-treated ARPE-19 cells., Results: In high glucose-treated ARPE-19 cells, miRNA expression was substantially downregulated, whereas that of inflammasome components was significantly increased. Following the transfection of the miR-17 mimic into high glucose-treated ARPE-19 cells, the levels of inflammasome components were significantly decreased., Conclusions: This study investigated the relationship between miRNAs and inflammasomes in diabetes-induced cells using high glucose-treated ARPE-19 cells. These findings suggested that miR-17 suppresses inflammasomes, thereby reducing the subsequent inflammatory response and indicating that miRNAs and inflammasomes could serve as new therapeutic targets for DR., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Ji Hong Kim et al.)

This report describes the successful intrahepatic duct incision and closure for the treatment of multiple cholelithiasis in a dog with untreated hypothyroidism. A 12-year-old spayed female Spitz dog weighing 11.3 kg was diagnosed with multiple cholelithiasis, and a quadrate liver lobectomy and cholecystectomy were performed. Large gallstones were located in the left liver lobe's intrahepatic duct distal to the anastomosis of the intrahepatic ducts of the left medial and lateral lobes. The dilated intrahepatic duct was packed off with wet gauze, and incision and closure were performed on the most dilated section, which was proximal to the largest gallstone. After surgery, the patient showed normal liver function and was discharged with normal total bilirubin and C-reactive protein levels. On postoperative day 83, no stones were observed in the dilated common bile duct (CBD), and the degree of dilatation of the CBD had decreased from 9 mm to 4 mm, with no obstructions. Right intrahepatic gallstones were confirmed without dilatation. Hypothyroidism was managed medically. Hepatic duct incision and closure can be performed in dogs with multiple cholelithiasis. Although not the first option, intrahepatic bile duct incision proves to be a new alternative for the successful treatment of cholelithiasis in dogs.

High-aspect-ratio patterns are required for next-generation three-dimensional (3D) semiconductor devices. However, it is challenging to eliminate voids and seams during gap-filling of these high-aspect-ratio patterns, such as deep trenches, especially for nanoscale high-aspect-ratio patterns. In this study, a SiO 2 plasma-enhanced atomic layer deposition process incorporated with ion collision using bias power to the substrate was used for bottom-up trench gap-filling. The effect of bias power frequency on SiO 2 trench gap-filling was then investigated. Results showed that changes in bias power frequency did not significantly change the process rate, such as SiO 2 growth per cycle. At relatively low bias power frequencies, high-energy ions formed an overhang at the entrance of the high-aspect-ratio trench pattern through sputter etching and redeposition, blocking the pattern entrance. However, at relatively high-frequency bias power, overhang formation due to sputtering did not occur. In the trench interior, due to a scattering effect of ions, deposition was thicker at the bottom of the trench than that at the top, achieving bottom-up gap-filling and void-free gap-filling.

The systemic delivery of oligonucleotide therapeutics to the brain is challenging but highly desirable for the treatment of brain diseases undruggable with traditional small-molecule drugs. In this study, a set of DNA nanostructures is prepared and screened them to develop a protein corona-assisted platform for the brain delivery of oligonucleotide therapeutics. The biodistribution analysis of intravenously injected DNA nanostructures reveals that a cube-shaped DNA nanostructure (D-Cb) can penetrate the brain-blood barrier (BBB) and reach the brain tissue. The brain distribution level of D-Cb is comparable to that of other previous nanoparticles conjugated with brain-targeting ligands. Proteomic analysis of the protein corona formed on D-Cb suggests that its brain distribution is driven by endothelial receptor-targeting ligands in the protein corona, which mediate transcytosis for crossing the BBB. D-Cb is subsequently used to deliver an antisense oligonucleotide (ASO) to treat glioblastoma multiforme (GBM) in mice. While free ASO is unable to reach the brain, ASO loaded onto D-Cb is delivered efficiently to the brain tumor region, where it downregulates the target gene and exerts an anti-tumor effect on GBM. D-Cb is expected to serve as a viable platform based on protein corona formation for systemic brain delivery of oligonucleotide therapeutics., (© 2024 The Author(s). Small Methods published by Wiley‐VCH GmbH.)

Background/objectives: Given that adolescents watch Mukbang (eating broadcast) more frequently than other age groups, interest in the potential health effects of watching Mukbang and Cookbang (cooking broadcast) is growing. This study aimed to determine the status of watching Mukbang and Cookbang among Korean adolescents and its relationship with their dietary behaviors., Subjects/methods: We used data from the 18th Korea Youth Risk Behavior Survey, conducted in 2022 (n = 51,850). The study included the frequency of watching Mukbang and Cookbang and the self-rated impact of watching them. Dietary behaviors included consumption of the following items: fruits (≥ once a day), vegetables (≥ 3 times a day), fast foods (≥ 3 times a week), late-night snacks (≥ 3 times a week), caffeinated drinks (≥ 3 times a week), and sweet-flavored drinks (≥ 3 times a week). Furthermore, obesity, weight loss attempts during the past 30 days, body image distortion, and inappropriate methods to control weight were also included., Results: Among adolescents, 70.6% watched Mukbang and Cookbang, and 13.2% watched them more than 5 times a week. Approximately 27.6% of the adolescents responded that they were influenced by watching Mukbang and Cookbang. Adolescents who frequently watched Mukbang and Cookbang consumed less vegetable and fruit; however, the likelihood of consuming fast food, late-night snacks, sugary drinks, and caffeinated drinks increased. In addition, they were more likely to attempt inappropriate weight-loss methods and become obese. Adolescents who responded that their eating habits were influenced by watching Mukbang and Cookbang were more likely to have unhealthy eating behavior compared to the group who responded that their habits were not influenced by these shows., Conclusion: Watching Mukbang and Cookbang is common among Korean adolescents and is associated with unhealthy dietary behaviors. Prospective studies, including broadcasting content, should evaluate the impact of Mukbang and Cookbang on health., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interests., (©2024 The Korean Nutrition Society and the Korean Society of Community Nutrition.)

Objectives: To analyze the characteristics of spinal metastasis in CT scans across diverse cancers for effective diagnosis and treatment, using MRI as the gold standard., Methods: A retrospective study of 309 patients from four centers, who underwent concurrent CT and spinal MRI, revealing spinal metastasis, was conducted. Data on metastasis including total number, volume, visibility on CT (visible, indeterminate, or invisible), and type of bone change were collected. Through chi-square and Mann-Whitney U tests, we characterized the metastasis across diverse cancers and investigated the variation in the intra-individual ratio representing the percentage of lesions within each category for each patient., Results: Out of 3333 spinal metastases from 309 patients, 55% were visible, 21% indeterminate, and 24% invisible. Sclerotic and lytic lesions made up 47% and 43% of the visible and indeterminate categories, respectively. Renal cell carcinoma (RCC), prostate cancer, and hepatocellular carcinoma (HCC) had the highest visibility at 86%, 73%, and 67% (p < 0.0001, p < 0.0001, and p = 0.003), while pancreatic cancer was lowest at 29% (p < 0.0001). RCC and HCC had significantly high lytic metastasis ratios (interquartile range (IQR) 0.96-1.0 and 0.31-1.0, p < 0.001 and p = 0.005). Prostate cancer exhibited a high sclerotic lesion ratio (IQR 0.52-0.97, p < 0.001). About 39% of individuals had invisible or indeterminate lesions, even with a single visible lesion on CT. The intra-individual ratio for indeterminate and invisible metastases surpassed 18%, regardless of the maximal size of the visible metastasis., Conclusions: This study highlights the variability in characteristics of spinal metastasis based on the primary cancer type through unique lesion-centric analysis., (© 2024. The Author(s), under exclusive licence to International Skeletal Society (ISS).)

