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Human immunodeficiency virus-1 (HIV-1) encodes a transcriptional factor called Tat, which is critical for viral transcription. Tat-mediated transcription is highly ordered apart from the cellular manner; therefore, it is considered a target for developing anti-HIV-1 drugs. However, drugs targeting Tat-mediated viral transcription are not yet available. Our high-throughput screen of a compound library employing a dual-reporter assay identified a 1,3,4-oxadiazole scaffold against Tat and HIV-1 infection. Furthermore, a serial structure-activity relation (SAR) study performed with biological assays found 1,3,4-oxadiazole derivatives ( 9 and 13 ) containing indole and acetamide that exhibited potent inhibitory effects on HIV-1 infectivity, with half-maximal effective concentrations (EC 50 ) of 0.17 ( 9 ) and 0.24 µM ( 13 ), respectively. The prominent derivatives specifically interfered with the viral transcriptional step without targeting other infection step(s) and efficiently inhibited the HIV-1 replication cycle in the T cell lines and peripheral blood mononuclear cells infected with HIV-1. Additionally, compared to the wild type, the compounds exhibited similar potency against anti-retroviral drug-resistant HIV-1 strains. In a series of mode-of-action studies, the compounds inhibited the ejection of histone H3 for facilitating viral transcription on the long-terminal repeat (LTR) promoter. Furthermore, SAHA (a histone deacetylase inhibitor) treatment abolished the compound potency, revealing that the compounds can possibly target Tat-regulated epigenetic modulation of LTR to inhibit viral transcription. Overall, our screening identified novel 1,3,4-oxadiazole compounds that inhibited HIV-1 Tat, and subsequent SAR-based optimization led to the derivatives 9 and 13 development that could be a promising scaffold for developing a new class of therapeutic agents for HIV-1 infection.

Background: Computerized cognitive training (CCT) has been proposed as a potential therapy for cognitive decline. One of the benefits of CCT is a transfer effect, but its mechanism on the memory domain is unclear. This study aimed to investigate the transfer effect of non-memory multidomain CCT on the memory domain and its neural basis in patients with mild cognitive impairment (MCI) through a randomized controlled trial., Methods: Patients with MCI recruited from memory clinics were randomly assigned to either the CCT or the control group. The CCT group received multidomain CCT training excluding memory training, while the control group read educational books with learning-based quizzes twice a week for 8 weeks. Participants underwent memory tests yielding a composite score, other cognitive domain tests, non-cognitive scales, and resting-state functional magnetic resonance imaging (rsfMRI), at baseline and after intervention. Within- and between-group comparisons, group × time interactions, and seed-to-voxel analyses in memory-involving brain networks were performed., Results: The CCT group showed improvement over the control group in memory domain (Group × time, F = 5.87, P = 0.03, η 2  = 0.31), which was related with the increased connectivity in the hippocampal-frontal and fusiform-occipital network. No other cognitive and non-cognitive symptoms differed between groups after adjusting for covariates., Conclusion: Eight weeks of multidomain CCT without memory training improved memory function and restored functional network in the hippocampal and medial temporal region in MCI patients. These results can provide evidence for the transferring ability of CCT on memory functioning with its neural basis., (© 2024 The Author(s). Psychogeriatrics published by John Wiley & Sons Australia, Ltd on behalf of Japanese Psychogeriatric Society.)

Background: Evidence for the long-term use of antiplatelet drugs to prevent hepatic vascular complications (HVC) is scarce in liver transplantation (LT)., Methods: From national claim data, LT recipients (about 80 % of living donor LT [LDLT]) without graft loss, HVC, or cardiovascular events within 1 year, were classified into those who took antiplatelets for ≥1 year (n = 1744) and for <1 year (n = 1975). Outcomes were compared after the 1-postoperative year index time point., Results: During a mean follow up of 4.5 years, the risk of graft loss was similar between the groups (aHR 1.16, P = 0.23). However, ≥1-year antiplatelet therapy was associated with a higher risk of graft loss after 3 years (aHR 2.19, P < 0.01). HVC (aHR 0.94, P = 0.87) and major adverse cardiac events (aHR 1.20, P = 0.46) did not correlate with antiplatelet therapy for both groups. In contrast, ≥1-year antiplatelet therapy showed a significantly higher risk of severe bleeding compared to <1-year antiplatelet therapy (aHR 2.24, P < 0.01). This trend was similar in the LDLT subgroup. In our cohort, antiplatelet therapy for ≥1 year did not improve graft survival or HVC; however, it increased the risk of severe bleeding., Conclusion: We recommend against antiplatelet therapy for more than 1 year in clinically stable LT recipients., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Asian Surgical Association and Taiwan Society of Coloproctology. Published by Elsevier B.V. All rights reserved.)

