Search

Background: Previous studies have used machine learning to identify clinically relevant atrophic regions in progressive supranuclear palsy (PSP). This study applied Elastic Net (EN) in PSP to uncover key atrophic patterns, offering a novel approach to understanding its pathology., Methods: This study included baseline data from 74 patients with PSP enrolled in the Study of Comprehensive ANd multimodal marker-based cohort of PSP (SCAN-PSP, NCT05579301) in Seoul between January 2022 and August 2023. Participants were evaluated with PSP-rating scale (PSPRS) and Schwab & England Activity of daily living (SEADL). EN regression was used to identify regions with high explanatory power for clinical outcomes, which were combined with clinical parameters to build prediction models. Features selected from EN classification were applied to discriminate between the two groups., Results: EN identified the third ventricle, right anterior cingulate cortex, and left lateral orbitofrontal cortex as significant features, and multivariate linear regression models incorporating these regions with clinical variables showed high explainability for PSPRS (adjusted R 2  = 0.62) and SEADL (adjusted R 2  = 0.74). The EN-predicted values demonstrated strong correlation with actual scores of PSPRS (r = 0.75, p = 2·10 -14 ) and SEADL (r = 0.82, p = 2·10 -19 ). The combined EN-selected features and clinical parameters model robustly distinguished PSP-Richardson from the subcortical types (AUC = 0.94) and those with severe downgaze palsy from without (AUC = 0.90)., Conclusion: This study demonstrated that EN effectively identified significant regional atrophies in PSP, with a modest sample size. Future studies could incorporate multimodal analysis to identify markers for monitoring disease progression., 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 © 2025 Elsevier Ltd. All rights reserved.)

Plant-derived exosome-like nanovesicles (PENVs) contain various biomolecules that can be used as delivery cargoes, such as small compounds, small interfering RNAs, DNAs, and recombinant proteins. Edible PENVs are nontoxic, useful for oral administration, and easily prepared in high amounts from a variety of plants, vegetables, and fruits. In this study, we evaluated whether PENVs can be used as delivery cargoes for recombinant vaccine antigens. Thus, we isolated PENVs from grapefruits and mandarin oranges by differential centrifugation and characterized their sizes and morphologies. Our results showed lipid bilayer morphologies of grapefruit-derived nanovesicles (GNVs) with the average size of 46 ± 8.5 nm and mandarin orange-derived NVs (MNVs) with the average size of 227 ± 6.4 nm. However, exposure to GNVs and MNVs did not cause cytotoxicity in Vero monkey kidneys or in MDCK canine kidney cells. To evaluate their utility as carriers of mRNA or recombinant proteins, GNVs and MNVs were loaded with GFP mRNA, Alexa Fluor 647-labeled heat shock protein 70 (AF-HSP70), or recombinant hepatitis B surface antigen (HBsAg). Our results showed that mRNA-GFP, human HSP70 protein, and HBsAg were efficiently loaded into both GNVs and MNVs. Interestingly, the oral administration of HBsAg-loaded GNVs to mice resulted in significantly higher levels of serum IgG than in the experimental control group (HBsAg without NVs). Therefore, our results report, for the first time, that edible PENVs loaded with HBsAg administered to mice via oral vaccination were effective in vaccine development., 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. Published by Elsevier Ltd.)

Air pollutants directly and indirectly cause vitamin D deficiency (VDD). In addition, smoking increases oxidative stress and accelerates skin aging, thereby reducing the body's vitamin D concentration. Previous study reported that VDD increases total cholesterol concentration by reducing vitamin D receptor activity. We hypothesized that high air pollution exposure, smoking, and VDD would increase hypercholesterolemia. We investigated associations between long-term exposure to air pollutants, smoking status, VDD, and their combination with hypercholesterolemia using data from the 2008-2014 Korea National Health and Nutrition Examination Survey (KNHANES). We used linked data from the KNHANES to the daily moving average of air-pollution data from 730 days before the examination date, using participants' addresses in latitude and longitude coordinates. Results were analyzed using a survey logistic regression model for complex sample analyses. We included 28,134 adults with data on serum vitamin D, cholesterol concentrations, smoking status, and air pollutant concentrations. After adjusting for potential covariates, adults with exposure to high concentrations of air pollutants and ever smokers showed significantly higher risks of VDD (odds ratios [ORs], 1.70; 95 % confidence intervals [CIs], 1.44-2.00). In the group with high air-pollutant exposure, adults with low vitamin D status and ever smokers had significantly higher risks of hypercholesterolemia (ORs, 1.55; 95 % CIs, 1.09-2.19) than adults with high vitamin D status and never smokers. We found that high air-pollutant exposure, ever smokers, and VDD may increase hypercholesterolemia prevalence in Korean adults. Therefore, to reduce hypercholesterolemia risk, adults living in areas with high air-pollution exposure may need adequate vitamin D intake and to avoid smoking., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Host cabbage possesses an endophyte, Bacillus subtilis, which induced immune-priming of the diamondback moth, Plutella xylostella. In contrast, larvae raised under axenic conditions lost the chance to feed the bacteria and were highly susceptible to various pathogens. Addition of B. subtilis to axenic larvae significantly restored immune responses and enhanced survival rates following pathogen infections. The immune-priming factor(s) was determined among 18 apolipoprotein D (ApoD) genes identified as lipocalin candidates in P. xylostella, in which ApoD1 expression was functionally linked with B. subtilis-induced immune-priming. In addition, lipoxins were analyzed in immune-primed larvae via LC-MS/MS, in which LXB 4 was detected, but not LXA 4 . The LXB 4 titer was significantly higher than that that in the larvae reared under axenic conditions. Notably, LXB 4 alone sufficiently induced significant immune responses. To support lipoxin biosynthesis in insects, this study identified a lipoxygenase-like peroxidase gene, HemP2. Its expression was induced in the immune-primed larvae. However, its suppression prevented LXB 4 production under the immune-priming conditions. To explain the up-regulations of lipocalin/lipoxin by the gut commensal, Toll and IMD immune signaling pathways were analyzed. The up-regulation of ApoD1 and HemP2 expressions was mediated through the IMD, but not the Toll, immune signaling pathway in the larval gut of P. xylostella under B. subtilis-induced immune-priming conditions. This study highlights the potential role of commensal gut microbes including B. subtilis in driving immune-priming via an insect lipoxin-lipocalin complex through the IMD immune signaling pathway., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Introduction: Idiopathic blepharospasm is a clinically heterogeneous form of focal dystonia, also associated with psychiatric symptoms. The identification of the most relevant sets of motor and psychiatric manifestations may help better understand the specific phenomenology of the condition and delineate blepharospasm subtypes more accurately., Methods: Patients with idiopathic blepharospasm were from the Dystonia Coalition project. Factor analysis of several motor and psychiatric scales was performed to identify the relevant determinants of blepharospasm severity. The selected items were then used in a data-driven cluster analysis to subtype blepharospasm individuals., Results: Factor analysis reduced the many variables in the motor and psychiatric scales to 13 variables distributed in four factors. When the four sets were used as clustering variables, three blepharospasm clusters were identified: cluster 1 was characterized by low levels of motor and psychiatric factors; cluster 2 showed high levels of both motor and psychiatric factors; and cluster 3 showed high levels of psychiatric factors (similar to cluster 2) but low level of motor factors (similar to that of cluster 1)., Conclusions: Factor analysis enabled the identification of key motor and psychiatric determinants of blepharospasm severity. The derived factor sets provide a streamlined tool for predicting and measuring these dimensions. This approach also facilitated more precise cluster analysis and improved recognition of clinical subtypes., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest relevant to this work., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Semaglutide and liraglutide are long-acting glucagon-like peptide-1 receptor agonists used to treat type-2 diabetes and obesity. Recent advances in peptide synthesis and analytical technologies have enabled the development of synthetic generic peptide for reference listed drugs (RLD) originating from recombinant DNA (rDNA) technology. Since the original semaglutide and liraglutide were produced through rDNA technology, there has been great interest in developing their synthetic peptides as generic versions of the original drugs. Therefore, this study aimed to develop a peptide mapping method to describe the primary structure of semaglutide and liraglutide using ultra-performance liquid chromatography-high-resolution mass spectrometry (UPLC-HRMS), and to apply this method to demonstrate the sameness between synthetic peptides for generic drugs and rDNA peptides of the original drugs. Masses of the peptide fragments were identified using HRMS at an accurate level of mass error below 10 ppm, and their sequences were determined via MS E sequencing using in-source fragmentation, which was also useful for identifying the fatty acid chain modification site. Full sequence coverage of each semaglutide and liraglutide was accomplished by combining peptide maps generated using Glu-C and chymotrypsin. The proposed peptide mapping method using UPLC-HRMS was useful for determining active ingredient sameness between generic synthetic peptides and previously approved peptide drug products of rDNA origin., 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 © 2025 Elsevier B.V. All rights reserved.)