Background: Respiratory syncytial virus (RSV), a highly transmissible virus, is the leading cause of lower respiratory tract infections. We examined molecular changes in the RSV genome before and after the coronavirus disease 2019 (COVID-19) pandemic in Korea, and investigated whether drug-resistant mutations were present., Methods: In this prospective, single-center study, RSV-positive respiratory samples were collected between September 2019 and December 2022. Long-read whole-genome sequencing (WGS) was performed, and the presence of known drug-resistant substitutions for palivizumab, nirsevimab, and suptavumab was investigated., Results: Overall, 288 respiratory samples were collected from 276 children. WGS data were available for 133 samples (71 and 62 samples from the pre- and post-pandemic periods, respectively). All RSV-A strains (n = 56) belonged to the GA2.3.5 (ON1) genotype, whereas all RSV-B strains (n = 77) belonged to the GB5.0.5a (BA) genotype. No significant differences in genotypes were observed between the pre- and post-pandemic periods. In addition, no notable mutations related to nirsevimab or palivizumab resistance were detected in the F gene. However, the L172Q and S173L substitutions, which are known to confer resistance to suptavumab, were present in all RSV-B samples., Conclusion: Despite the unprecedented interruption of RSV seasonality, there were no significant molecular changes in circulating RSV strains in Korea related to nirsevimab or palivizumab resistance before and after the COVID-19 pandemic. However, RSV-specific drug-resistance substitutions for suptavumab were identified., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Desertification is known to be a major threat to biodiversity, yet our understanding of the consequent decline in biodiversity remains insufficient. Here, we predicted climate change-induced range shifts and genetic diversity losses in three model dung beetles: Colobopterus erraticus, Cheironitis eumenes, and Gymnopleurus mopsus, distributed across the Gobi Desert and Mongolian Steppe, areas known for desertification. Phylogeographic analyses of mitochondrial COI sequences and species distribution modeling, based on extensive field investigations spanning 14 years, were performed. Species confined to a single biome were predicted to contract and shift their distribution in response to climate change, whereas widespread species was predicted to expand even if affected by range shifts. We indicated that all species are expected to experience significant haplotype losses, yet the presence of high singleton frequencies and low genetic divergence across geographic configurations and lineages mitigate loss of genetic diversity. Notably, Cheironitis eumenes, a desert species with low genetic diversity, appears to be the most vulnerable to climate change due to the extensive degradation in the Gobi Desert. This is the first study to predict the response of insects to desertification in the Gobi Desert. Our findings highlight that dung beetles in the Gobi Desert and Mongolian Steppe might experience high rates of occupancy turnover and genetic loss, which could reshuffle the species composition., (© 2024. The Author(s).)

Glaucoma remains the primary cause of long-term blindness. While diabetes mellitus (DM) and hypertension (HTN) are known to influence glaucoma, other factors such as age and sex may be involved. In this retrospective study, we aimed to investigate the associations between age, sex, DM, HTN, and glaucoma risk. We employed optical coherence tomography (OCT) conducted using a 200 × 200-pixel optic cube (Cirrus HD OCT 6000, version 10.0; Carl Zeiss Meditec, Dublin, CA, USA). Effects obscured by low-test signals were disregarded. Data were amassed from 1337 patients. Among them, 218 and 402 patients had DM and HTN, respectively, with 133 (10%) exhibiting both. A sex-based comparison revealed slightly greater retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness in females. Patients without DM and HTN were predominantly in their 50 s and 60 s, whereas DM and HTN were most prevalent in those in their 60 s and 70 s. Both RNFL and GCIPL thicknesses decreased with advancing age in most patients. The study revealed that older individuals were more prone to glaucoma than younger individuals, with a higher incidence among patients with DM and HTN and reduced RNFL and GCIPL thicknesses. Furthermore, early detection before advancing age could furnish valuable preventive insights.

Objective: The purpose of this study is to evaluate the impact of tumor necrosis factor (TNF)-α blocker therapy on the Assessment of SpondyloArthritis international Society Health Index (ASAS-HI) among patients who have failed conventional nonsteroidal anti-inflammatory drugs., Methods: A comparative study was conducted involving axial spondyloarthritis (axSpA) patients treated with either TNF-α blocker or conventional therapy. Patient data, including demographics, disease characteristics, and ASAS-HI scores, were collected before and after treatment. Statistical analysis was performed to compare changes in ASAS-HI scores between the TNF-α blocker and the conventional therapy group., Results: The study population consisted of patients with axSpA, with a mean age of 38.3 years in conventional treatment group and 29.3 years in TNF-α blocker group. Most variables, including C-reactive protein levels, other comorbidities, and disease assessment scores showed no significant difference between groups. Longitudinal analysis within each treatment group from Week 0 to 12 showed no significant change in the conventional treatment group, whereas the TNF-α blocker group experienced a significant reduction in ASAS-HI scores, demonstrating the effectiveness of the treatment. The TNF-α blocker group exhibited a significantly greater improvement in ASAS-HI scores compared to the conventional therapy group. The Bath Ankylosing Spondylitis Functional Index and the Bath Ankylosing Spondylitis Disease Activity Index demonstrated strong positive correlations with ASAS-HI scores, indicating higher disease activity and functional limitation are associated with worse health outcomes in patients., Conclusion: The research demonstrates that ASAS-HI scores significantly improve with TNF-α blocker therapy in axSpA patients, underscoring ASAS-HI's effectiveness as a tool for evaluating drug responses., Competing Interests: CONFLICT OF INTEREST No potential conflict of interest relevant to this article was reported., (Copyright © 2024 by The Korean College of Rheumatology. All rights reserved.)

A new alkaloid, neohelicomyine A ( 1 ), along with two known alkaloids ( 2 - 3 ), were isolated from the fermentation of Neohelicomyces hyalosporus PF11-1. The structures of these compounds were elucidated by extensive analyses of spectroscopic methods including 1 D and 2 D NMR, HRESIMS and ECD. The bioactivities of all compounds were evaluated using cellular assays, and compounds 2 and 3 displayed moderate cytotoxicities against human cancer (A549, TCA, RD) cells with IC 50 values of 26-87 μg/mL.