Objective: To compare the risk of dementia associated with sodium-glucose cotransporter-2 (SGLT-2) inhibitors versus dipeptidyl peptidase-4 (DPP-4) inhibitors in adults aged 40-69 years with type 2 diabetes., Design: Population based cohort study., Setting: Korean National Health Insurance Service data, 2013-21., Participants: 110 885 propensity score matched pairs of adults with type 2 diabetes aged 40-69 years who were initiators of either an SGLT-2 inhibitor or a DPP-4 inhibitor., Main Outcome Measures: The primary outcome was new onset dementia. Secondary outcomes were dementia requiring drug treatment and individual types of dementia, including Alzheimer's disease and vascular dementia. Control outcomes were genital infections (positive), and osteoarthritis related clinical encounters and cataract surgery (negative). Hazard ratios and 95% confidence intervals (CIs) were estimated using Cox models. Follow-up time stratified analyses (>2 years and ≤2 years) and subgroup analyses by age, sex, concomitant use of metformin, and baseline cardiovascular risk were performed., Results: 110 885 propensity score matched pairs of initiators of an SGLT-2 inhibitor or a DPP-4 inhibitor were followed-up for a mean 670 (standard deviation 650) days, generating 1172 people with newly diagnosed dementia: incidence rate 0.22 per 100 person years in initiators of SGLT-2 inhibitors and 0.35 per 100 person years in initiators of DPP-4 inhibitors, with hazard ratios of 0.65 (95% CI 0.58 to 0.73) for dementia, 0.54 (0.46 to 0.63) for dementia requiring drugs, 0.61 (0.53 to 0.69) for Alzheimer's disease, and 0.48 (0.33 to 0.70) for vascular dementia. The hazard ratios for the control outcomes were 2.67 (2.57 to 2.77) for genital infections, 0.97 (0.95 to 0.98) for osteoarthritis related encounters, and 0.92 (0.89 to 0.96) for cataract surgery. When calibrated for residual confounding measured by cataract surgery, the hazard ratio for dementia was 0.70 (0.62 to 0.80). The association was greater for more than two years of treatment (hazard ratio of dementia 0.57, 95% CI 0.46 to 0.70) than for two years or less (0.52, 0.41 to 0.66) and persisted across subgroups., Conclusion: SGLT-2 inhibitors might prevent dementia, providing greater benefits with longer treatment. As this study was observational and therefore prone to residual confounding and informative censoring, the effect size could have been overestimated. Randomised controlled trials are needed to confirm these findings., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Korea Health Industry Development Institute (KHIDI)-AZ Diabetes Research programme; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. EHK receives grants from Celltrion and SK Chemicals to Seoul National University Bundang Hospital for unrelated studies. BKK receives grants from KHIDI to SMG-SNU Boramae Medical Centre for unrelated studies., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Targeted therapies for diabetic nephropathy (DN) are lacking, partly due to their irreversible nature. The role of Orai1, a store-operated Ca2+ channel, in DN remains debated, with conflicting evidence on its effect on proteinuria in animal models. We aimed to elucidate the functional relevance of Orai1 expression for clinicopathological parameters in patients with DN., Methods: In this study, we included 93 patients diagnosed with DN between 2009 and 2019. Immunohistochemical staining for Orai1 was performed on paraffin-embedded kidney sections. The significance of Orai1 expression in human DN was assessed by examining its correlation with DN's pathological and clinical parameters using Pearson's correlation coefficient and univariate logistic regression., Results: Orai1 was significantly overexpressed in DN patients compared to control. A strong correlation was observed between increased Orai1 expression and higher Renal Pathology Society DN classification, enhanced interstitial fibrosis and tubular atrophy scores. Positive correlations with serum creatinine levels and prognosis of chronic kidney disease (CKD) by glomerular filtration rate (GFR) and albuminuria category were noted but the estimated GFR was inversely related to Orai1 expression. Orai1's association with advanced CKD stages persisted even after adjusting for confounding variables in multivariate logistic regression analysis., Conclusion: Orai1 expression is closely associated with histological and clinical severities of DN, suggesting its potential as a predictive biomarker for disease progression and prognosis. These findings provide new perspectives on therapeutic interventions targeting Orai1 in DN.