Prior studies demonstrate that muscle and bone health are integrally related, and both independently impact orthopedic surgery outcomes. However, relationships between bone density, in vivo microarchitecture, and muscle area have not been previously investigated in orthopedic surgery patients. This study assessed associations between psoas cross sectional area (CSA), bone mineral density (BMD), and microstructure in a cohort undergoing spine fusion. Pre-operatively, bilateral psoas CSA was measured on axial lumbar spine CT in the L3-L4 disc space. To adjust for body size, Psoas Muscle Index (PMI) was calculated (CSA divided by the square of patient height). High resolution peripheral quantitative CT (HR-pQCT, XtremeCT2) assessed volumetric BMD (vBMD), cortical (Ct) and trabecular (Tb) microarchitecture at the distal radius and tibia. Areal BMD (aBMD) was measured by DXA at the lumbar spine (LS), total hip (TH), femoral neck (FN), and the 1/3 radius (1/3R). Pearson correlations related psoas CSA and bone imaging parameters before and after correcting for height and weight. Among 88 patients included, mean age was 63 ± 12 years, BMI was 28 ± 7 kg/m 2 , 47 (53 %) were female. Larger psoas CSA was associated with higher vBMD, greater Ct thickness and better Tb microarchitecture (higher Tb number and lower Tb separation) at the tibia and radius. Larger psoas CSA was also associated with greater aBMD at TH and FN bilaterally and 1/3R (r 0.33 to 0.61; p < 0.002 for all comparisons). Psoas CSA was not associated with aBMD at the LS. Similar results were observed when relating PMI, and adjusting for age, height and weight to HR-pQCT and DXA measurements. Investigation of subgroups by sex demonstrated that relationships were similar magnitude among women but not the men. Patients who underwent primary compared to revision spine surgery had similar associations. Our results demonstrate a link between psoas muscle size and peripheral bone microarchitecture among patients undergoing posterior lumbar spinal fusion. Given the importance of both muscle and skeletal integrity to the success of spine surgery, further study regarding the associations between measurements of psoas muscle, bone microarchitecture, and surgical outcomes is warranted., Competing Interests: Declaration of competing interest Mr. Raphael, Ms. D'Erasmo, Dr. Dash, Ms. Billings, and Dr. Song declare no competing financial interests. Dr. Kim reports relationships with Acuity Surgical (equity or stocks), Aspen Medical Products Inc. (board membership), HS2, LLC (equity or stocks), International Spine Study Group (funding grants), K2 Medical Systems Limited (equity or stocks and speaking and lecture fees), NuVasive Inc. (board membership), SPINE STUD (equity or stocks), Vivex Biologics, Inc. (board membership), and with Zimmer Biomet (consulting or advisory fees and equity or stocks). Dr. Cunningham reports relationships with Radius Health Inc. (funding grants) and Sustain Surgical (equity or stocks). Dr. Nieves reports relationships with Radius Health Inc. (funding grants). Dr. Stein reports relationships with Radius Health Inc. (funding grants) and Novartis (funding grants). Dr. Iyer reports relationships with HS2,LLC (ownership interest and editorial board), HSS ASC Development network, LLC (ownership interest), Joint Effort Administrative Services Organization, LLC (ownership interest), Innovasis (consultant), and Intrinsic Therapeutics (consultant). Dr. Qureshi reports relationships with AMOM opportunities (Honoraria), Globus Medical, Inc. (speakers' bureau, consultant, and royalties), HS2, LLC (ownership interest), HSS ASC Development Network, LLC (ownership interest), Stryker K2M (consultant, royalties and designer), Tissue Differentiation Intelligence (ownership interest), See All AI (ownership interest, scientific advisory board), and Viseon, Inc. (research support, consultant). Dr. Breighner reports a relationship with Stryker (consulting). FUNDING: This research was supported by R01AR081574 NIH/NIAMS and the Anna-Maria and Stephen Kellen Foundation., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: This study aimed to investigate the association of the grit scale, a personality trait characterized by perseverance and passion, with both the presence and the severity of insomnia in the Korean adult population., Methods: A nationwide population-based cross-sectional survey was conducted through face-to-face interviews using structured questionnaires between September and December 2018 in Korea. Grit was assessed by using the 8-item Short Grit Scale. Participants were categorized into insomnia and non-insomnia groups based on a threshold of 10 on the Insomnia Severity Index (ISI). The association between girt and insomnia was analyzed using multiple linear regression and multivariable logistic regression, controlling for sociodemographic factors, lifestyles, and comorbidities., Results: A total of 2453 participants (49.9 % male; aged 19-92 years) were enrolled in the study. Individual grit scores ranged from 1.75 to 5.00 points (mean [SD], 3.27 [0.42]), and insomnia was present in 16.5 % of the population. The insomnia group exhibited lower grit score compared to the non-insomnia group (3.11 [0.40] vs. 3.30 [0.42], p < 0.001, Cohen's d = 0.46). Grit was negatively associated with ISI scores (β = -0.15, 95 % CI = -0.19, -0.11, p < 0.001) and with having insomnia (OR 0.40, 95 % CI = 0.30, 0.55, p < 0.001), after controlling for covariates., Conclusions: Individuals with higher grit were less likely to have insomnia. Clinicians should consider personality traits, such as grit, in the evaluation and the management of insomnia., 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 B.V. All rights reserved.)

Reactive oxygen species (ROS) play a vital role in cellular functions but can lead to oxidative stress and contribute to degenerative diseases when produced in excess. Maintaining redox balance is essential and can be achieved through innate defense mechanisms or external antioxidants. Superoxide dismutase (SOD) is a key enzyme that mitigates intracellular oxidative stress by converting harmful free radicals into hydrogen peroxide, which is subsequently neutralized by catalase and glutathione peroxidase. Previous studies have demonstrated the antioxidant capabilities of SOD derived from Bacillus amyloquefaciens GF424 (BA-SOD) in murine models exposed to either irradiation or SOD1 gene deletion. In this study, a randomized clinical trial was conducted to evaluate the antioxidative benefits of BA-SOD in healthy individuals undergoing acute aerobic exercise (AAE). Eighty participants were randomly assigned to receive either BA-SOD or a placebo for 8 weeks. Antioxidant enzyme activities and glutathione levels were measured before, immediately after, and 30 min post-exercise. A single dose of BA-SOD significantly reduced ROS levels induced by AAE, primarily by enhancing SOD activity in erythrocytes and activating glutathione peroxidase. Continuous BA-SOD administration was associated with a sustained increase in catalase activity and elevated levels of reduced glutathione (GSH). Transcriptomic and metabolomic analyses revealed that a single BA-SOD dose facilitated GSH oxidation, as evidenced by decreased levels of serine, glutamine, and glycine, and increased pyroglutamate levels. Additionally, repeated dosing led to increased expression of genes encoding isocitrate dehydrogenase and malic enzyme, which are involved in NADPH synthesis, as well as nicotinamide phosphoribosyl transferase and NAD kinase, which are essential for NADP availability-critical for converting oxidized glutathione (GSSG) back to GSH. These molecular insights align with clinical observations, suggesting that both acute and long-term BA-SOD supplementation may effectively enhance antioxidant defenses and maintain redox balance under oxidative stress conditions., 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.)

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with cardiovascular diseases and other disorders, possibly via inflammation. Recent research suggests a connection of CHIP with neurodegenerative disorders., Objective: We aimed to investigate the association between multiple system atrophy (MSA) and CHIP., Methods: We included 100 patients with MSA and 4457 controls. Targeted sequencing of peripheral blood DNA samples was performed, focusing on a panel of 25 genes commonly., Linked to Chip: The prevalence of CHIP in patients with MSA was assessed against controls at variant allele frequency (VAF) thresholds of 1.5 % and 2.0 %., Results: DNMT3A mutation rates were significantly higher in patients with MSA, with a VAF of 1.5 %, which remained significant after adjusting for age and sex (adjusted odds ratio, 1.848; 95 % CI, 1.024-3.335; p = 0.0416)., Conclusion: Our results suggest an association between DNMT3A mutations and MSA., 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.)