Purpose: The association between nonobese/lean nonalcoholic fatty liver disease (NAFLD) and gallstone formation remains unclear. We aimed to assess whether NAFLD is an independent risk factor for gallstones, even in nonobese or lean individuals., Methods: We analyzed 265 353 asymptomatic adults who underwent abdominal ultrasonography. The risk of gallstone was assessed on the basis of obesity and NAFLD status., Results: The overall prevalence rates of NAFLD and gallstones were 27.1% and 2.6%, respectively. The prevalence rates of NAFLD among the 195 204 nonobese and 136 194 lean participants were 14.7% and 7.4%, respectively. Individuals with NAFLD had a significantly increased risk of gallstones (adjusted odds ratio [OR], 1.23; 95% confidence interval [CI], 1.14-1.32). Moreover, NAFLD significantly increased the risk of gallstone (adjusted OR, 1.29; 95% CI, 1.17-1.41) among nonobese individuals. Lean individuals with NAFLD also exhibited a significantly increased risk of gallstones (adjusted OR, 1.20; 95% CI, 1.03-1.40). Furthermore, these findings remained consistent even in nonobese and lean individuals without insulin resistance., Conclusion: Nonobese/lean NAFLD is an independent risk factor for gallstone formation, suggesting its role in gallstone pathogenesis, regardless of obesity status. Therefore, when hepatic steatosis is detected on abdominal ultrasonography, a more thorough evaluation of the gallstones may be necessary, even in nonobese or lean individuals., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Polysaccharides and polyphenols are bioactive components that co-exist in many plant foods. Their binary interaction in terms of the structure-function relationships, however, has not been well clarified. This study elucidated the correlation between the structural and physiological properties of galactomannan (GM) -catechin monomer complexes and GM with different branching or molecular weight (Mw). Results indicated that locus bean gum with lower branching degree (Gal/Man is 0.259) bound more readily to EGCG with adsorption rate of 19.42 %. EGCG and ECG containing galloyl groups were more inclined to form hydrogen bonds with GMs, significantly improving the adsorption by GMs. The introduction of EGCG could enhance the antioxidant activity and starch digestion inhibition of GM, which positively correlated with the adsorption capacity of EGCG. The guar gum (GG) with higher Mw (7384.3 kDa) could transport 71.51 % EGCG into the colon, while the retention rate of EGCG reaching the colon alone was only 46.33 %. Conversely, GM-EGCG complex with lower Mw (6.9 kDa) could be readily utilized by gut microbiota, and increased production of short-chain fatty acids (SCFAs). This study elucidated the structure-properties relationship of GM-EGCG complexes, and provide a new idea for the development and precision nutrition of polysaccharides-polyphenol complexes fortified functional foods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Memory plays a crucial role in cognitive health. Social isolation (SI) and loneliness (LON) are recognized risk factors for global cognition, although their combined effects on memory have been understudied in the literature. This study used three waves of data over six years from the Canadian Longitudinal Study on Aging to examine whether SI and LON are individually and jointly associated with memory in community-dwelling middle-aged and older adults (n = 14,208). LON was assessed with the question: "In the last week, how often did you feel lonely?". SI was measured using an index based on marital/cohabiting status, retirement status, social activity participation, and social network contacts. Memory was evaluated with combined z-scores from two administrations of the Rey Auditory Verbal Learning Test (immediate-recall, delayed-recall). We conducted our analyses using all available data across the three timepoints and retained participants with missing covariate data. Linear mixed models were used to regress combined memory scores onto SI and LON, adjusting for sociodemographic, health, functional ability, and lifestyle variables. Experiencing both SI and LON had the greatest inverse effect on memory (least-squares mean: -0.80 [95 % confidence-interval: -1.22, -0.39]), followed by LON alone (-0.73 [-1.13, -0.34]), then SI alone (-0.69 [-1.09, -0.29]), and lastly by being neither lonely nor isolated (-0.65 [-1.05, -0.25]). Sensitivity analyses confirmed this hierarchy of effects. Policies developed to enhance memory in middle-aged and older adults might achieve greater benefits when targeting the alleviation of both SI and LON rather than one or the other individually., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Sleep deficiency is a rampant issue in modern society, serving as a pathogenic element contributing to learning and memory impairment, with heightened sensitivity observed in children. Clinical observations suggest that learning disabilities associated with insufficient sleep during adolescence can persist through adulthood, but experimental evidence for this is lacking. In this study, we examined the impact of early-life sleep deprivation on both short-term and long-term memory, tracking the effects sequentially into adulthood. We employed a modified multiple platform method (MMPM) mouse model to investigate these outcomes. Sleep deprivation induced over a 14-day period, beginning on postnatal day 28 (PND28) in mice, led to significant impairment in long-term memory (while short-term memory remained unaffected) at PND42. Notably, this dysfunction persisted into adulthood at PND85. The specific impairment observed in long-term memory was elucidated through histopathological alterations in hippocampal neurogenesis, as evidenced by bromodeoxyuridine (BrdU) signals, observed both at PND42 and PND85. Furthermore, the hippocampal region exhibited significantly diminished protein expressions of astrocyte, characterized by lowered levels of aquaporin 4 (AQP4), a representative molecule involved in brain clearance processes, and reduced protein expressions of brain-derived neurotrophic factor (BDNF). In conclusion, we have presented experimental evidence indicating that sleep deficiency-related impairment of long-term memory in adolescence can endure into adulthood. The corresponding mechanisms may indicate that the modification of astrocyte-related molecules has led to changes in hippocampal neurogenesis., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society.)

Background/Objectives : This study aimed to assess the effectiveness of bi-monthly brolucimumab treatment in patients with neovascular age-related macular degeneration (nAMD) refractory to monthly aflibercept treatment. Methods : A retrospective chart review included 32 eyes of patients with refractory nAMD who switched from monthly intravitreal aflibercept treatment to bi-monthly intravitreal brolucizumab treatment. This study evaluated changes in visual acuity (VA), intraretinal fluid (IRF), subretinal fluid (SRF), pigment epithelial detachment (PED), and central macular thickness (CMT), at specific times as follows: baseline before switching (T0), 2 months after switching (T1), 4 months after switching (T2), and 6 months after switching (T3). Results : The mean best-corrected visual acuity (BCVA) did not significantly change across all time points (0.52 ± 0.12, 0.48 ± 0.27, 0.48 ± 0.28, and 0.50 ± 0.27 logarithms of the minimum angle of resolution in T0, T1, T2, and T3, respectively). CMT significantly decreased after additional brolucizumab injections compared to the baseline (218.2 ± 48.6 and 207.9 ± 49.8 μm, respectively; p = 0.001). The PED height also significantly decreased from 251.0 ± 165.4 to 154.4 ± 115.65 μm ( p < 0.001), with complete resolution in nine patients (28%). The mean subfoveal choroidal thickness (SFCT) before brolucizumab treatment was 262.8 ± 79.7 μm, which decreased to 233.0 ± 71.2 μm ( p = 0.001) after the first injection. The final SFCT also significantly decreased after additional brolucizumab injections compared to the baseline SFCT ( p = 0.012). Conclusions : Bi-monthly brolucizumab treatment proves effective for patients refractory to monthly fixed aflibercept, resulting in positive anatomical changes without significant deterioration in visual acuity. This approach provides a promising prognosis while reducing the treatment burden on refractory patients.

This study aimed to characterize the Magnetic Resonance Imaging (MRI) features of the Anterolateral Ligament (ALL) in young adults without Anterior Cruciate Ligament (ACL) injury and evaluate its visibility using MRI. In this retrospective analysis, MRI scans of 66 young adults without ACL injuries were assessed by two radiologists. The ALL was examined from its bone-to-bone attachment between the lateral femoral epicondyle and the lateral tibia. The visibility of the ALL was classified as normal, probably normal, abnormal, or non-visualized, based on ligament continuity and thickness relative to the Meniscotibial Ligament (MTL). A continuous structure with thickness equal to or greater than the MTL was considered normal; continuous but wavy and thin features were categorized as probably normal; discontinuity and angulation were deemed abnormal. The proximal attachment of the ALL was categorized as anterior, central, or posterior to the Fibular Collateral Ligament (FCL), while the distal attachment was noted as either at the same location or distal to the MTL. The ALL was identified in 87.9-95.5% of knees and was non-visualized in 4.5-12.1% of cases. Continuous ligamentous structures were observed in 63.7-71.2% of knees (normal in 30.3-37.9%; probably normal in 27.3-40.9%), whereas 19.7-30.3% exhibited abnormal features. Inter-observer agreement was moderate to substantial (κ = 0.66, 0.56), and intra-observer agreement was substantial to excellent (κ = 0.82, 0.66). Among the 58 visible ALLs, proximal attachments were predominantly anterior (63.8%) or central (32.8%) to the FCL, with a minority posterior (1.7%). In total, 4 of the 19 central insertions were incorporated into the FCL mid-substance, and one case was blended into the meniscofemoral ligament. Distal attachments were equally distributed between the same location (50%) and distal to the MTL (50%) (mean 3.7 mm distal). In conclusion, MRI was feasible for detecting the ALL in most young adults without ACL injury, revealing continuous ligament structures in about two-thirds of cases. Approximately 40% of cases exhibited a thickness equal to or greater than the MTL, with the majority of proximal attachments located anterior to the FCL and distal attachments evenly divided between the same insertion and distal to the MTL.

Dry-powder inhalers (DPIs) are valued for their stability but formulating them is challenging due to powder aggregation and limited flowability, which affects drug delivery and uniformity. In this study, the incorporation of L-leucine (LEU) into hot-melt extrusion (HME) was proposed to enhance dispersibility while simultaneously maintaining the high aerodynamic performance of inhalable microparticles. This study explored using LEU in HME to improve dispersibility and maintain the high aerodynamic performance of inhalable microparticles. Formulations with crystalline itraconazole (ITZ) and LEU were made via co-jet milling and HME followed by jet milling. The LEU ratio varied, comparing solubility, homogenization, and aerodynamic performance enhancements. In HME, ITZ solubility increased, and crystallinity decreased. Higher LEU ratios in HME formulations reduced the contact angle, enhancing mass median aerodynamic diameter (MMAD) size and aerodynamic performance synergistically. Achieving a maximum extra fine particle fraction of 33.68 ± 1.31% enabled stable deep lung delivery. This study shows that HME combined with LEU effectively produces inhalable particles, which is promising for improved drug dispersion and delivery.