Background: Altered thyroid hormone levels have been associated with increased risk of Alzheimer's disease (AD) dementia and related cognitive decline. However, the neuropathological substrates underlying the link between thyroid hormones and AD dementia are not yet fully understood. We first investigated the association between serum thyroid hormone levels and in vivo AD pathologies including both beta-amyloid (Aβ) and tau deposition measured by positron emission tomography (PET). Given the well-known relationship between Aβ and tau pathology in AD, we additionally examined the moderating effects of thyroid hormone levels on the association between Aβ and tau deposition., Methods: This cross-sectional study was conducted as part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) cohort. This study included a total of 291 cognitively normal adults aged 55 to 90. All participants received comprehensive clinical assessments, measurements for serum total triiodothyronine (T3), free triiodothyronine (fT3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH), and brain imaging evaluations including [ 11 C]-Pittsburgh compound B (PiB)- PET and [ 18 F] AV-1451 PET., Results: No associations were found between either thyroid hormones or TSH and Aβ and tau deposition on PET. However, fT4 (p = 0.002) and fT3 (p = 0.001) exhibited significant interactions with Aβ on tau deposition: The sensitivity analyses conducted after the removal of an outlier showed that the interaction effect between fT4 and Aβ deposition was not significant, whereas the interaction between fT3 and Aβ deposition remained significant. However, further subgroup analyses demonstrated a more pronounced positive relationship between Aβ and tau in both the higher fT4 and fT3 groups compared to the lower group, irrespective of outlier removal. Meanwhile, neither T3 nor TSH had any interaction with Aβ on tau deposition., Conclusion: Our findings suggest that serum thyroid hormones may moderate the relationship between cerebral Aβ and tau pathology. Higher levels of serum thyroid hormones could potentially accelerate the Aβ-dependent tau deposition in the brain. Further replication studies in independent samples are needed to verify the current results., (© 2024. The Author(s).)

Background: Kidney transplantation (KT) improves physical and psychological prognoses for patients with end-stage kidney disease (ESKD). However, few comparative studies have examined depression and suicide rates among patients with ESKD treated with dialysis versus KT., Methods: Data on 21,809 patients with ESKD were extracted from the Korean National Health Insurance Service database, extending from January 2002 to December 2018. These patients exhibited no history of depression or insomnia before starting renal replacement therapy. Outcomes were compared between dialysis and KT recipients using 1:2 propensity score matching (PSM)., Results: Of the patients, 17,649 received dialysis (hemodialysis, 15,537; peritoneal dialysis, 2,112), while 4,160 underwent KT. Of those on dialysis, 45.04% (7,949) experienced insomnia, compared to 25.72% (1,070) of KT recipients (P<0.001). Depression was more frequent among dialysis recipients (22.77%, 4,019) than KT recipients (8.61%, 358; P<0.001). Additionally, those on dialysis had a higher incidence of suicide (0.19%, 33) than recipients of KT (0.12%, 5; P=0.047). After PSM, the hazard ratio (HR) for depression in patients on dialysis compared to KT recipients was 1.76 (95% confidence interval [CI], 1.56-1.99). In subgroup analysis, the relative likelihood of depression among dialysis recipients was particularly high for residents of urban areas (HR, 2.10; 95% CI, 1.80-2.44) and patients under 65 years old (HR, 1.82; 95% CI, 1.62-2.09)., Conclusions: KT recipients exhibit a lower suicide rate than patients on dialysis. Furthermore, KT is associated with a lower prevalence of depression among Korean patients with ESKD, particularly urban residents and individuals under 65 years old.

Moderately elevated albuminuria (30-300 mg/g) is a marker of renal dysfunction and a risk factor of cardiovascular disease. Additionally, several recent studies have reported a relationship between moderately elevated albuminuria and triglyceride (TG) levels. Therefore, we aimed to evaluate the relationship between the urine albumin-to-creatinine ratio (UACR) and total cholesterol (TC), TG, and high-density lipoprotein C (HDL-C) levels. We analyzed data from 19,340 patients from the 2011-2014 and 2019-2020 from the Korea National Health and Nutrition Examination Surveys. Multivariate linear regression analysis showed that the UACR was positively associated with TC and TG levels and negatively associated with HDL-C levels in both Korean women and men. These results were reanalyzed according to the degree of proteinuria (normal, moderately elevated albuminuria, and severely elevated albuminuria (≥ 300 mg/g)). We found a positive relationship between UACR and TC and TG levels, but a negative association with HDL-C levels, except for TC (moderately elevated albuminuria) and HDL-C (moderately elevated albuminuria) in Korean men and TC (severely elevated albuminuria), TG (severely elevated albuminuria), and HDL-C (normal range albuminuria) in Korean women. The correlation between albuminuria and lipid profiles became more evident as albuminuria shift from normal to the severely elevated albuminuria. Thus our multivariate linear regression analysis showed that lipid profiles (TG, TC, and HDL-C levels) were associated with the UACR., (© 2024. The Author(s).)