The skin acts as a vital barrier, shielding the body from external threats that can trigger dryness, itching, and inflammation. Pilea mongolica, a traditional Chinese medicinal herb, holds promise for various ailments, yet its anti-inflammatory properties remain understudied. This study aimed to explore the potential anti-inflammatory effects of the methanol extract of P. mongolica (MEPM) and its underlying molecular mechanisms and active compounds in LPS-stimulated human keratinocytes. MEPM treatment, at concentrations without cytotoxicity, significantly decreased NO productions and the iNOS, IL-6, IL-1β, and TNF-α levels in LPS-induced HaCaT cells. Moreover, MEPM suppressed IRAK4 expression and phosphorylation of JNK, ERK, p38, p65, and c-Jun, suggesting that the anti-inflammatory effects of MEPM result from the inhibition of IRAK4/MAPK/NF-κB/AP-1 signaling pathway. Through LC/MS/MS analysis, 30 compounds and 24 compounds were estimated in negative and positive modes, respectively, including various anti-inflammatory compounds, such as corilagin and geraniin. Through HPLC analysis, geraniin was found to be present in MEPM at a concentration of 18.87 mg/g. Similar to MEPM, geraniin reduced iNOS mRNA expression and inhibited NO synthesis. It also decreased mRNA and protein levels of inflammatory cytokines, including IL-6 and TNF-α, and inhibited IRAK4 expression and the phosphorylation of MAPKs, NF-κB, and AP-1 pathways. Therefore, it can be inferred that the anti-inflammatory effects of MEPM are attributable to geraniin. Thus, MEPM and its active compound geraniin are potential candidates for use in natural functional cosmetics., 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 B.V. All rights reserved.)

Psoriasis is a chronic inflammatory skin disease occurring worldwide. Initially viewed as a keratinocyte disorder, psoriasis is now recognized to involve a complex interplay between genetic predisposition, environmental triggers, and a dysregulated immune system, with a significant role of CD4 + T cells producing IL-17. Recent genetic studies have identified susceptibility loci that underscore the importance of innate immune responses, particularly the roles of myeloid cells, such as dendritic cells, macrophages, and neutrophils. These cells initiate and sustain inflammation through cytokine production triggered by external stimuli. They influence keratinocyte behavior and interact with adaptive immune cells. Recent techniques have further revealed the heterogeneity of myeloid cells in psoriatic lesions, highlighting the contributions of less-studied subsets, such as eosinophils and mast cells. This review examines the multifaceted roles of myeloid innate immune cells in psoriasis, emphasizing their functional diversity in promoting psoriatic inflammation. It also describes current treatment targeting myeloid innate immune cells and explores potential new therapeutic strategies based on the functional characteristics of these subsets. Future research should focus on the detailed characterization of myeloid subsets and their interactions to develop targeted treatments that address the complex immune landscape of psoriasis., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Parkinson's disease (PD) encompasses a range of non-motor symptoms attributed to deficits in various neurotransmitter systems. This study aimed to investigate the associations between cognitive and autonomic symptoms and the degeneration of brainstem monoaminergic nuclei, particularly the serotonergic and noradrenergic nuclei, in a prospective cohort of early PD patients., Methods: Twenty-eight early PD patients (with an average disease duration of approximately three years) underwent baseline [ 18 F]FP-CIT positron emission tomography (PET) scans, Montreal Cognitive Assessment (MoCA), and Composite Autonomic Symptom Scale-31 (COMPASS-31) evaluations, followed by repeat MoCA and COMPASS-31 assessments three years later. Regression models were utilized to analyze both cross-sectional and longitudinal changes in non-motor symptoms relative to baseline degeneration of the noradrenergic locus coeruleus (LC) and serotonergic raphe, normalized by striatal dopaminergic terminal loss., Results: Baseline LC and raphe degeneration in early PD was cross-sectionally associated with poorer MoCA performances. Over the three-year follow-up, gastrointestinal symptoms exhibited progression, while cognitive scores remained stable. Profound baseline degeneration of the LC and raphe, relative to nigrostriatal terminal loss, were predictive of subsequent accelerated deterioration in gastrointestinal symptoms., Conclusion: Brainstem non-dopaminergic dysfunction in early PD is linked to cognitive dysfunction and predicts progression in gastrointestinal symptoms, offering potential indicators for worsening non-motor trajectories., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jung Hwan Shin reports financial support provided by the Ministry of Science and ICT (MSIT), South Korea. Other authors declare 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.)

Design, synthesis, and biological evaluation of two series of O 4' -benzyl-hispidol derivatives and the analogous corresponding O 3' -benzyl derivatives aiming to develop selective monoamine oxidase-B inhibitors endowed with anti-neuroinflammatory activity is reported herein. The first O 4' -benzyl-hispidol derivatives series afforded several more potentially active and MAO-B inhibitors than the O 3' -benzyl derivatives series. The most potential compound 2e of O 4' -benzyl derivatives elicited sub-micromolar MAO-B IC 50 of 0.38 µM with a selectivity index >264 whereas most potential compound 3b of O 3' -benzyl derivatives showed only 0.95 MAO-B IC 50 and a selectivity index >105. Advancement of the most active compounds showing sub-micromolar activities to further cellular evaluations of viability and induced production of pro-neuroinflammatory mediators confirmed compound 2e as a potential lead compound inhibiting the production of the neuroinflammatory mediator nitric oxide significantly by microglial BV2 cells at 3 µM concentration without significant cytotoxicity up to 30 µM. In silico molecular docking study predicted plausible binding modes with MAO enzymes and provided insights at the molecular level. Overall, this report presents compound 2e as a potential lead compound to develop potential multifunctional compounds., 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. Published by Elsevier Ltd.)

Introduction: Levodopa-induced dyskinesia is a common complication of long-term treatment of Parkinson's disease (PD), but its impact on daily activities is somewhat controversial. This study investigated the prevalence and severity of dyskinesia, particularly non-troublesome dyskinesia, to provide insights into its significance for long-term PD management., Methods: We reviewed electronic medical records of 2571 PD patients, who had been followed up at Seoul National University Hospital and were seen between January 2016 and June 2017. Dyskinesia severity had been assessed during follow-up and was recorded with the highest score by considering its impact on functioning (0 = no dyskinesia, 1 = minimal with patient unaware, 2 = mild disability, 3 = moderate disability, 4 = severe disability)., Results: The prevalence of dyskinesia increased progressively with longer PD duration; 8.2% in the group with disease duration of 0-5 years, 40.7% for 6-10 years, 66.0% for 11-15 years, 74.6% for 16-20 years, and 83.2% for 21 years or more. The prevalence of dyskinesia scores ≥2 also increased with disease duration, with rates of 6.3% for 0-5 years, 31.9% for 6-10 years, 54.8% for 11-15 years, 62.9% for 16-20 years and 73.7% for 21 or more years., Conclusion: Despite the increasing prevalence and severity of dyskinesia with longer PD duration, the study found that less than non-troublesome dyskinesia remained at approximately 26.3% even after more than 21 years of disease duration. These findings suggest that dyskinesia may not be troublesome for many PD patients even in long-term., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest relevant to this work., (Copyright © 2024. Published by Elsevier Ltd.)

Given that individuals with latent tuberculosis (TB) infection represent the major reservoir of TB infection, latency-associated antigens may be promising options for development of improved multi-antigenic TB subunit vaccine. Thus, we selected RipA, a peptidoglycan hydrolase required for efficient cell division of Mycobacterium tuberculosis (Mtb), as vaccine candidate. We found that RipA elicited activation of dendritic cells (DCs) by induction of phenotypic maturation, increased production of inflammatory cytokines, and prompt stimulation of MAPK and NF-κB signaling pathways. In addition, RipA-treated DCs promoted Th1-polarzied immune responses of naïve CD4 + T cells with increased proliferation and activated T cells from Mtb-infected mice, which conferred enhanced control of mycobacterial growth inside macrophages. Moreover, mice immunized with RipA formulated in GLA-SE adjuvant displayed remarkable generation of Ag-specific polyfunctional CD4 + T cells in both lung and spleen. Following an either conventional or ultra-low dose aerosol challenges with 2 Mtb Beijing clinical strains, RipA/GLA-SE-immunization was not inferior to BCG by mediating protection as single Ag. Collectively, our findings highlighted that RipA could be a novel candidate as a component of multi-antigenic TB subunit vaccines., 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.)