The aim of this study was to fabricate mini-tablets of polyhedrons containing theophylline using a fused deposition modeling (FDM) 3D printer, and to evaluate the correlation between release kinetics models and their geometric shapes. The filaments containing theophylline, hydroxypropyl cellulose (HPC), and EUDRAGIT RS PO (EU) could be obtained with a consistent thickness through pre-drying before hot melt extrusion (HME). Mini-tablets of polyhedrons ranging from tetrahedron to icosahedron were 3D-printed using the same formulation of the filament, ensuring equal volumes. The release kinetics models derived from dissolution tests of the polyhedrons, along with calculations for various physical parameters (edge, SA: surface area, SA/W: surface area/weight, SA/V: surface area/volume), revealed that the correlation between the Higuchi model and the SA/V was the highest (R 2 = 0.995). It was confirmed that using 3D- printing for the development of personalized or pediatric drug products allows for the adjustment of drug dosage by modifying the size or shape of the drug while maintaining or controlling the same release profile.

Herein we present a flow-based, rapid, and straightforward approach to synthesize diverse functionalized sulfonyl fluorides by harnessing an aryllithium intermediate. The aryllithium intermediate was fully utilized under optimized conditions (0.016 s, -18 °C) to afford various functionalized sulfonyl fluorides and also intramolecular SuFEx cyclization products in high yields (27-94%). Furthermore, the integrated synthesis incorporating subsequent SuFEx connections with even unstable organolithium nucleophiles facilitated one-flow molecular assembly in high yields (42-72%).

Background: Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder characterized by fever, arthritis, skin rash, and systemic symptoms. The etiology of AOSD is unknown; however, it is thought to be related to immune dysregulation. Although a rare disease, AOSD can significantly impact reproductive health, particularly during pregnancy. This case study assesses the implications of pregnancy in a patient with AOSD, as well as the potential for heredity of the disease. Neonatal hemophagocytic lympho-histiocytosis (HLH) is a rare and life-threatening disorder characterized by hyperinflammation and uncontrolled activation of immune cells, leading to multiple organ dysfunction. This case report aimed to introduce neonatal HLH from a mother with AOSD., Case Summary: This case study presents a 29-year-old female with AOSD who became pregnant and gave birth to a premature infant who was diagnosed with neonatal HLH. AOSD can significantly impact pregnancy and childbirth, as it may become more severe during pregnancy, with an increased risk of fetal loss and preterm birth. The management of AOSD during pregnancy involves the use of nonsteroidal anti-inflammatory drugs and glucocorticoids, as well as immunosuppressive agents in severe cases. However, the use of immunosuppressive agents during pregnancy may be associated with potential risks to the fetus. The hereditary implications of AOSD are unclear; however, available evidence suggests that genetic factors may play a role in the disease development., Conclusion: AOSD can have significant implications for pregnancy and childbirth, including an increased risk of fetal loss and preterm birth. Neonatal HLH, a complication of AOSD in pregnancy, requires prompt diagnosis and management. Women with AOSD who are considering pregnancy should discuss their options with their healthcare provider and develop a management plan that addresses the potential risks to both mother and fetus., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: We aimed to analyze the effects of an antimicrobial stewardship program (ASP) on the proportion of antimicrobial-resistant pathogens in bacteremia, antimicrobial use, and mortality in pediatric patients., Methods: A retrospective single-center study was performed on pediatric inpatients under 19 years old who received systemic antimicrobial treatment from 2001 to 2019. A pediatric infectious disease attending physician started ASP in January 2008. The study period was divided into the pre-intervention (2001-2008) and the post-intervention (2009-2019) periods. The amount of antimicrobial use was defined as days of therapy per 1,000 patient-days, and the differences were compared using delta slope (= changes in slopes) between the two study periods by an interrupted time-series analysis. The proportion of resistant pathogens and the 30-day overall mortality rate were analyzed by the χ²., Results: The proportion of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae bacteremia increased from 17% (39 of 235) in the pre-intervention period to 35% (189 of 533) in the post-intervention period ( P < 0.001). The total amount of antimicrobial use significantly decreased after the introduction of ASP (delta slope value = -16.5; 95% confidence interval [CI], -30.6 to -2.3; P = 0.049). The 30-day overall mortality rate in patients with bacteremia did not increase, being 10% (55 of 564) in the pre-intervention and 10% (94 of 941) in the post-intervention period ( P = 0.881)., Conclusion: The introduction of ASP for pediatric patients reduced the delta slope of the total antimicrobial use without increasing the mortality rate despite an increased incidence of ESBL-producing gram-negative bacteremia., Competing Interests: The authors have no potential conflicts of interest to declare., (© 2024 The Korean Academy of Medical Sciences.)

Observational studies have shown controversial associations between alcohol intake and radiographic osteoarthritis (OA). This study investigated whether this association was causal using a Mendelian randomization (MR) study in a population-based cohort in Korean. The study enrolled 2429 subjects (1058 men, 1371 women) from the Dong-gu Study. X-rays of the hand and knee joints were scored using a semi-quantitative grading system to calculate the total score of the hand and knee joints. ALDH2 rs671 genotyping was performed by high-resolution melting analysis. MR instrumental variable analysis and observational multivariable regression analysis were used to estimate the association between genetically predicted alcohol intake and the radiographic severity of OA. Subjects with the G/G genotype had a higher current alcohol intake than those with the G/A and A/A genotypes in both men and women (all P < 0.001). Men with the G/G genotype had higher total knee (P < 0.001) and hand scores (P = 0.042) compared to those with the G/A and A/A genotypes after adjusting for age and body mass index, but not in women. In the observational multivariable regression analysis, each alcohol drink per day in men was associated with increased knee (P = 0.001) and hand joint scores (P = 0.013) after adjustment, but not in women. In our MR analysis, utilizing ALDH2 rs671 genotypes as instrumental variables for alcohol consumption, has shown a significant link between each additional daily alcohol drink and increased radiographic joint severity in men., (© 2024. The Author(s).)