Background: This study aims to report the midterm outcomes after surgical treatment of Hawkins Classification III Talar neck fractures., Methods: From March 2010 to April 2022, among a total of 155 patients who visited our hospital with talus fractures, 31 patients underwent surgical treatment for Hawkins classification III talar neck fractures. The inclusion criteria comprised patients with a symptom duration of over 1 year who were available for outpatient follow-up and underwent magnetic resonance imaging (MRI) follow-up 2 months after surgery. Exclusion criteria included patients without preoperative ankle periarticular arthritis, and a total of 27 patients were enrolled. Traffic accidents and falls accounted for 86% of 23 cases, open fractures were 8 cases, and the mean follow-up period was 34.10 months (range, 12-80 months). Clinical outcomes were measured by American Orthopaedic Foot and Ankle Society (AOFAS) score and Foot function index (FFI), and radiological results were obtained using simple radiographs before and after surgery and MRI at 2 months postoperatively to confirm bone union and complications., Results: Complete bone union was achieved in all cases, and the mean duration of union was 4.9 months (range, 4-6 months) and there were no nonunion and varus malunion. At the final follow-up, the mean AOFAS score was 80.18 points (range, 36-90 points) and the mean FFI score was 31.43 points (range, 10-68 points), showing relatively good clinical outcomes. There were 15 cases of avascular necrosis, 6 cases of traumatic arthritis of the ankle joint, 6 cases of irritation of the posterior tibial nerve, and 4 cases of wound problems., Conclusions: Hawkins classification III talar neck fractures are mostly caused by high-energy injuries and have a relatively poor prognosis due to the high incidence of complications such as avascular necrosis or posttraumatic arthritis. However, if correct anatomical reduction and rigid internal fixation are performed within a short time after the injury, good results can be expected., Competing Interests: CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported., (Copyright © 2024 by The Korean Orthopaedic Association.)

This study aimed to explore the predictors of posttraumatic stress disorder (PTSD) in women who have recently experienced sexual assault, by examining psychological and neurophysiological factors using a prospective design with resting-state electroencephalogram (EEG) functional connectivity. The study enrolled 33 women who had been recently traumatized by sexual assault and conducted assessments within a month of the trauma. These survivors were evaluated for PTSD three months later and were classified into two groups: PTSD positive (n = 12) and PTSD negative (n = 21). They were compared to two control groups comprising women who had not experienced any extremely traumatic events: 25 with depression and 25 healthy controls. The evaluation focused on resting-state EEG functional connectivity within default mode network (DMN) using small-worldness (SW), based on graph theory. We also assessed self-reported levels of depression, anxiety, anger, and executive functions. The findings indicated that survivors who developed PTSD three months post-trauma exhibited higher anxiety levels and reduced DMN SW in the beta 3 frequency, compared to those who did not develop PTSD. Contrary to expectations, survivors without PTSD showed decreased executive functioning and lower prefrontal centrality compared to those with PTSD. This study underscores the importance of early assessment and intervention for sexual assault survivors at risk of developing PTSD., Competing Interests: Declaration of competing interest The author declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The functional properties of complex oxides, including magnetism and ferroelectricity, are closely linked to subtle structural distortions. Ultrafast optical excitations provide the means to manipulate structural features and ultimately to affect the functional properties of complex oxides with picosecond-scale precision. We report that the lattice expansion of multiferroic BiFeO 3 following above-bandgap optical excitation leads to distortion of the oxygen octahedral rotation (OOR) pattern. The continuous coupling between OOR and strain was probed using time-resolved X-ray free-electron laser diffraction with femtosecond time resolution. Density functional theory calculations predict a relationship between the OOR and the elastic strain consistent with the experiment, demonstrating a route to employing this approach in a wider range of systems. Ultrafast control of the functional properties of BiFeO 3 thin films is enabled by this approach because the OOR phenomena are related to ferroelectricity, and via the Fe-O-Fe bond angles, the superexchange interaction between Fe atoms.

Background: Application of visual scoring scales for regional atrophy in Alzheimer's disease (AD) in clinical settings is limited by their high time cost and low intra/inter-rater agreement., Objective: To provide automated atrophy scoring using objective volume driven from deep-learning segmentation methods for AD subtype classification using magnetic resonance imaging (MRI)., Methods: We enrolled 3,959 participants (1,732 cognitively normal [CN], 1594 with mild cognitive impairment [MCI], and 633 with AD). The occupancy indices for each regional volume were calculated by dividing each volume by the size of the lateral and inferior ventricular volumes. MR images from 355 participants (119 CN, 119 MCI, and 117 AD) from three different centers were used for validation. Two neuroradiologists performed visual assessments of the medial temporal, posterior, and global cortical atrophy scores in the frontal lobe using T1-weighted MR images. Images were also analyzed using the deep learning-based segmentation software, Neurophet AQUA. Cutoff values for the three scores were determined using the data distribution according to age. The scoring results were compared for consistency and reliability., Results: Four volumetric-driven scoring results showed a high correlation with the visual scoring results for AD, MCI, and CN. The overall agreement with human raters was weak-to-moderate for atrophy scoring in CN participants, and good-to-almost perfect in AD and MCI participants. AD subtyping by automated scores also showed usefulness as a research tool., Conclusions: Determining AD subtypes using automated atrophy scoring for late-MCI and AD could be useful in clinical settings or multicenter studies with large datasets., Competing Interests: This article utilized the segmentation tool, AQUA developed by Neurophet Research Institute, Inc., Seoul, South Korea. Y.S.C, R.E.K, H.W.K, H.L, M.L, D.K, and H.K.L are employees of Neurophet Inc. All other authors have no conflict of interest to report., (© 2024 – The authors. Published by IOS Press.)