Asthma is an inflammatory disease characterized by chronic inflammation in lung tissues and excessive mucus production. High-fat diets have long been assumed to be a potential risk factor for asthma. However, to date, very few direct evidence indicating the involvement of high sucrose intake (HSI) in asthma progression exists. In this study, we investigate the effect of HSI on ovalbumin (OVA)-sensitized allergic asthma mice. We observed that HSI increased the expression of inflammatory genes (IL-1β, IL-6, TNF-α) in adipose tissues and led to reactive oxygen species generation in the liver and lung. In addition, HSI accelerated the TLR4/NF-κB signaling pathway leading to MMP9 activation, which promotes the chemokines and TGF-β secretion in the lungs of OVA-sensitized allergic asthma mice. More importantly, HSI significantly promoted the pathogenic Th2 and Th17 responses. The increase of IL-17A secretion by HSI increased the expression of chemokines (MCP-1, CXCL1, CXCL5, CXCL8). It resulted in eosinophil and mast cell infiltration in the lung and trachea. We also demonstrated that HSI increased mucus hypersecretion, which was validated by increased main mucin protein (MUC5AC) secreted in the lungs. Our findings suggest that HSI exacerbates the development of Th2/Th17-predominant asthma by upregulating the TLR4-mediated NF-κB pathway, leading to excessive MMP9 production., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Although the epidemiology of Huntington's disease (HD) in Korea differs notably from that in Western countries, the genetic disparities between these regions remain unclear., Objective: To investigate the characteristics and clinical significance of cytosine-adenine-guanine (CAG) repeat size associated with HD in the Korean population., Methods: We analyzed the CAG repeat lengths of the HTT gene in 941 healthy individuals (1,882 alleles) and 954 patients with chorea (1,908 alleles) from two referral hospitals in Korea. We presented normative CAG repeat length data for the Korean population and computed the reduced penetrance (36-39 CAG) and intermediate allele (27-35 CAG) frequencies in the two groups. Furthermore, we investigated the relationship between intermediate alleles and chorea development using logistic regression models in individuals aged ≥55 years., Results: The mean (±standard deviation) CAG repeat length in healthy individuals was 17.5 ± 2.0, with a reduced penetrance allele frequency of 0.05 % (1/1882) and intermediate allele frequency of 0.69 % (13/1882). We identified 213 patients with genetically confirmed HD whose CAG repeat length ranged from 39 to 140, with a mean of 45.2 ± 7.9 in the longer allele. Compared with normal CAG repeat alleles, intermediate CAG repeat alleles were significantly related to a higher risk of developing chorea (age of onset range, 63-84 years) in individuals aged ≥55 years., Conclusions: This study provides insights into the specific characteristics of CAG repeat lengths in the HTT gene in the Korean population. The reduced penetrance and intermediate allele frequencies in the Korean general population seem to be lower than those reported in Western populations. The presence of intermediate alleles may increase the risk of chorea in the Korean elderly population, which requires further large-scale investigations., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jee-Young Lee reports financial support was provided by SMG-SNU Boramae Medical Center focused clinical research grant-in-aid (04-2022-0014)., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Many attempts have been made to use mitochondria (MT) to treat human diseases; however, MT are large, making them difficult to deliver effectively. Therefore, a transfer strategy based on membrane fusion was established. Fusogenic mitochondrial capsules (FMCs) comprising a neutral lipid (PE), a cationic lipid (DOTAP), an aromatic lipid (Liss Rhod PE), and three types of liposome (FMC0, FMC1, and FMC2), were designed and synthesized. The amount of DOTAP, which affects membrane fusion efficiency, differed between FMC preparations. The characteristics of these FMCs were analyzed by DLS, TEM, and AFM, and the encapsulation and fusion efficiency between FMC-MT and FMC-chondrocytes were confirmed by FRET, mtDNA copy number, and CLSM, respectively. Compared with naked MT, delivery of FMCs to chondrocytes was faster and more efficient. Moreover, fusion was a more stable delivery method than endocytosis, as evidenced by reduced induction of mitophagy. In vitro and in vivo experiments revealed that FMCs reduced expression of inflammatory cytokines and MMP13, increased expression of extracellular matrix components, and promoted cartilage regeneration. These findings suggest that FMCs are a highly effective and promising strategy for delivery of MT to promote cartilage regeneration, and highlight their potential as a novel platform for MT transfer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To map thermal safety boundaries during ureteroscopy (URS) with laser activation in two in vivo porcine subjects to better understand the interplay between laser power, irrigation rate, and fluid temperature in the collecting system., Methods: URS was performed in two in vivo porcine subjects with a prototype ureteroscope containing a thermocouple at its tip. Up to 6 trials of 60 seconds laser activation were carried out at each selected power setting and irrigation rate. Thermal dose was calculated for each trial, and laser power-irrigation rate parameter pairs were categorized based on number of trials that exceeded a thermal dose of 120 equivalent minutes., Results: The collecting fluid temperature was increased with greater laser power and slower irrigation rate. In the first porcine subject, 25 W of laser power could safely be applied if irrigation was at least 15 mL/min, and 48 W with at least 30 mL/min. Intermediate values followed a linear curve between these bounds. For the second subject, where the calyx appeared larger, 15 W laser power required 9 mL/min irrigation, 48 W required 24 mL/min, and intermediate points also followed a near-linear curve., Conclusion: This study validates previous bench research and provides a conceptual framework for selection of safe laser lithotripsy settings and irrigation rates during URS with laser lithotripsy. Additionally, it provides insight and guidance for future development of thermal mitigation strategies and devices., Competing Interests: Declaration of Competing Interest Khurshid R. Ghani paid consultant to companies – “Boston Scientific,” “Ambu,” “Olympus,” “Coloplast,” and “Karl Storz.” William W. Roberts, MD paid consultant to company “Boston Scientific.” All the other authors have no conflict of interest to declare., (Published by Elsevier Inc.)

Background: Speech therapy is highly effective for patients with Parkinson's disease (PD) who have speech difficulties; however, its accessibility is limited. Online video-call speech therapy has been explored as an alternative option for PD patients., Objectives: To evaluate the feasibility and efficacy of video-call speech therapy for PD patients., Methods: This prospective, comparative study was conducted between July and September 2022. PD patients with speech difficulties were divided into two groups, online speech therapy via video call and in-person therapy at hospital, based on their willingness to visit the hospital frequently. The patients underwent 12 sessions of speech therapy, focusing on respiration and phonation. Acoustic assessments, auditory-perceptual assessment, and voice handicap index (K-VHI10) were evaluated at baseline, post-therapy, and follow-up., Results: Eleven patients were enrolled in the study, though one patient from the online group withdrew. Ten patients completed the therapy (five in each group) without missing a session. The baseline acoustic measurements did not differ between the two groups. After therapy, both group showed an increase in voice intensity and improvement in overall loudness. The post-therapy change from baseline in the acoustic measurements was not significantly different between the two groups. The effect of therapy were maintained in the follow-up evaluation in both groups. The K-VHI10 decreased significantly from baseline to post-therapy and further at follow-up in both groups, with no significant difference between two groups., Conclusion: The online speech therapy via video call is feasible in PD patients with speech difficulties and as effective as in-person therapy., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest relevant to this work., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Although lipid nanoparticles (LNP) are potential carriers of various pharmaceutical ingredients, further investigation for maintaining their stability under various environmental stressors must be performed. This study evaluated the influence of PEGylation and stress conditions on the stability of siRNA-loaded LNPs with different concentrations of PEG (0.5 mol%; 0.5 % PEG-LNP and 1.0 mol%; 1.0 % PEG-LNP) anchored to their surface. We applied end-over-end agitation, elevated temperature, and repeated freeze and thaw (F/T) cycles as physicochemical stressors of pH and ionic strength. Dynamic light scattering (DLS), flow imaging microscopy (FIM), and ionic-exchange chromatography (IEX) were to determine the degree of aggregation and change in siRNA content. The results indicate that 0.5 % PEG-LNP resisted aggregation only at low pH levels or with salt, whereas 1.0 % PEG-LNP had increased colloidal stability except at pH 4. 0.5 % PEG-LNP withstood aggregation until 71 °C and three cycles of F/T. In contrast, 1.0 % PEG-LNP maintained colloidal stability at 90 °C and seven F/T cycles. Moreover, 1.0 % PEG-LNP had higher siRNA stability under all stress conditions. Therefore, to ensure the stability of LNP and encapsulated siRNA, the PEG concentration must be carefully controlled while considering LNPs' colloidal instability mechanisms under various stress conditions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: It is reported that a diet that lowers oxidative stress reduces the prodromal Parkinson's disease (pPD) probability as well as the risk of Parkinson's disease (PD). In this study, we evaluated whether the diet quality of patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD) were associated with the pPD probability score, PD risk markers, or prodromal markers., Methods: Polysomnography (PSG)-confirmed iRBD patients from the Neurology Department at Seoul National University Hospital were enrolled. We calculated the pPD probability using the "Web-based Medical Calculator for Prodromal Risk in Parkinsonism" Diet quality was assessed using the Recommended Food Score (RFS)., Results: We enrolled 101 patients with iRBD. The mean RFS score of patients with iRBD was 28.23 ± 9.29, which did not differ from the general population. Among patients with iRBD, the probability of pPD did not differ between the high and low RFS groups. In patients aged <70 years, although total RFS was not correlated with pPD probability (p = 0.529, Spearman rank correlation), legume consumption was negatively correlated with pPD probability (p = 0.032): furthermore, legume consumption was significantly higher in patients with fewer prodromal markers (p = 0.016)., Conclusion: Diet quality assessed by RFS did not differ between the general population and patients with iRBD in Korea. Further studies are needed to confirm these protective effects of legume consumption on iRBD, which may have strong implications for the prevention and management of PD., Competing Interests: Declaration of competing interest All authors declare no relevant conflicts of interests in this study., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