Secreted protein acidic and cysteine rich/osteonectin, cwcv and kazal-like domain proteoglycan 2 (SPOCK2) is a protein that regulates cell differentiation and growth. Recent studies have reported that SPOCK2 plays important roles in the progression of various human cancers; however, the role of SPOCK2 in melanoma remains unknown. Therefore, this study investigated the roles of SPOCK2 and the related mechanisms in melanoma progression. To evaluate the clinical significance of SPOCK2 expression in patients with melanoma, we analysed the association between SPOCK2 expression and its prognostic value for patients with melanoma using systematic multiomic analysis. Subsequently, to investigate the roles of Spock2 in melanoma progression in vitro and in vivo, we knocked down Spock2 in the B16F10 melanoma cell line. High SPOCK2 levels were positively associated with good prognosis and long survival rate of patients with melanoma. Spock2 knockdown promoted melanoma cell proliferation by inducing the cell cycle and inhibiting apoptosis. Moreover, Spock2 downregulation significantly increased cell migration and invasion by upregulating MMP2 and MT1-MMP. The increased cell proliferation and migration were inhibited by MAPK inhibitor, and ERK phosphorylation was considerably enhanced in Spock2 knockdown cells. Therefore, Spock2 could function as a tumour suppressor gene to regulate melanoma progression by regulating the MAPK/ERK signalling pathway. Additionally, Spock2 knockdown cell injection induced considerable tumour growth and lung metastasis in C57BL6 mice compared to that in the control group. Our findings suggest that SPOCK2 plays crucial roles in malignant progression of melanoma and functions as a novel therapeutic target of melanoma., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Myocardial infarction (MI) is a major cause of morbidity and mortality worldwide. Although clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) gene editing holds immense potential for genetic manipulation, its clinical application is hindered by the absence of an efficient heart-targeted drug delivery system. Herein, we developed CRISPR-Cas9 ribonucleoprotein (RNP)-loaded extracellular vesicles (EVs) conjugated with cardiac-targeting peptide (T) for precise cardiac-specific genome editing. RNP complexes containing Cas9 and single guide RNA targeting miR-34a, an MI-associated molecular target, were loaded into EVs (EV@RNP). Gene editing by EV@RNP attenuated hydrogen peroxide-induced apoptosis in cardiomyocytes via miR-34a inhibition, evidenced by increased B-cell lymphoma 2 levels, decreased Bcl-2-associated X protein levels, and the cleavage of caspase-3. Additionally, to improve cardiac targeting in vivo, we used click chemistry to form functional T-EV@RNP by conjugating T peptides to EV@RNP. Consequently, T-EV@RNP-mediated miR-34a genome editing might exert a protective effect against MI, reducing apoptosis, ameliorating MI injury, and facilitating the recovery of cardiac function. In conclusion, the genome editing delivery system established by loading CRISPR/Cas9 RNP with cardiac-targeting EVs is a powerful approach for precise and tissue-specific gene therapy for cardiovascular disease., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Biopharmaceuticals have emerged as powerful therapeutic agents, revolutionizing the treatment landscape for various diseases, including cancer, infectious diseases, autoimmune and genetic disorders. These biotherapeutics pave the way for precision medicine with their unique and targeted capabilities. The production of high-quality biologics entails intricate manufacturing processes, including cell culture, fermentation, purification, and formulation, necessitating specialized facilities and expertise. These complex processes are subject to rigorous regulatory oversight to evaluate the safety, efficacy, and quality of biotherapeutics prior to clinical approval. Consequently, these drugs undergo extensive purification unit operations to achieve high purity by effectively removing impurities and contaminants. The field of personalized precision medicine necessitates the development of novel and highly efficient technologies. Microfluidic technology addresses unmet needs by enabling precise and compact separation, allowing rapid, integrated and continuous purification modules. Moreover, the integration of intelligent biomanufacturing systems with miniaturized devices presents an opportunity to significantly enhance the robustness of complex downstream processing of biopharmaceuticals, with the benefits of automation and advanced control. This allows seamless data exchange, real-time monitoring, and synchronization of purification steps, leading to improved process efficiency, data management, and decision-making. Integrating autonomous systems into biopharmaceutical purification ensures adherence to regulatory standards, such as good manufacturing practice (GMP), positioning the industry to effectively address emerging market demands for personalized precision nano-medicines. This perspective review will emphasize on the significance, challenges, and prospects associated with the adoption of continuous, integrated, and intelligent methodologies in small-scale downstream processing for various types of biologics. By utilizing microfluidic technology and intelligent systems, purification processes can be enhanced for increased efficiency, cost-effectiveness, and regulatory compliance, shaping the future of biopharmaceutical production and enabling the development of personalized and targeted therapies.

Objective: The somatic symptom disorder (SSD) is characterized by one or more distressing or disabling somatic symptoms accompanied by an excessive amount of time, energy and emotion related to the symptoms. These manifestations of SSD have been linked to alterations in perception and appraisal of bodily signals. We hypothesized that SSD patients would exhibit changes in interoceptive accuracy (IA), particularly when emotional processing is involved., Methods: Twenty-three patients with SSD and 20 healthy controls were recruited. IA was assessed using the heartbeat perception task. The task was performed in the absence of stimuli as well as in the presence of emotional interference, i.e., photographs of faces with an emotional expression. IA were examined for correlation with measures related to their somatic symptoms, including resting-state heart rate variability (HRV)., Results: There was no significant difference in the absolute values of IA between patients with SSD and healthy controls, regardless of the condition. However, the degree of difference in IA without emotional interference and with neutral facial interference was greater in patients with SSD than in healthy controls (p = 0.039). The IA of patients with SSD also showed a significant correlation with low-frequency HRV (p = 0.004) and high-frequency HRV (p = 0.007)., Conclusion: SSD patients showed more significant changes in IA when neutral facial interference was given. These results suggest that bodily awareness is more affected by emotionally ambiguous stimuli in SSD patients than in healthy controls., (© 2024. The Author(s).)

Background: Understanding the molecular mechanisms of Alzheimer's disease (AD) has important clinical implications for guiding therapy. Impaired amyloid beta (Aβ) clearance is critical in the pathogenesis of sporadic AD, and blood monocytes play an important role in Aβ clearance in the periphery. However, the mechanism underlying the defective phagocytosis of Aβ by monocytes in AD remains unclear., Methods: Initially, we collected whole blood samples from sporadic AD patients and isolated the monocytes for RNA sequencing analysis. By establishing APP/PS1 transgenic model mice with monocyte-specific cystatin F overexpression, we assessed the influence of monocyte-derived cystatin F on AD development. We further used a nondenaturing gel to identify the structure of the secreted cystatin F in plasma. Flow cytometry, enzyme-linked immunosorbent assays and laser scanning confocal microscopy were used to analyse the internalization of Aβ by monocytes. Pull down assays, bimolecular fluorescence complementation assays and total internal reflection fluorescence microscopy were used to determine the interactions and potential interactional amino acids between the cystatin F protein and Aβ. Finally, the cystatin F protein was purified and injected via the tail vein into 5XFAD mice to assess AD pathology., Results: Our results demonstrated that the expression of the cystatin F protein was specifically increased in the monocytes of AD patients. Monocyte-derived cystatin F increased Aβ deposition and exacerbated cognitive deficits in APP/PS1 mice. Furthermore, secreted cystatin F in the plasma of AD patients has a dimeric structure that is closely related to clinical signs of AD. Moreover, we noted that the cystatin F dimer blocks the phagocytosis of Aβ by monocytes. Mechanistically, the cystatin F dimer physically interacts with Aβ to inhibit its recognition and internalization by monocytes through certain amino acid interactions between the cystatin F dimer and Aβ. We found that high levels of the cystatin F dimer protein in blood contributed to amyloid pathology and cognitive deficits as a risk factor in 5XFAD mice., Conclusions: Our findings highlight that the cystatin F dimer plays a crucial role in regulating Aβ metabolism via its peripheral clearance pathway, providing us with a potential biomarker for diagnosis and potential target for therapeutic intervention., (© 2024. The Author(s).)

Device engineering based on computer-aided simulations is essential to make silicon (Si) quantum bits (qubits) be competitive to commercial platforms based on superconductors and trapped ions. Combining device simulations with the Bayesian optimization (BO), here we propose a systematic design approach that is quite useful to procure fast and precise entangling operations of qubits encoded to electron spins in electrode-driven Si quantum dot (QD) systems. For a target problem of the controlled-X (CNOT) logic operation, we employ BO with the Gaussian process regression to evolve design factors of a Si double QD system to the ones that are optimal in terms of speed and fidelity of a CNOT logic driven by a single microwave pulse. The design framework not only clearly contributes to cost-efficient securing of solutions that enhance performance of the target quantum operation, but can be extended to implement more complicated logics with Si QD structures in experimentally unprecedented ways., (© 2024. The Author(s).)