Importance: Many epidemiologic studies have suggested that low levels of plasma leptin, a major adipokine, are associated with increased risk of Alzheimer disease (AD) dementia and cognitive decline. Nevertheless, the mechanistic pathway linking plasma leptin and AD-related cognitive decline is not yet fully understood., Objective: To examine the association of plasma leptin levels with in vivo AD pathologies, including amyloid-beta (Aβ) and tau deposition, through both cross-sectional and longitudinal approaches among cognitively unimpaired older adults., Design, Setting, and Participants: This was a longitudinal cohort study from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer Disease. Data were collected from January 1, 2014, to December 31, 2020, and data were analyzed from July 11 to September 6, 2022. The study included a total of 208 cognitively unimpaired participants who underwent baseline positron emission tomography (PET) scans for brain Aβ deposition. For longitudinal analyses, 192 participants who completed both baseline and 2-year follow-up PET scans for brain Aβ deposition were included., Exposure: Plasma leptin levels as assessed by enzyme-linked immunosorbent assay., Main Outcomes and Measures: Baseline levels and longitudinal changes of global Aβ and AD-signature region tau deposition measured by PET scans., Results: Among the 208 participants, the mean (SD) age was 66.0 (11.3) years, 114 were women (54.8%), and 37 were apolipoprotein E ε4 carriers (17.8%). Lower plasma leptin levels had a significant cross-sectional association with greater brain Aβ deposition (β = -0.04; 95% CI, -0.09 to 0.00; P = .046), while there was no significant association between plasma leptin levels and tau deposition (β = -0.02; 95% CI, -0.05 to 0.02; P = .41). In contrast, longitudinal analyses revealed that there was a significant association between lower baseline leptin levels and greater increase of tau deposition over 2 years (β = -0.06; 95% CI, -0.11 to -0.01; P = .03), whereas plasma leptin levels did not have a significant association with longitudinal change of Aβ deposition (β = 0.006; 95% CI, 0.00-0.02; P = .27)., Conclusions and Relevance: The present findings suggest that plasma leptin may be protective for the development or progression of AD pathology, including both Aβ and tau deposition.

Free-living amoebae (FLA) are found in diverse environments, such as soils, rivers, and seas. Hence, they can be used as bioindicators to assess the water quality based solely on their presence. In this study, we determined the presence of FLA in river water by filtering water samples collected from various sites and culturing the resulting filtrates. FLA were detected in all the water samples with varying quality grades (Grades Ι-V). The significant increase in the size of the amoebae population with the deterioration in the water quality. Monoxenic cultures of the amoebae were performed, and genomic DNAs were isolated, among which 18S rDNAs were sequenced to identify the amoeba species. Of the 12 species identified, 10 belonged to the Acanthamoeba genus; of the remaining 2 species, one was identified as Vannella croatica and the other as a species of Vermamoeba. Acanthamoeba was detected in samples with Grades Ι to VI quality, whereas the Vermamoeba species was present only in Grade Ι water. V. croatica was found exclusively in water with Grade ΙΙ quality. Following morphological observations, genomic DNA was sequenced using 16S rDNA to determine whether the species of Acanthamoeba harbored endosymbionts. Most of the isolated Acanthamoeba contained endosymbionts, among which 4 species of endogenous bacteria were identified and examined using transmission electron microscopy. This study provides evidence that the distribution of amoebae other than Acanthamoeba may be associated with water quality. However, further confirmation will be required based on accurate water quality ratings and assessments using a more diverse range of FLA.

Metal-organic frameworks (MOFs) have garnered attention across various fields due to their noteworthy features like high specific surface area, substantial porosity, and adjustable performance. In the realm of water treatment, MOFs exhibit great potential for eliminating pollutants such as organics, heavy metals, and oils. Nonetheless, the inherent powder characteristics of MOFs pose challenges in terms of recycling, pipeline blockage, and even secondary pollution in practical applications. Addressing these issues, the incorporation of MOFs into sponges proves to be an effective solution. Strategies like one-pot synthesis, in situ growth, and impregnation are commonly employed for loading MOFs onto sponges. This review comprehensively explores the synthesis strategies of MOFs and sponges, along with their applications in water treatment, aiming to contribute to the ongoing advancement of MOF materials.