In May 2015, a high mortality event in farmed rainbow trout occurred in Jeollabuk-do province in Korea. Histopathological analysis revealed necrosis in the kidney, liver, branchial arch, and gills of moribund fish, and infectious hematopoietic necrosis virus (IHNV) was detected in the lesions by immunohistochemistry. Cytopathic effects were observed in EPC, FHM, and RTG-2 cell lines after inoculation with kidney and spleen tissues and IHNV was detected by reverse transcription polymerase chain reaction (PCR). The amplified PCR product was sequenced, and phylogenetic analysis placed IHNV in the JRt Nagano group. Both in vivo and in vitro trials were performed to compare the virulence properties between RtWanju15 isolate, which causes 100% mortality in imported fry, and a previous isolate RtWanju09 of the JRt Shizuoka group isolated from eggs of healthy broodfish. In vivo challenge with high dose on specific pathogen free (SPF) rainbow trout fry performed in Denmark with isolates RtWanju09, RtWanju15 and DF04/99 isolates showed a survival rates of 60%, 37.5% and 52.5% (average), respectively without statistical difference. The replication efficiency of the two isolates in the in vitro challenge was similar., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Calcific aortic valve stenosis (CAVS), the third most prevalent cardiovascular disorder is known to impose a huge social and economic burden on patients. However, no pharmacotherapy has yet been established. Aortic valve replacement is the only treatment option, although its lifelong efficacy is not guaranteed and involves inevitable complications. So, there is a crucial need to find novel pharmacological targets to delay or prevent CAVS progression. Capsaicin is well known for its anti-inflammatory and antioxidant properties and has recently been revealed to inhibit arterial calcification. We thus investigated the effect of capsaicin in attenuating aortic valve interstitial cells (VICs) calcification induced by pro-calcifying medium (PCM). Capsaicin reduced the level of calcium deposition in calcified VICs, along with reductions in gene and protein expression of the calcification markers Runx2, osteopontin, and BMP2. Based on Gene Ontology biological process and Kyoto Encyclopedia of Genes and Genomes pathway analysis oxidative stress, AKT and AGE-RAGE signaling pathways were selected. The AGE-RAGE signaling pathway activates oxidative stress and inflammation-mediated pathways including ERK and NFκB signaling pathways. Capsaicin successfully inhibited oxidative stress- and reactive oxygen species-related markers NOX2 and p22 phox . The markers of the AKT, ERK1/2, and NFκB signaling pathways, namely, phosphorylated AKT, ERK1/2, NFκB, and IκBα were upregulated in calcified cells, while being significantly downregulated upon capsaicin treatment. Capsaicin attenuates VICs calcification in vitro by inhibition of redox-sensitive NFκB/AKT/ERK1/2 signaling pathway, indicating its potential as a candidate to alleviate CAVS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Whilst sonothrombolysis is a promising and noninvasive ultrasound technique for treating blood clots, bleeding caused by thrombolytic agents used for dissolving clots and potential obstruction of blood flow by detached clots (i.e., embolus) are the major limitations of the current approach. In the present study, a new sonothrombolysis method is proposed for treating embolus without the use of thrombolytic drugs. Our proposed method involves (a) generating a spatially localised acoustic radiation force in a blood vessel against the blood flow to trap moving blood clots (i.e., generation of an acoustic net), (b) producing acoustic cavitation to mechanically destroy the trapped embolus, and (c) acoustically monitoring the trapping and mechanical fractionation processes. Three different ultrasound transducers with different purposes were employed in the proposed method: (1) 1-MHz dual focused ultrasound (dFUS) transducers for capturing moving blood clots, (2) a 2-MHz High Intensity Focused Ultrasound (HIFU) source for fractionating blood clots and (3) a passive acoustic emission detector with broad bandwidth (10 kHz to 20 MHz) for receiving and analysing acoustic waves scattered from a trapped embolus and acoustic cavitation. To demonstrate the feasibility of the proposed method, in vitro experiments with an optically transparent blood vessel-mimicking phantom filled with a blood mimicking fluid and a blood clot (1.2 to 5 mm in diameter) were performed with varying the dFUS and HIFU exposure conditions under various flow conditions (from 1.77 to 6.19 cm/s). A high-speed camera was used to observe the production of acoustic fields, acoustic cavitation formation and blood clot fragmentation within a blood vessel by the proposed method. Numerical simulations of acoustic and temperature fields generated under a given exposure condition were also conducted to further interpret experimental results on the proposed sonothrombolysis. Our results clearly showed that fringe pattern-like acoustic pressure fields (fringe width of 1 mm) produced in a blood vessel by the dFUS captured an embolus (1.2 to 5 mm in diameter) at the flow velocity up to 6.19 cm/s. This was likely to be due to the greater magnitude of the dFUS-induced acoustic radiation force exerted on an embolus in the opposite direction to the flow in a blood vessel than that of the drag force produced by the flow. The acoustically trapped embolus was then mechanically destructed into small pieces of debris (18 to 60 μm sized residual fragments) by the HIFU-induced strong cavitation without damaging the blood vessel walls. We also observed that acoustic emissions emitted from a blood clot captured by the dFUS and cavitation produced by the HIFU were clearly distinguished in the frequency domain. Taken together, these results can suggest that our proposed sonothrombolysis method could be used as a promising tool for treating thrombosis and embolism through capturing and destroying blood clots effectively., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Concurrent outbreaks of circulating vaccine-derived poliovirus serotypes 1 and 2 (cVDPV1, cVDPV2) were confirmed in the Republic of the Philippines in September 2019 and were subsequently confirmed in Malaysia by early 2020. There is continuous population subgroup movement in specific geographies between the two countries. Outbreak response efforts focused on sequential supplemental immunization activities with monovalent Sabin strain oral poliovirus vaccine type 2 (mOPV2) and bivalent oral poliovirus vaccines (bOPV, containing Sabin strain types 1 and 3) as well as activities to enhance poliovirus surveillance sensitivity to detect virus circulation. A total of six cVDPV1 cases, 13 cVDPV2 cases, and one immunodeficiency-associated vaccine-derived poliovirus type 2 case were detected, and there were 35 cVDPV1 and 31 cVDPV2 isolates from environmental surveillance sewage collection sites. No further cVDPV1 or cVDPV2 have been detected in either country since March 2020. Response efforts in both countries encountered challenges, particularly those caused by the global COVID-19 pandemic. Important lessons were identified and could be useful for other countries that experience outbreaks of concurrent cVDPV serotypes., 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 © 2022. Published by Elsevier Ltd.)

Spine fusion surgery is one of the most common orthopedic procedures, with over 400,000 performed annually to correct deformities and pain. However, complications occur in approximately one third of cases. While many of these complications may be related to poor bone quality, it is difficult to detect bone abnormalities prior to surgery. Areal BMD (aBMD) assessed by DXA may be artifactually high in patients with spine pathology, leading to missed diagnosis of deficits. In this study, we related preoperative imaging characteristics of both central and peripheral sites to direct measurements of bone quality in vertebral biopsies. We hypothesized that pre-operative imaging outcomes would relate to vertebral bone mineralization and collagen properties. Pre-operative assessments included DXA measurements of aBMD of the spine, hip, and forearm, central quantitative computed tomography (QCT) of volumetric BMD (vBMD) at the lumbar spine, and high resolution peripheral quantitative computed tomography (HRpQCT; Xtreme CT2) measurements of vBMD and microarchitecture at the distal radius and tibia. Bone samples were collected intraoperatively from the lumbar vertebrae and analyzed using Fourier-transform Infrared (FTIR) spectroscopy. Bone samples were obtained from 23 postmenopausal women (mean age 67 ± 7 years, BMI 28 ± 8 kg/m 2 ). We found that patients with more mature bone by FTIR, measured as lower acid phosphate content and carbonate to phosphate ratio, and greater collagen maturity and mineral maturity/crystallinity (MMC), had greater cortical vBMD at the tibia and greater aBMD at the lumbar spine and one-third radius. Our data suggests that bone quality at peripheral sites may predict bone quality at the spine. As bone quality at the spine is challenging to assess prior to surgery, there is a great need for additional screening tools. Pre-operative peripheral bone imaging may provide important insight into vertebral bone quality and may foster identification of patients with bone quality deficits., Competing Interests: Declaration of competing interest AKH, AD, BES, LS, SG, KBA, AJ, SC, and EB have nothing to disclose. HJK reports personal fees from Alphatec, personal fees from K2M, personal fees from Zimmerbiomet, outside the submitted work. MC reports grants and personal fees from K2M, personal fees from Zimmerbiomet, grants from Radius Health, grants from RTI, outside the submitted work. DL reports. Consultant role for Depuy Synthes, Stryker, Viseon, Inc., ownership interest in HS2,LLC, ISPH II,LLC, Remedy Logic, Vestia Ventures MiRus Investment LLC, Woven Orthopedic Technologies, Viseon, Inc.; royalty fees from Nuvasive, Inc., Stryker; Advisory Board membership for Remedy Logic (all activities outside the submitted work). ED has nothing to disclose. EMS reports grants from Novartis, grants from Radius Health, all outside the submitted work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: The objective of this study was to determine the area in the cricopharyngeus muscle (CPM) where botulinum neurotoxin (BoNT) can be injected safely and effectively by evaluating neural distribution in the CPM., Methods: Eleven specimens of the CPM were gathered from human cadavers. The anatomical relationship between the posterior cricoarytenoid muscle (PCAM) and the CPM was evaluated. Myelinated nerve fibers in the CPM were stained using modified Sihler's method. The CPM was classified into five zones according to the area accessible within the CPM via transcutaneous and transluminal approaches for BoNT injection as follows: i) lateral area including upper area (zone 1) and lower area (zone 2); ii) posterolateral area including upper area (zone 3) and lower area (zone 4); and iii) posterior area (zone 5). Neural distribution originating from the pharyngeal plexus and the extralaryngeal branches of recurrent laryngeal nerve (EBRLN) within each classified zone in stained specimens was determined., Results: Six specimens (12 lateral areas, 12 posterolateral areas, and 6 posterior areas) were suitable for evaluating neural distribution within the CPM. Zone 1 was adjacent to the PCAM the most in all specimens. Nerve endings originating from the EBRLN were observed on four sides of zone 2 (33.3%, 4/12 sides) in three specimens (3/6, 50%). Neural distribution originating from the pharyngeal plexus was found on ten sides (83.3%, 10/12 sides) of zone 3 in five specimens (83.3%, 5/6 specimens) and on nine sides (75.0%, 9/12 sides) of zone 4 in five specimens (83.3%, 5/6 specimens)., Conclusion: The posterolateral area (zone 3 and zone 4) is thought to be the most suitable area for alleviating the spasticity of CPM with a minimum dose of BoNT., Competing Interests: Declaration of Competing Interest The authors have no potential conflicts or competing interests relevant to this study to disclose., (Copyright © 2022. Published by Elsevier B.V.)