Objectives: To assess the association of primary and third doses of vaccination with the risk of post-acute sequelae of COVID-19., Methods: This retrospective cohort study utilized a combined database of nationwide health care claims data, COVID-19 patient registry, and vaccination records from South Korea. Individuals diagnosed with COVID-19 in the Omicron variant-dominant period of January-March 2022 were tracked for 30-120 days post-infection. The exposure of interest was the receipt of primary and third doses of the SARS-CoV-2 vaccine. The occurrence of 26 specific conditions in eight domains was compared using Cox regression with inverse probability of treatment weighting., Results: This study included 394 773 unvaccinated individuals and 7 604 081 individuals receiving ≥2 doses of vaccine. Compared with unvaccinated individuals, vaccination with at least two doses was associated with a reduced risk (adjusted hazard ratio; 95% CI) of several conditions, including ischaemic heart disease (0.73; 0.57-0.94), heart failure (0.55; 0.48-0.63), cardiac dysrhythmia (0.72; 0.61-0.85), cardiac arrest (0.41; 0.33-0.51), pulmonary embolism (0.66; 0.52-0.84), venous thromboembolism (0.54; 0.44-0.66), acute renal failure (0.56; 0.46-0.67), new dialysis (0.45; 0.34-0.59), chronic obstructive pulmonary disease (0.74; 0.65-0.84), acute pancreatitis (0.64; 0.51-0.80), and diabetes (0.82; 0.71-0.95). The risks of heart failure, cardiac dysrhythmias, cardiac arrest, pulmonary embolism, and new dialysis were lower in those who were vaccinated with three doses compared with those who were vaccinated with two doses., Discussion: Vaccination was associated with a decreased risk of post-acute sequelae of COVID-19, suggesting its potential role in mitigating the indirect impacts of COVID-19., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Hyperpigmentation occurs due to irregular secretion of melanin pigment in the skin. This can affect quality of life depending on its severity, so prevention and management are essential. Oats ( Avena sativa L.), a grain consumed worldwide, are known to offer improved health benefits upon germination and fermentation. This study is aimed to investigate the protective effects of lactobacilli-fermented sprouted oat extracts on oxidative stress and melanin overproduction in vitro. The anti-melanogenic effect was investigated using melanin content and tyrosinase activity assays in B16F10 cells, as well as a mushroom tyrosinase-based enzyme inhibition assay. The results showed that L. casei -fermented oat extracts were the most effective for reducing melanin formation by reducing the mRNA expression of microphthalmia-associated transcription factor, tyrosinase, and tyrosinase-related protein 2. Furthermore, L. casei fermentation was effective in improving the total phenolic, flavonoid, and avenanthramide A contents of sprouted oat extracts. The results also demonstrated the antioxidant effects of L. casei -fermented sprouted oat extracts in promoting DPPH radical-scavenging activity, superoxide dismutase-like activity, and reduction in reactive oxygen species levels. Overall, the findings indicate that fermented sprouted oat extracts are promising candidates for antioxidant and anti-hyperpigmentation treatments.

Blood-brain barrier (BBB) disruption is increasingly recognized as an early contributor to the pathophysiology of cerebral ischemia/reperfusion (I/R) injury, and is also a key event in triggering secondary damage to the central nervous system. Recently, long non-coding RNA (lncRNA) have been found to be associated with ischemic stroke. However, the roles of lncRNA in BBB homeostasis remain largely unknown. Here, we report that long intergenic non-coding RNA-p21 (lincRNA-p21) was the most significantly down-regulated lncRNA in human brain microvascular endothelial cells (HBMECs) after oxygen and glucose deprivation/reoxygenation (OGD/R) treatment among candidate lncRNA, which were both sensitive to hypoxia and involved in atherosclerosis. Exogenous brain-endothelium-specific overexpression of lincRNA-p21 could alleviate BBB disruption, diminish infarction volume and attenuate motor function deficits in middle cerebral artery occlusion/reperfusion (MCAO/R) mice. Further results showed that lincRNA-p21 was critical to maintain BBB integrity by inhibiting the degradation of junction proteins under MCAO/R and OGD/R conditions. Specifically, lincRNA-p21 could inhibit autophagy-dependent degradation of occludin by activating PI3K/AKT/mTOR signaling pathway. Besides, lincRNA-p21 could inhibit VE-cadherin degradation by binding with miR-101-3p. Together, we identify that lincRNA-p21 is critical for BBB integrity maintenance, and endothelial lincRNA-p21 overexpression could alleviate cerebral I/R injury in mice, pointing to a potential strategy to treat cerebral I/R injury., 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.

This study aimed to investigate the effect of exosomes derived from bone marrow mesenchymal stem cells (BMSCs-EXO) on lung ischemia-reperfusion injury (IRI) in rats and to explore the role of miR-335. The model of rat lung IRI was established by clipping the hilum of left lung for 60 min and opening for 180 min. Forty Sprague-Dawley rats were randomly divided into sham group, IRI group, IRI+PBS group, IRI+EXO group, and IRI+miR-335 inhibitor EXO (IRI+inhibitor-EXO) group (n = 8). Rats in the sham group underwent thoracotomies without IRI. Rats in the IRI group were used to establish IRI model without any additional treatment. In the IRI+PBS, IRI+EXO, and IRI+inhibitor-EXO groups, the rats were used to establish IRI model and given PBS, EXO from BMSCs without any treatment, and EXO from BMSCs with miR-335 inhibitor treatment before reperfusion, respectively. Blood gases were analyzed during the experiment. Lung tissue wet/dry ratio (W/D), interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), myeloperoxidase (MPO), malondialdehyde (MDA), and superoxide dismutase (SOD) were measured at the end of reperfusion. Mitochondria were observed by electron microscopy and the Flameng scores were counted. Lung histopathology and apoptosis (TUNEL staining) were observed by light microscopy, and the lung injury scores (LIS) and apoptosis index (AI) were detected. The miR-335 expression was detected by RT-qPCR, and the expression of caspase-3, cleaved-caspase-3, caspase-9, cleaved-caspase-9, and NF-κB proteins were detected by Western blot at the end of reperfusion. The results showed that compared with the sham group, the oxygenation index, pH, and base excess (BE) were significantly lower in the IRI group and IRI+PBS group after reperfusion, whereas those indices were significantly higher in the IRI+EXO group than those in the IRI+PBS group (P < 0.05). Compared with the sham group, there were significant increases in W/D, IL-1β, TNF-α, MPO, MDA, LIS, AI, Flameng score, caspase-3, cleaved-caspase-3, caspase-9, and cleaved-caspase-9, however significant decreases in the SOD, miR-335 and NF-κB in the IRI group (P < 0.05). These indices in the IRI and IRI+PBS groups showed no significant differences. Compared with the IRI+PBS group, there were significant decreases in W/D, IL-1β, TNF-α, MPO, MDA, LIS, AI, Flameng score, caspase-3, cleaved-caspase-3, caspase-9, and cleaved-caspase-9, however significant increases in the SOD, miR-335 and NF-κB in the IRI+EXO group (P < 0.05). While, the changes of the above mentioned indices were reversed in the IRI+inhibitor-EXO group compared with IRI+EXO group, which were still better than those in the IRI+PBS group (P < 0.05). The results suggest that BMSCs-EXO could attenuate lung IRI in rats, activate NF-κB pathway, and maintain mitochondrial stability by up-regulating miR-335.

To obtain high-quality SiN x films applicable to an extensive range of processes, such as gate spacers in fin field-effect transistors (FinFETs), the self-aligned quadruple patterning process, etc, a study of plasma with higher plasma density and lower plasma damage is crucial in addition to study on novel precursors for SiN x plasma-enhanced atomic layer deposition (PEALD) processes. In this study, a novel magnetized PEALD process was developed for depositing high-quality SiN x films using di(isopropylamino)silane (DIPAS) and magnetized N 2 plasma at a low substrate temperature of 200 °C. The properties of the deposited SiN x films were analyzed and compared with those obtained by the PEALD process using a non-magnetized N 2 plasma source under the same conditions. The PEALD SiN x film, produced using an external magnetic field (ranging from 0 to 100 G) during the plasma exposure step, exhibited a higher growth rate (∼1 Å/cycle) due to the increased plasma density. Additionally, it showed lower surface roughness, higher film density, and enhanced wet etch resistance compared to films deposited using the PEALD process with non-magnetized plasmas. This improvement can be attributed to the higher ion flux and lower ion energy of the magnetized plasma. The electrical characteristics, such as interface trap density and breakdown voltage, were also enhanced when the magnetized plasma was used for the PEALD process. Furthermore, when SiN x films were deposited on high-aspect-ratio (30:1) trench patterns using the magnetized PEALD process, an improved step coverage of over 98% was achieved, in contrast to the conformality of SiN x deposited using non-magnetized plasma. This enhancement is possibly a result of deeper radical penetration enabled by the magnetized plasma., (© 2024 IOP Publishing Ltd.)