Background: Recombinant human interleukin (rhIL)-7-hyFc (efineptakin alfa; NT-I7) is a potent T-cell amplifier, with two IL-7 molecules fused to IgD/IgG4 elements. rhIL-7-hyFc promotes extensive infiltration of CD8 + T cells into the tumor, concurrently increasing the numbers of intratumoral PD-1 + CD8 + T cells. The hIL-2/TCB2 complex (SLC-3010) inhibits tumor growth by preferential activation of CD122 (IL-2Rβ) high CD8 + T cells and natural killer cells, over regulatory T cells (Tregs). We investigated the underlying mechanisms of rhIL-7-hyFc and hIL-2/TCB2c antitumor activity and the potential synergistic efficacy, specifically focusing on tumor-specific CD8 + cells within the tumor and the tumor-draining lymph nodes (tdLN)., Methods: MC38 and CT26 tumor-bearing mice were administered with 10 mg/kg rhIL-7-hyFc intramuscularly and 0.9 mg/kg hIL-2/TCB2c intravenously. Anti-PD-1 monoclonal antibody was administered intraperitoneally three times at 3-day intervals at a dose of 5 mg/kg. Tumor volume was measured to assess efficacy. To compare the composition of immune cells between each monotherapy and the combination therapy, we analyzed tumors and tdLNs by flow cytometry., Results: Our data demonstrate that the combination of rhIL-7-hyFc and hIL-2/TCB2c increases efficacy and generates an immune-stimulatory tumor microenvironment (TME). The TME is characterized by an increased infiltration of tumor-specific CD8 + T cells, and a decreased frequency of CD39 high TIM-3 + Treg cells. Most importantly, rhIL-7-hyFc increases infiltration of a CD62L + Ly108 + early progenitor population of exhausted CD8 + T cells (T PEX ), which may retain long-term proliferation capacity and replenish functional effector CD8 + T cells. hIL-2/TCB2c induces differentiation of CD62L + Ly108 + T PEX rapidly into CD101 + terminally differentiated subsets (terminally exhausted T cell (T EX term )). Our study also demonstrates that rhIL-7-hyFc significantly enhances the proliferation rate of T PEX in the tdLNs, positively correlating with their abundance within the tumor. Moreover, rhIL-7-hyFc and hIL-2/TCB2c can overcome the limited therapeutic effectiveness of PD-1 blockade, culminating in the complete regression of tumors., Conclusions: rhIL-7-hyFc can expand and maintain the progenitor pool of exhausted CD8 + T cells, whereas hIL-2/TCB2c promotes their differentiation into T EX term . Together, this induces an immune-stimulatory TME that improves the efficacy of checkpoint blockade., Competing Interests: Competing interests: ML, S-KI, SB, MJ, MK, EJL, STJ, SF-M, AW and DC are currently employed by NeoImmuneTech. J-YL and DK work for Selecxine., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Neuropsychiatric symptoms and delusions are highly prevalent among people with dementia. However, multiple roots of neurobiological bases and shared neural basis of delusion and cognitive function remain to be characterized. By utilizing a fine-grained multivariable approach, we investigated distinct neuroanatomical correlates of delusion symptoms across a large population of dementing illnesses., Methods: In this study, 750 older adults with mild cognitive impairment and Alzheimer's disease completed brain structural imaging and neuropsychological assessment. We utilized principal component analysis followed by varimax rotation to identify the distinct multivariate correlates of cortical thinning patterns. Five of the cognitive domains were assessed whether the general cognitive abilities mediate the association between cortical thickness and delusion., Results: The result showed that distributed thickness patterns of temporal and ventral insular cortex (component 2), inferior and lateral prefrontal cortex (component 1), and somatosensory-visual cortex (component 5) showed negative correlations with delusions. Subsequent mediation analysis showed that component 1 and 2, which comprises inferior frontal, anterior insula, and superior temporal regional thickness accounted for delusion largely through lower cognitive functions. Specifically, executive control function assessed with the Trail Making Test mediated the relationship between two cortical thickness patterns and delusions., Discussion: Our findings suggest that multiple distinct subsets of brain regions underlie the delusions among older adults with cognitive impairment. Moreover, a neural loss may affect the occurrence of delusion in dementia largely due to impaired general cognitive abilities., (© 2024. The Author(s).)