Background: Postoperative delirium is a common complication in elderly patients who have undergone hip fracture surgery. Since postoperative delirium is associated with poor outcomes and the treatment is very complicated, identifying the patients at high risk for delirium and providing more attentive care to prevent postoperative delirium is essential. In this study, we aimed to assess the association of an elevated C-reactive protein (CRP)/albumin ratio with the increased incidence of postoperative delirium in elderly people who had undergone hip fracture surgery., Methods: A total of 629 patients who underwent hip fracture surgery between January 2014 and December 2018 were retrospectively analyzed. Patients were classified into two groups according to preoperative CRP/albumin cut-off levels (<1.5 and ≥1.5). We performed a propensity score matching analysis to compare the incidence of postoperative delirium and overall mortality between the two groups. Multivariate logistic regression and Cox regression analyses were performed to examine the association of the preoperative CRP/albumin ratio with postoperative delirium and overall mortality., Results: There were significant differences in the incidence of postoperative delirium (18.0 % vs. 35.8 %, P < 0.001) and overall mortality (26.7 % vs. 46.9 %, P < 0.001) between the groups before matching. We also observed significant differences in the incidence of postoperative delirium (20.7 % vs. 32.7 %, P = 0.019) and overall mortality (34.7 % vs. 46.0 %, P = 0.046) between the groups after matching. A high CRP/albumin ratio (≥1.5) was significantly associated with a higher incidence of postoperative delirium (adjusted odds ratio [OR]: 2.11, 95 % confidence interval [CI]: 1.40-3.18, P < 0.001) and a higher rate of overall mortality (adjusted hazard ratio [HR]: 1.44, 95 % CI: 1.07-1.93, P = 0.015)., Conclusion: Preoperative CRP/albumin ratio might be an independent risk factor of postoperative delirium and surgical prognosis in elderly patients undergoing hip fracture surgery., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Severe obstructive sleep apnea (OSA) in patients with rapid eye movement (REM) sleep behavior disorder (RBD) may result in frequent fragmentation of REM sleep and consequently lead to a false negative diagnosis of RBD on a video-polysomnography (video-PSG). Thus, we determined whether OSA has the negative impact on video-PSG diagnostic accuracy for RBD., Methods: Patients with clinically diagnosed idiopathic RBD were included. RBD was confirmed if a video-PSG demonstrated complex motor behavior during REM sleep or REM sleep without atonia (RWA). Motor behavior was measured using the RBD Severity Scale. Cohen's kappa coefficient was calculated for qualitative assessment of RWA. A stepwise logistic regression analysis was performed., Results: Of a total 254 patients included, a diagnosis of RBD was confirmed by a video-PSG in 221 patients (87.0%). RWA, vocalization, and axial or proximal muscle movements in REM sleep were noted in 86.6%, 58.3%, and 35.9%, respectively. A video-PSG diagnosis of RBD was less likely associated with severe OSA (odds ratio [OR] 0.284, p = 0.010) and moderate OSA (OR 0.404, p = 0.071) whereas was more likely associated with longer REM sleep time (OR 1.036, p < 0.001). In 43 patients who underwent a continuous positive airway pressure (CPAP) titration study, a diagnosis of RBD was more common on a CPAP titration study (88.4%) than on a first video-PSG (65.1%) (p = 0.013). Twelve (27.9%) of 43 CPAP patients were diagnosed with RBD according only to CPAP titration study., Conclusions: OSA that requires CPAP may reduce a diagnostic accuracy for RBD by a video-PSG. False negative results were probably due to frequent electromyographic artifacts and/or severe sleep disruption from apneic events during REM sleep., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest in relation to this study., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Adipocyte lipid accumulation causes adipocyte hypertrophy and adipose tissue increment, leading to obesity. As part of our efforts to isolate antiobesity agents from natural products, we first isolated the active compound from the extract of Gelidium amansii through bioassay-guided fractionation. We then hypothesized that pheophorbide A isolated from G amansii inhibits adipogenesis by downregulating adipogenic transcription factors; therefore, the antiadipogenic effects of pheophorbide A were investigated in 3T3-L1 adipocytes. On differentiation of 3T3-L1 preadipocytes into adipocytes, they were treated with pheophorbide A (0-83 µM). Pheophorbide A inhibited triglyceride accumulation (half maximal inhibitory concentration = 114.2 µM) and stimulated glycerol release in a dose-dependent manner in 3T3-L1 adipocytes. In addition, pheophorbide A significantly decreased leptin concentrations in 3T3-L1 adipocytes. Pheophorbide A inhibited adipogenesis by suppressing the expression of adipogenic transcriptional factors including peroxisome proliferator-activated receptor γ, CCATT/enhancer binding protein α, sterol regulatory element binding protein 1c, and fatty acid synthase. It also induced the expression of phosphorylation of AMP-activated protein kinase. Therefore, these results suggest that pheophorbide A may be useful for preventing or treating obesity because of its inhibitory effect on adipogenesis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Idiopathic blepharospasm is a clinically heterogeneous dystonia also characterized by non motor symptoms., Methods: We used a k-means cluster analysis to assess 188 patients with idiopathic blepharospasm in order to identify relatively homogeneous subpopulations of patients, using a set of motor and psychiatric variables to generate the cluster solution., Results: Blepharospasm patients reached higher scores on scales assessing depressive- and anxiety-related disorders than healthy/disease controls. Cluster analysis suggested the existence of three groups of patients that differed by type of spasms, overall motor severity, and presence/severity of psychiatric problems. The greater severity of motor symptoms was observed in Group 1, the least severity in Group 3, while the severity of blepharospasm in Group 2 was between that observed in Groups 1 and 3. The three motor subtypes also differed by psychiatric features: the lowest severity of psychiatric symptoms was observed in the group with least severe motor symptoms (group 3), while the highest psychiatric severity scores were observed in group 2 that carried intermediate motor severity rather than in the group with more severe motor symptoms (group 1). The three groups did not differ by disease duration, age of onset, sex or other clinical features., Conclusions: The present study suggests that blepharospasm patients may be classified in different subtypes according to the type of spasms, overall motor severity and presence/severity of depressive symptoms and anxiety., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: In the present study, real-time quaking-induced conversion (RT-QuIC) assay was used to evaluate pathologic alpha-synuclein (AS) seeding activity in formalin-fixed paraffin-embedded (FFPE) tissue from the gastrointestinal (GI) tract of Parkinson's disease (PD) patients., Methods: This study was conducted in two parts: Part I. a preliminary autopsy study that included four autopsy-confirmed patients with synucleinopathy (2 PD, 1 dementia with Lewy bodies [DLB], and 1 multiple system atrophy [MSA]) and two normal autopsy controls. Frozen and FFPE tissues of the brain were obtained. Part II. a clinical case-control study that included 20 clinically diagnosed PD patients and matched controls. Surgically resected FFPE tissues from the upper and lower GI tracts were used. The RT-QuIC assay was performed to evaluate pathologic seed amplification using frozen or FFPE tissues. The presence or absence of AS aggregation was confirmed by conventional phosphorylated AS (pAS) immunohistochemistry (IHC)., Results: In Part I, RT-QuIC assay showed pathologic AS amplification in frozen and FFPE brain tissues of PD and DLB patients, and FFPE stomach tissue of PD patients but not in the MSA patient and controls. In Part II, pathologic seeding activity was found in 10% (2/20) of the stomach tissues of clinical PD patients but in none of the matched controls. IHC showed pAS-positive staining in 55% of patients (11/20) and 15% of controls (3/20)., Conclusion: The present study results showed that the RT-QuIC assay using FFPE tissue of the GI tract was inadequate as a biomarker in PD., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Diet is a critical risk factor for gastric cancer, and Koreans consume significantly high amounts of carbohydrates. This study examined the association between carbohydrate intake, glycemic index, and glycemic load and the risk of gastric cancer and whether the association varied based on the general risk factors for gastric cancer. We hypothesized that carbohydrate intake, glycemic index, and glycemic load elevated gastric cancer risk and the relationship differed by the gastric cancer risk factors. This was a case-control study with a total of 307 matched pairs aged 20 to 79 years. Data collection was completed at two hospitals from December 2002 to September 2006. A food frequency questionnaire was applied for dietary assessment. Carbohydrate intake was not related to gastric cancer risk. However, a high glycemic index (odds ratio [OR], 1.88; 95% confidence interval (95% CI), 1.18-2.97) and glycemic load (OR, 2.51; 95% CI, 1.53-4.12) were significantly associated with the elevated risk of gastric cancer. When the relationship between glycemic load and gastric cancer risk was stratified by risk factors for gastric cancer, the gastric cancer risk especially increased among men, ≥65 years, smokers, drinkers, and people with Helicobacter pylori infection. Although there was no association between carbohydrate consumption and gastric cancer, high glycemic index and glycemic load were associated with the increased gastric cancer risk., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: The objective biomarker for prediction of gait and balance in the long-term follow-up of Parkinson's disease(PD) patients with subthalamic nucleus deep brain stimulation(STN-DBS) has not yet been elucidated. We investigated the value of pre-operative quantitative gait parameters for the prediction of long-term prognosis of gait in PD patients with DBS., Methods: We retrospectively collected gait videos(both medication ON/OFF states) of PD patients recorded as preoperative evaluation before STN DBS. We enrolled patients who were followed-up for more than 5 years after the surgery from 2006 to 2014. We derived objective gait parameters from video-based gait analysis algorithm. We defined the clinical milestones of frequent falling, impaired walking, and loss of autonomy based on the Unified Parkinson's disease rating scale and Hoehn and Yahr stage, which were regularly followed up to 156 months after surgery. We calculated hazard ratios(HRs) of baseline gait parameters for predicting the clinical milestones., Results: A total of 96 gait videos from 63 PD patients were analyzed. The mean follow-up duration(standard deviation) was 88.0(34.2) months after surgery. Relatively high (>mean + 1 standard deviation) variability for step length, step time and stride time (HR = 2.92[1.02-8.33], 3.91[1.38-11.11] and 7.16[2.09-24.52],respectively) in medication-ON state significantly predicted reaching any of the three clinical milestones of frequent falling, impaired walking and loss of autonomy. Gait parameters from the medication-OFF state did not predict any clinical milestone., Conclusions: High preoperative gait variability from the medication-ON state predicts long-term outcomes for gait and balance in PD patients with STN DBS., (Copyright © 2022. Published by Elsevier Ltd.)