To understand the changes in arabinoxylan (AX) during breadmaking, multi-step enzyme digestion was conducted to re-extract arabinoxylan (AX-B) from AX-fortified bread. Their structural changes were compared using HPSEC, HPAEC, FT-IR, methylation analysis, and 1 H NMR analysis; their properties changes in terms of enzymatic inhibition activities and in vitro fermentability against gut microbiota were also compared. Results showed that AX-B contained a higher portion of covalently linked protein while the molecular weight was reduced significantly after breadmaking process (from 677.1 kDa to 15.6 kDa); the structural complexity of AX-B in terms of the degree of branching was increased; the inhibition activity against α-amylase (76.81 % vs 73.89 % at 4 mg/mL) and α-glucosidase (64.43 % vs 58.08 % at 4 mg/mL) was improved; the AX-B group produced a higher short-chain fatty acids concentration than AX (54.68 ± 7.86 mmol/L vs 44.03 ± 4.10 mmol/L). This study provides novel knowledge regarding the structural and properties changes of arabinoxylan throughout breadmaking, which help to predict the health benefits of fibre-fortified bread and achieve precision nutrition., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Solid organ transplant recipients (SOTRs) are at higher risk for severe infection. However, the risk for severe COVID-19 and vaccine effectiveness among SOTRs remain unclear., Methods: This retrospective study used a nationwide health care claims database and COVID-19 registry from the Republic of Korea (2020 to 2022). Adult SOTRs diagnosed with COVID-19 were matched with up to 4 non-SOTR COVID-19 patients by propensity score. Severe COVID-19 was defined as treatment with high-flow nasal cannulae, mechanical ventilation, or extracorporeal membrane oxygenation., Results: Among 6783 SOTRs with COVID-19, severe COVID-19 was reported with the highest rate in lung transplant recipients (13.16%), followed by the heart (6.30%), kidney (3.90%), and liver (2.40%). SOTRs had a higher risk of severe COVID-19 compared to non-SOTRs, and lung transplant recipients showed the highest risk (adjusted odds ratio, 18.14; 95% confidence interval [CI], 8.53-38.58). Vaccine effectiveness against severe disease among SOTRs was 47% (95% CI, 18%-65%), 64% (95% CI, 49%-75%), and 64% (95% CI, 29%-81%) for 2, 3, and 4 doses, respectively., Conclusions: SOTRs are at significantly higher risk for severe COVID-19 compared to non-SOTRs. Vaccination is effective in preventing the progression to severe COVID-19. Efforts should be made to improve vaccine uptake among SOTRs, while additional protective measures should be developed., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Patients with STAT1 gain-of-function (GOF) mutations often exhibit autoimmune features. The JAK1/2 inhibitor ruxolitinib can be administered to alleviate autoimmune symptoms; however, it is unclear how immune cells are molecularly changed by ruxolitinib treatment. Then, we aimed to investigate the trnscriptional and epigenetic status of immune cells before and after ruxolitinib treatment in a patient with STAT1 GOF., Methods: A patient with a heterozygous STAT1 GOF variant (p.Ala267Val), exhibiting autoimmune features, was treated with ruxolitinib, and peripheral blood mononuclear cells (PBMCs) were longitudinally collected. PBMCs were transcriptionally analyzed by single-cell cellular indexing of the transcriptomes and epitopes by sequencing (CITE-seq), and epigenetically analyzed by assay of transposase-accessible chromatin sequencing (ATAC-seq)., Results: CITE-seq analysis revealed that before treatment, the patient's PBMCs exhibited aberrantly activated inflammatory features, especially IFN-related features. In particular, monocytes showed high expression levels of a subset of IFN-stimulated genes (ISGs). Ruxolitinib treatment substantially downregulated aberrantly overexpressed ISGs, and improved autoimmune features. However, epigenetic analysis demonstrated that genetic regions of ISGs-e.g., STAT1, IRF1, MX1, and OAS1-were highly accessible even after ruxolitinib treatment. When ruxolitinib was temporarily discontinued, the patient's autoimmune features were aggravated, which is in line with sustained epigenetic abnormality., Conclusions: In a patient with STAT1 GOF, ruxolitinib treatment improved autoimmune features and downregulated aberrantly overexpressed ISGs, but did not correct epigenetic abnormality of ISGs., (© 2024. The Author(s).)

Objective: To investigate the effects of the serum HCQ concentration on clinical manifestations, disease activity and organ damage in a longitudinal cohort of SLE patients., Methods: The 338 SLE patients were assessed with respect to their demographic data, clinical and laboratory findings, Physician's Global Assessment (PGA), adjusted mean SLEDAI-2000 (AMS) and SLICC Damage Index (SDI) annually for 5 consecutive years. Patients were divided into two groups according to their serum HCQ concentration at baseline: subtherapeutic (<500 ng/ml) and therapeutic (≥500 ng/ml) groups. The impact of the HCQ concentration on the clinical outcomes was evaluated in a longitudinal analysis using a generalized estimating equation (GEE)., Results: Of the 338 patients, 287 (84.9%) were in the subtherapeutic group at baseline. This group had a higher incidence of newly developed LN (P = 0.036) and had been prescribed higher mean and cumulative doses of prednisolone (P = 0.003 and P = 0.013, respectively) than the therapeutic group. In multivariable analyses based on GEE, the subtherapeutic group had a higher AMS score (β = 1.398, 95% CI 0.607, 2.189; P < 0.001), higher PGA score (β = 0.328, 95% CI 0.215, 0.441; P < 0.001) and higher SDI score (β = 0.366, 95% CI 0.061, 0.671; P = 0.019) across all 5 years., Conclusion: The subtherapeutic HCQ concentration was associated with the development of new-onset LN, and had significant associations with disease activity and cumulative organ damage in SLE patients over time., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background The Society of Radiologists in Ultrasound (SRU) has proposed thresholds for acoustic radiation force impulse techniques to diagnose compensated advanced chronic liver disease (cACLD). However, the diagnostic performance of these thresholds has not been extensively validated. Purpose To validate the SRU thresholds in patients with chronic liver disease who underwent supersonic shear imaging and, if suboptimal diagnostic performance is observed, to identify optimal values for diagnosing cACLD. Materials and Methods This retrospective single-center study included high-risk patients with chronic liver disease who had liver stiffness (LS) measurements and had undergone endoscopy or liver biopsy between January 2018 and December 2021. Patients were randomly allocated to test and validation sets. cACLD was defined as varices at endoscopy and/or severe fibrosis or cirrhosis at liver biopsy. The diagnostic performance of the SRU guidelines was evaluated, and optimal threshold values were identified using receiver operating characteristic (ROC) curve analysis. Results A total of 1180 patients (median age, 57 years [IQR, 50-64 years]; 761 men), of whom 544 (46%) had cACLD, were included. With the SRU recommended thresholds of less than 9 kPa and greater than 13 kPa in the test set ( n = 786), the sensitivity and specificity for ruling out and ruling in cACLD were 81% (303 of 374 patients; 95% CI: 77, 85) and 92% (380 of 412 patients; 95% CI: 89, 94), respectively. In ROC curve analysis, the identified optimal threshold values were less than 7 kPa and greater than 12 kPa, showing 91% sensitivity (340 of 374 patients; 95% CI: 88, 93) for ruling out cACLD and 91% specificity (373 of 412 patients; 95% CI: 87, 93) for ruling in cACLD, respectively. In the validation set ( n = 394), the optimal thresholds showed 91% sensitivity (155 of 170 patients; 95% CI: 86, 95) and 92% specificity (206 of 224 patients; 95% CI: 88, 95). Conclusion Compared with the SRU guidelines, the dual LS threshold values of less than 7 kPa and greater than 12 kPa were better for diagnosing cACLD. © RSNA, 2024 Supplemental material is available for this article . See also the editorial by Barr in this issue.