Although injuries are a leading cause of death and affect the life expectancy of individuals who live with disabilities globally, the potential role of air pollution exposure on injuries due to external causes has received little scientific attention, especially compared with that given to the association of air pollution and non-external causes of morbidity and mortality. We investigated the association between emergency department visits for externally caused injuries and short-term exposure to major ambient air pollutants, with focus on the intentions and mechanisms of injuries. We identified 2,049,855 injured patients in Seoul, South Korea between 2008 and 2016 using the National Emergency Database. Daily short-term exposure to air pollution including particles <10 μm (PM 10 ) and <2.5 μm (PM 2.5 ), nitrogen dioxide (NO 2 ), sulfur dioxide (SO 2 ), carbon monoxide (CO), and ozone (O 3 ) was estimated based on hourly concentrations. We employed a time-stratified case-crossover study design using a conditional Poisson regression model adjusted for meteorological variables, influenza epidemics, and holidays. Immediate exposure (lag 0) to most pollutants significantly increased the risk of total injuries (PM 2.5 , 0.42 %; NO 2 , 0.68 %; SO 2 , 1.05 %; CO, 0.57 %; O 3 , 1.86 % per interquartile range increment), and the associations differed according to the intention and mechanism of injury. Unintentional and assault injuries were significantly associated with air pollution exposure, whereas self-harm injuries showed no association. In mechanism-specific analyses, injuries caused by falls, blunt objects, penetration, traffic accidents, machinery, and slips were associated with specific air pollutants, even in the co-pollutant models. The associations were stronger in injured patients aged <15 years, and in males than in their counterparts. Our results suggest that short-term air pollution exposure might play a role in the risk of externally caused injuries and the association may differ depending on the intention and mechanism of injury, which provide important evidence for injury prevention and air quality strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The prevalence of atrial fibrillation (AF) in patients with end-stage kidney disease (ESKD) is high and increasing. However, evidence regarding oral anticoagulant (OAC) use in these patients is insufficient and conflicting., Methods: This retrospective cohort study included patients in the Korea National Health Insurance System diagnosed with AF after ESKD onset from January 2007 to December 2017. The primary outcome was all-cause death. Secondary outcomes were ischaemic stroke, hospitalization for major bleeding and major adverse cardiovascular events (MACE). Outcomes were compared between OAC users and non-users using 6-month landmark analysis and 1:3 propensity score matching (PSM)., Results: Among patients with ESKD and AF, the number of prescribed OACs increased 2.3-fold from 2012 ( n  = 3579) to 2018 ( n  = 8341) and the proportion of direct OACs prescribed increased steadily from 0% in 2012 to 51.4% in 2018. After PSM, OAC users had a lower risk of all-cause death {hazard ratio [HR] 0.67 [95% confidence interval (CI) 0.55-0.81]}, ischaemic stroke [HR 0.61 (95% CI 0.41-0.89)] and MACE [HR 0.70 (95% CI 0.55-0.90)] and no increased risk of hospitalization for major bleeding [HR 0.99 (95% CI 0.72-1.35)] compared with non-users. Unlike warfarin, direct OACs were associated with a reduced risk of all-cause death and hospitalization for major bleeding., Conclusions: In patients with ESKD and AF, OACs were associated with reduced all-cause death, ischaemic stroke and MACE., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Recently, CRISPR proteins have been recognized as promising candidates for drug development. However, there is still a lack of substances with the appropriate sensitivity and stability for targeted drug delivery systems. 89 Zr is a radioactive isotope that emits positrons, allowing real-time in vivo tracking with proven safety. In this study, we confirmed that labeling with 89 Zr did not compromise the functionality of CRISPR proteins during in vivo behavioral imaging. Furthermore, we demonstrated the therapeutic efficacy of the CRISPR interference system in a mouse model of liver fibrosis, highlighting the theragnostic potential of isotope-labeled CRISPR proteins. The findings of this research could contribute to various aspects of ongoing clinical studies exploring the in vivo applications of CRISPR proteins., Competing Interests: Declaration of Competing Interest The authors declare that no competing interests exist., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The pathophysiological mechanism of cardiovascular disease in patients with chronic kidney disease (CKD) is complicated. Mediation analysis is an important statistical tool for gaining insight into the complex mechanisms of exposure-outcome effects. We investigated the potential mediating role of the left ventricular mass index (LVMI) on the association between fluid balance (overhydration/extracellular water, OH/ECW) and left ventricular diastolic function (E/e´ ratio) in patients with CKD not yet on dialysis., Methods: Bioimpedance spectroscopy, echocardiography, and laboratory evaluations were performed on 425 consecutive patients on the same day. The patients were classified into two groups according to the estimated glomerular filtration rate corresponding to CKD stages 3 and 5. Mediation analysis was performed using the PROCESS macro and bootstrapping methods., Results: OH/ECW and LVMI were positively correlated with the E/e´ ratio in both the CKD stages 3 and five groups. In CKD stage 5, there was a statistically significant association between OH/ECW and LVMI, whereas no correlation was observed in CKD stage 3. In the mediation analysis, LVMI positively mediated the relationship between OH/ECW and E/e´ ratio when controlling for confounders in patients with CKD stage 5 (B = 2.602; Boot 95% confidence interval, 1.313-4.076)., Conclusion: In our analysis, the indirect effect of mediators was significant in patients with advanced CKD. Therefore, our study suggests that further research on several other risk factors may be needed to determine the underlying mechanisms of association between the associated factors in all CKD stages.