Human in vitro hepatic models that faithfully recapitulate liver function are essential for successful basic and translational research. A limitation of current in vitro models, which are extensively used for drug discovery and toxicity testing, is the loss of drug metabolic function due to the low expression and activity of cytochrome P450 (CYP450) enzymes. Here, we aimed to generate human pluripotent stem cell-derived hepatic organoids (hHOs) with a high drug metabolic ability. We established a two-step protocol to produce hHOs from human pluripotent stem cells for long-term expansion and drug testing. Fully differentiated hHOs had multicellular composition and exhibited cellular polarity and hepatobiliary structures. They also displayed remarkable CYP450 activity and recapitulated the metabolic clearance, CYP450-mediated drug toxicity, and metabolism. Furthermore, hHOs successfully modeled Wilson's disease in terms of Cu metabolism, drug responses, and diagnostic marker expression and secretion. In conclusion, hHOs exhibit high capacity for drug testing and disease modeling. Hence, this hepatic model system provides an advanced tool for studying hepatic drug metabolism and diseases., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Electrical stimulation can facilitate wound healing with high efficiency and limited side effects. However, current electrical stimulation devices have poor conformability with wounds due to their bulky nature and the rigidity of electrodes utilized. Here, a flexible electrical patch (ePatch) made with conductive hydrogel as electrodes to improve wound management was reported. The conductive hydrogel was synthesized using silver nanowire (AgNW) and methacrylated alginate (MAA), with the former chosen as the electrode material considering its antibacterial properties, and the latter used due to its clinical suitability in wound healing. The composition of the hydrogel was optimized to enable printing on medical-grade patches for personalized wound treatment. The ePatch was shown to promote re-epithelization, enhance angiogenesis, mediate immune response, and prevent infection development in the wound microenvironment. In vitro studies indicated an elevated secretion of growth factors with enhanced cell proliferation and migration ability in response to electrical stimulation. An in vivo study in the Sprague-Dawley rat model revealed a rapid wound closure within 7 days compared to 20 days of usual healing process in rodents., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The bleeding disorder hemophilia A (HA) is caused by a single-gene (F8) defect and its clinical symptom can be substantially improved by a small increase in the plasma coagulation factor VIII (FVIII) level. In this study, we used F8-defective human induced pluripotent stem cells from an HA patient (F8d-HA hiPSCs) and F8-corrected (F8c) HA hiPSCs produced by CRISPR/Cas9 genome engineering of F8d-HA hiPSCs. We obtained a highly enriched population of CD157 + cells from CRISPR/Cas9-edited F8c-HA hiPSCs. These cells exhibited multiple cellular and functional phenotypes of endothelial cells (ECs) with significant levels of FVIII activity, which was not observed in F8d-HA hiPSC-ECs. After transplantation, the engineered F8c-HA hiPSC-ECs dramatically changed bleeding episodes in HA animals and restored plasma FVIII activity. Notably, grafting a high dose of ECs substantially reduced the bleeding time during multiple consecutive bleeding challenges in HA mice, demonstrating a robust hemostatic effect (90% survival). Furthermore, the engrafted ECs survived more than 3 months in HA mice and reversed bleeding phenotypes against lethal wounding challenges. We also produced F8c-HA hiPSC-derived 3D liver organoids by assembling three different cell types in microwell devices and confirmed its therapeutic effect in HA animals. Our data demonstrate that the combination of genome-engineering and iPSC technologies represents a novel modality that allows autologous cell-mediated gene therapy for treating HA., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective/background: When isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is combined with obstructive sleep apnea (OSA), the pattern of temporal association between REM without atonia (RWA) and apnea-hypopnea events may be related to improvements in RBD symptoms after positive airway pressure (PAP) treatment. We evaluated the frequency of improvement in RBD symptoms after PAP and the relationship of the degree of co-occurrence between RWA and apnea-hypopnea events to RBD symptom improvement after PAP treatment., Patients/methods: In an institutional cohort with sleep disorders, 31 patients with video-polysomnography confirmed iRBD and concomitant OSA with an apnea-hypopnea index (AHI) of ≥15/h who received PAP treatment were included. Along with gross video-polysomnography parameters such as AHI and electromyography activity index during REM sleep, a mini-epoch-based parameter apnea-hypopnea-electromyography activity ratio (AH EMG activity ratio) was used to evaluate the co-occurrence between RWA and apnea-hypopnea events. Improvement in RBD symptoms after PAP treatment was designated as a clinical global impression-improvement (CGI-I) score of 0-3 at three-month., Results: Twenty-three (74.2%) patients exhibited improvement in RBD symptoms after PAP treatment. No patient was taking an antidepressant medication. An AH EMG activity ratio of ≥15% (Odds ratio [OR] 10.146, 95% CI 1.302-79.032, P = 0.027) was significantly associated with clinical improvement after PAP treatment in a regression model adjusted for age, sex, AHI, and electromyography activity index during REM., Conclusions: Treatment of concomitant OSA with PAP can improve symptoms of iRBD. Respiratory events that co-occur with RWA may predict improvement in RBD symptoms after PAP treatment., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Despite the extensive usage of synthetic musk compounds (SMCs) and siloxanes in various personal care products (PCPs), trophic magnification of such chemicals in aquatic environments remains unexplored. In June and September 2020, eleven SMCs and nineteen siloxanes were measured in water, sediments, and biota. Samples were collected from two sites where levels were expected to be influenced by the distance from the wastewater treatment plant (WWTP) in the Geum River, Republic of Korea, were expected. High concentrations of SMCs and siloxanes entered through WWTP were measured in water, sediment, and biota at the both sites and both seasons. The δ 15 N of amino acids provided a high-resolution food web and accurate trophic position (TP), which is an important factor for determining the trophic magnification factor (TMF). Among 24 TMFs, 19 of them were <1, ranging 0.7-0.8 for 1,3,4,6,7,8‑hexahydro‑4,6,6,7,8,8‑hexamethyl‑cyclopenta‑γ‑2‑benzopyran (HHCB), 0.6-0.8 for 6-Acetyl-1,1,2,4,4,7-hexamethyltetralin (AHTN), 0.7-0.8 for 4-tert-Butyl-3,5-dinitro-2,6-dimethylacetophenone (MK), 0.7-0.9 for octamethylcyclotetrasiloxane (D4), 0.1-0.4 for decamethylcyclopentasiloxane (D5), and 0.04-0.8 for dodecamethylcyclohexasiloxane (D6), and the remaining ones including HHCB, AHTN, MK, and D4 showed values close to 1 or slightly higher (TMF range: 1.0-2.3) indicating no or a little trophic magnification. The TMFs of these compounds were constant across sites and seasons. The TMF values of PCPs might be affected by species specificity and food web structure rather than by chemical properties such as log K ow , which describes a wide range of TMF values in various environments. This study presents valuable implications for assessing risk and managing environmental fate and trophic transfer of SMCs and siloxanes in freshwater environments., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This research investigated variations in alcohol consumption by socioeconomic factors and hypertensive status in South Korean adults, aged ≥19 years. This is a secondary data analysis using the Korea National Health and Nutrition Examination Survey (KNHANES). Alcohol intake by socioeconomic and hypertensive status was examined using data from the 2013 to 2016 KNHANES. Total participants were 19,641 adults, with 8,123 men and 11,518 women. Consumption of alcohol in the Korean population was estimated from