Background: Infections are considered risk factors for autoimmune inflammatory rheumatic diseases (AIRDs), the incidence of which is considered to have been impacted by the COVID-19 pandemic. The impact of non-pharmaceutical interventions (NPIs) on the incidence of AIRDs and their associated health care services and medical expenses in Korea was investigated., Methods: We included all AIRD cases reported between January 2016 and February 2021 based on the National Health Insurance Service data. We evaluated changes in incidence trends for each AIRD before and after NPI implementation (Feb 2020 to Feb 2021) using segmented regression analysis. Changes in health care utilization and medical costs for each AIRD before and after NPI implementation were also investigated., Results: After NPI implementation, monthly incidence rates declined significantly by 0.205 per 1 000 000 (95% confidence interval [CI], -0.308 to -0.101, p < .001) in patients with systemic lupus erythematosus (SLE). No significant changes in the incidence of all AIRDs other than SLE were observed before and after implementation. Further, annual outpatient department visits per patient were lower during implementation for all diseases, except juvenile idiopathic arthritis (JIA). The prescription days per outpatient visit increased significantly during implementation for all diseases, except JIA and ankylosing spondylitis. During implementation, the total annual medical costs per patient tended to decrease for all diseases, except JIA and mixed connective tissue disease., Conclusion: Implementation of NPIs to contain the pandemic led to a reduction in the incidence of SLE and changed patterns of medical care utilization and treatment cost for most AIRDs., (© 2024 The Authors. International Journal of Rheumatic Diseases published by Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Four new drimane-type sesquiterpenoids and two new nucleoside derivatives (1-6), were isolated from the fungus Helicoma septoconstrictum. Their structures were determined based on the combination of the analysis of their HR-ESI-MS, NMR, ECD calculations data and acid hydrolysis. All the isolated compounds were detected for their bio-activities against MDA-MB-231, A549/DDP, A2780 and HepG2 cell lines. Helicoside C (4) exhibited superior cytotoxicity against the A2780 cell line with IC 50 7.5 ± 1.5 µM. The analysis of reactive oxygen species (ROS) revealed that Helicoside C induced an increase in intracellular ROS. Furthermore, the flow cytometry and mitochondrial membrane potential (MMP) analyses unveiled that Helicoside C mediated mitochondrial-dependent apoptosis in A2780 cells. The western blotting test showed that Helicoside C could suppress the STAT3's phosphorylation. These findings offered crucial support for development of H. septoconstrictum and highlighted the potential application of drimane-type sesquiterpenoids in pharmaceuticals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To develop and evaluate a deep learning model for automated segmentation and detection of bone metastasis on spinal MRI., Materials and Methods: We included whole spine MRI scans of adult patients with bone metastasis: 662 MRI series from 302 patients (63.5 ± 11.5 years; male:female, 151:151) from three study centers obtained between January 2015 and August 2021 for training and internal testing (random split into 536 and 126 series, respectively) and 49 MRI series from 20 patients (65.9 ± 11.5 years; male:female, 11:9) from another center obtained between January 2018 and August 2020 for external testing. Three sagittal MRI sequences, including non-contrast T1-weighted image (T1), contrast-enhanced T1-weighted Dixon fat-only image (FO), and contrast-enhanced fat-suppressed T1-weighted image (CE), were used. Seven models trained using the 2D and 3D U-Nets were developed with different combinations (T1, FO, CE, T1 + FO, T1 + CE, FO + CE, and T1 + FO + CE). The segmentation performance was evaluated using Dice coefficient, pixel-wise recall, and pixel-wise precision. The detection performance was analyzed using per-lesion sensitivity and a free-response receiver operating characteristic curve. The performance of the model was compared with that of five radiologists using the external test set., Results: The 2D U-Net T1 + CE model exhibited superior segmentation performance in the external test compared to the other models, with a Dice coefficient of 0.699 and pixel-wise recall of 0.653. The T1 + CE model achieved per-lesion sensitivities of 0.828 (497/600) and 0.857 (150/175) for metastases in the internal and external tests, respectively. The radiologists demonstrated a mean per-lesion sensitivity of 0.746 and a mean per-lesion positive predictive value of 0.701 in the external test., Conclusion: The deep learning models proposed for automated segmentation and detection of bone metastases on spinal MRI demonstrated high diagnostic performance., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2024 The Korean Society of Radiology.)

Distinct neutrophil populations arise during certain pathological conditions. The generation of dysfunctional neutrophils during sepsis and their contribution to septicemia-related systemic immune suppression remain unclear. In this study, using an experimental sepsis model that features immunosuppression, we identified a novel population of pathogenic CD200R high neutrophils that are generated during the initial stages of sepsis and contribute to systemic immune suppression by enhancing regulatory T (T reg ) cells. Compared to their CD200R low counterparts, sepsis-generated CD200R high neutrophils exhibit impaired autophagy and dysfunction, with reduced chemotactic migration, superoxide anion production, and TNF-α production. Increased soluble CD200 blocks autophagy and neutrophil maturation in the bone marrow during experimental sepsis, and recombinant CD200 treatment in vitro can induce neutrophil dysfunction similar to that observed in CD200R high neutrophils. The administration of an α-CD200R antibody effectively reversed neutrophil dysfunction by enhancing autophagy and protecting against a secondary infection challenge, leading to increased survival. Transcriptome analysis revealed that CD200R high neutrophils expressed high levels of Igf1, which elicits the generation of T reg cells, while the administration of an α-CD200R antibody inhibited T reg cell generation in a secondary infection model. Taken together, our findings revealed a novel CD200R high neutrophil population that mediates the pathogenesis of sepsis-induced systemic immunosuppression by generating T reg cells., (© 2024. The Author(s), under exclusive licence to CSI and USTC.)

Thermosassemble Ionizable Reverse Pluronic (TIRP) platform stands out for its distinctive combination of thermoassemble and ionizable features, effectively overcoming challenges in previous siRNA delivery systems. This study opens up a formation for long-term stabilization, and high loading of siRNA, specifically crafted for targeting oncogenic pathways. TIRP-Bcl2 self-assembles into a unique micelle structure with a nanodiameter of 75.8 ± 5.7 nm, efficiently encapsulating Bcl2 siRNA while maintaining exceptional colloidal stability at 4 °C for 8 months, along with controlled release profiles lasting 180 h. The dual ionizable headgroup enhance the siRNA loading and the revers pluronic unique structural orientation enhance the stability of the siRNA. The thermoassemble of TIRP-Bcl2 facilitates flexi-rigid response to mild hyperthermia, enhancing deep tissue penetration and siRNA release in the tumor microenvironment. This responsive behavior improves intracellular uptake and gene silencing efficacy in cancer cells. TIRP, with its smaller particle size and reverse pluronic nature, efficiently transports siRNA across the blood-brain barrier, holding promise for revolutionizing glioblastoma (GBM) treatment. TIRP-Bcl2 shows significant potential for precise, personalized therapies, promising prolonged siRNA delivery and in vitro/in vivo stability. This research opens avenues for further exploration and clinical translation of this innovative nanocarrier system across different cancers., Competing Interests: Declaration of competing interest The authors declare no financial or personal conflict of interest to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Aims: Previous epidemiological data on the association between cigarette smoking and risk of gallstone development remain controversial, and most relevant studies have relied on self-reported questionnaires. We aimed to elucidate this association using both an objective biomarker of tobacco exposure (urinary cotinine) and a self-reported questionnaire., Methods: We analyzed 221,721 asymptomatic adults who underwent abdominal ultrasonography and urinary cotinine measurement between January 2011 and December 2016. Cotinine-verified current smokers were defined as participants with urinary cotinine levels ≥50 ng/mL., Results: The mean age of the study population was 35.9 years, and the proportion of men was 55.8%. The proportions of self-reported and cotinine-verified current smokers were 21.3% and 21.2%, respectively. After adjusting for confounding factors, self-reported current smoking was associated with an increased risk of gallstone development [adjusted odds ratio (aOR) 1.14; 95% confidence interval (95%CI), 1.04-1.25]. Moreover, among the current smokers, the risk of gallstone development increased with an increase in the amount of cigarette smoking (<20 and ≥20 pack-years vs. never smoked; aOR=1.11 and 1.25; 95%CI: 1.01-1.22 and 1.07-1.45, respectively). Cotinine-verified current smoking was also associated with an increased risk of gallstone development (aOR=1.16; 95%CI: 1.07-1.25). Among the self-reported never or former smokers, the cotinine-verified current smokers (aOR=1.20; 95%CI: 1.01-1.44) showed a significantly higher risk of gallstones than cotinine-verified never smokers., Conclusions: Cotinine-verified and self-reported current smoking were independent risk factors for gallstones, suggesting a distinct role of tobacco smoking in gallstone development.