a single 24-hour dietary recall. Alcohol intake differed, according to socioeconomic status, and, particularly, by occupation among Korean adults. Women with lower education consumed more alcohol daily than those with a higher education (p = 0.018). Furthermore, adult men with hypertension consumed a greater amount of alcohol daily, 30.9 g, than those with pre-hypertension, 23.7 g, followed by those without hypertension, 15.9 g (p < 0.001). In women, adults with pre-hypertension and hypertension consumed more alcohol daily, 9.4 g and 9.0 g, respectively, than those without, 6.6 g (p < 0.001). In addition, men with hypertension who were unaware of their disease and those who were cognizant consumed a higher amount of alcohol daily, 32.4 g and 28.6 g, respectively, than individuals without hypertension, 19.7 g (p < 0.001). Moreover, men with hypertension who had not been treated for hypertension and those in treatment consumed a greater amount of alcohol daily, 32.6 g and 28.0 g, respectively, than those without hypertension, 19.7 g (p < 0.001). In conclusion, Korean adults consume alcohol differently by socioeconomic status, and alcohol intake was more prevalent among people with hypertension., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Patients with multiple system atrophy (MSA) are conventionally identified as having MSA-P (prominent parkinsonism) or MSA-C (prominent cerebellar ataxia) based on their predominant motor manifestations. The objective of the present study was to conduct latent class analysis (LCA) of various motor and nonmotor symptoms in early MSA to characterize data-driven subgroups., Methods: Sixty-one probable or possible MSA patients with disease durations of 3 years or less were included prospectively. LCAs were performed to identify similar clinical subgroups giving even weights to a wide range of MSA motor and nonmotor features. We ran latent models of up to 6 class solutions; the overall model fit was evaluated based on the parsimony of the derived classes, the fit indices, and clinical interpretability., Results: The LCA outcome supported categorization of at least three subgroups of patients with early MSA: the largest class 1, labeled "moderate parkinsonism + extensive dysautonomia", included approximately half of our study patients and showed marked autonomic dysfunction with a burden of parkinsonism. The two other classes, class 2 "predominant parkinsonism + limited dysautonomia" and class 3 "predominant cerebellar symptoms + limited dysautonomia", showed marked core motor features (parkinsonism or cerebellar symptoms) with generally mild dysautonomia., Conclusions: To our knowledge, this is the first data-driven identification of disease subtypes covering various symptom constellations in early MSA (<3 years from motor symptom onset). The present LCA result did not replicate the conventional motor classification and supported the heterogeneity within MSA-P and MSA-C subtypes., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Emerging contaminants (EC) such as benzotriazole are being released into the environment in various ways, therefore it is necessary to understand how organisms are affected by EC. In this study, we exposed medaka (Oryzias latipes) and zebrafish (Danio rerio) during their embryonic period (1 day after hatching) to benzotriazole to investigate its effects on oxidative stress (ROS, GSH, GST, SOD, CAT and MDA) and changes in gene expression patterns. In both medaka and zebrafish, the influence of oxidative stress was confirmed through an increased MDA level and changes in the ROS and GSH levels. Antioxidant enzymes such as GST, CAT, and SOD were affected by benzotriazole; however, medaka and zebrafish showed different patterns in the effects by benzotriazole. Results of oxidative stress genes expression showed that medaka had either no influence or had a decrease in the gene expression profile, whereas zebrafish had a statistically significant increase in the expression of some genes. The cyp1a gene expression was increased in both species. However, vtg gene expression was increased only in zebrafish but decreased in medaka, indicating no estrogenic effects in medaka. Apoptosis genes showed changes in expression in both the species but was these changes were not dose-dependent. However, zebrafish caspase-9 gene expression was increased in all of the exposed groups, suggesting the effects on the intrinsic pathway associated with caspase-9. In conclusion, the results indicate that the toxic effects of benzotriazole differ at various levels in the two small fish medaka and zebrafish embryos., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To characterise the antibody response for 12 weeks following second dose of the Pfizer/BioNTech BNT162b2 mRNA vaccine in hospital workers of a Korean general hospital., Methods: We measured the level of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) anti-receptor binding domain (anti-RBD) and neutralising antibodies every week in the first 4 weeks, and at weeks 8 and 12 following the second dose of vaccination in 71 hospital workers., Results: The initial median level of anti-RBD and neutralising antibodies were 3898.0 U/mL (interquartile range [IQR], 2107.5-5478.5) and 97.54 % (IQR, 96.85-97.81), respectively. The levels declined the fastest and the most significantly between weeks 1 and 2 (p < 0.01, both), and continuously decreased thereafter, and were 1163.0 U/mL (683.4-1743.0) and 94.87% (89.24-96.99) at weeks 12. The antibodies levels showed a trend of rapid decrease in the older group over time. The slope of the decrease in the antibodies level was observed for each individual. Within 8 weeks, the anti-RBD antibody levels decreased to less than half of the initial levels in most of the participants (88.7%: 63/71). The SARS-CoV-2 anti-RBD and neutralising antibodies levels showed a strong positive correlation (Spearman's coefficient = 0.7833)., Conclusions: Considerably high levels of SARS-CoV-2 anti-RBD and neutralising antibodies were produced following the second dose of vaccination. The levels decreased continuously, showing a tendency to decline over time; however, reasonable levels persisted up to weeks 12. Moreover, considering individual variations in antibody response following vaccination, a further inter-individual analysis is needed., 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 © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Obesity is a serious health problem with tremendous economic and social consequences, which is associated with metabolic diseases and cancer. Currently available anti-obesity drugs acting in the gastrointestinal tract, or the central nervous system have shown limited efficacy in the reduction of obesity, accompanied by severe side effects. Therefore, a novel therapeutic delivery targeting adipocytes and normalizing excess fat transport and accumulation is necessary to maximize efficacy and reduce side effects for long-term treatment. Fatty acid binding protein 4 (FABP4) is an adipokine that coordinates lipid transport in mature adipocyte and its inhibition in obesity model showed weight loss and normalized insulin response. Reduction of FABP4 level in adipocytes was compensated by fatty acid binding protein 5 (FABP5), which resulted in reduction of recovery of obesity and co-morbidities related to obesity by FABP4 knock-down alone. In this study, we developed a non-viral gene delivery system, sh (FABP4/5)/ATS9R, that silences FABP4 and FABP5 simultaneously with oligopeptide (ATS9R) that can selectively target mature adipocyte. For future clinical application to increase patient compliance, sh (FABP4/5)/ATS9R was administered subcutaneously and intraperitoneally to obese animal model and both routes demonstrated startling dual gene efficacy in visceral adipose tissues. Furthermore, dual gene silencing efficiently alleviated obesity, improved insulin sensitivity and restored hepatic metabolism in high fat diet-induced type 2 diabetes mouse model. Targeted-dual gene silencing of sh (FABP4/5)/ATS9R in adipose tissues demonstrated synergistic effects to overcome obesity and obesity-induced metabolic diseases and beneficial effects against liraglutide, providing a great potential for future translational research., (Copyright © 2021 Elsevier Ltd. All rights reserved.)