In recent times, the utilization of three-dimensional (3D) printing technology, particularly a variant using digital light processing (DLP), has gained increasing fascination in the realm of microfluidic research because it has proven advantageous and expedient for constructing microscale 3D structures. The surface wetting characteristics (e.g., contact angle and contact angle hysteresis) of 3D-printed microstructures are crucial factors influencing the operational effectiveness of 3D-printed microfluidic devices. Therefore, this study systematically examines the surface wetting characteristics of DLP-based 3D printing objects, focusing on various printing conditions such as lamination (or layer) thickness and direction. We preferentially examine the impact of lamination thickness on the surface roughness of 3D-printed structures through a quantitative assessment using a confocal laser scanning microscope. The influence of lamination thicknesses and lamination direction on the contact angle and contact angle hysteresis of both aqueous and oil droplets on the surfaces of 3D-printed outputs is then quantified. Finally, the performance of a DLP 3D-printed microfluidic device under various printing conditions is assessed. Current research indicates a connection between printing parameters, surface roughness, wetting properties, and capillary movement in 3D-printed microchannels. This correlation will greatly aid in the progress of microfluidic devices produced using DLP-based 3D printing technology.

Background: White matter (WM) microstructural changes in the hippocampal cingulum bundle (CBH) in Alzheimer's disease (AD) have been described in cohorts of largely European ancestry but are lacking in other populations., Methods: We assessed the relationship between CBH WM integrity and cognition or amyloid burden in 505 Korean older adults aged ≥ 55 years, including 276 cognitively normal older adults (CN), 142 with mild cognitive impairment (MCI), and 87 AD patients, recruited as part of the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's disease (KBASE) at Seoul National University., Results: Compared to CN, AD and MCI subjects showed significantly higher RD, MD, and AxD values (all p-values < 0.001) and significantly lower FA values (left p ≤ 0.002, right p ≤ 0.015) after Bonferroni adjustment for multiple comparisons. Most tests of cognition and mood (p < 0.001) as well as higher medial temporal amyloid burden (p < 0.001) were associated with poorer WM integrity in the CBH after Bonferroni adjustment., Conclusion: These findings are consistent with patterns of WM microstructural damage previously reported in non-Hispanic White (NHW) MCI/AD cohorts, reinforcing existing evidence from predominantly NHW cohort studies., (© 2023. The Author(s).)

Introduction: Using nationwide cohort data, we aimed to elucidate whether baseline obesity altered the relationship between loss in body mass index (BMI) or waist circumference (WC) and risk of dementia., Methods: Among 9689 participants whose BMIs and WCs were repeatedly measured over 1 year, 1:1 propensity score matching was conducted between participants with and without obesity (n = 2976 per group, mean age 70.9). For each group, we explored the association between loss in BMI, or WC, and incidence of dementia during an approximately 4-year follow-up period., Results: BMI loss was associated with an increased risk of all-cause dementia and Alzheimer's disease in participants without obesity; however, this association was absent in participants with obesity. WC loss was associated with decreased Alzheimer's disease risk only in participants with obesity., Discussion: Only unfavorable loss (loss from non-obese state) in BMI, not WC, can be a metabolic biomarker of prodromal dementia., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Texture analysis may capture subtle changes in the gray matter more sensitively than volumetric analysis. We aimed to investigate the patterns of neurodegeneration in semantic variant primary progressive aphasia (svPPA) and Alzheimer's disease (AD) by comparing the temporal gray matter texture and volume between cognitively normal controls and older adults with svPPA and AD., Methods: We enrolled all participants from three university hospitals in Korea. We obtained T1-weighted magnetic resonance images and compared the gray matter texture and volume of regions of interest (ROIs) between the groups using analysis of variance with Bonferroni posthoc comparisons. We also developed models for classifying svPPA, AD and control groups using logistic regression analyses, and validated the models using receiver operator characteristics analysis., Results: Compared to the AD group, the svPPA group showed lower volumes in five ROIs (bilateral temporal poles, and the left inferior, middle, and superior temporal cortices) and higher texture in these five ROIs and two additional ROIs (right inferior temporal and left entorhinal cortices). The performances of both texture- and volume-based models were good and comparable in classifying svPPA from normal cognition (mean area under the curve [AUC] = 0.914 for texture; mean AUC = 0.894 for volume). However, only the texture-based model achieved a good level of performance in classifying svPPA and AD (mean AUC = 0.775 for texture; mean AUC = 0.658 for volume)., Conclusion: Texture may be a useful neuroimaging marker for early detection of svPPA in older adults and its differentiation from AD., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

Background: Despite the high prevalence of alcohol use disorders (AUDs) in Korea, few studies have been conducted on the temporal priority with comorbid mental disorders. We investigated the temporal priority of lifetime AUDs and comorbid mood and anxiety disorders among the general population of Korea., Methods: Data of 18,807 respondents aged 18 years or older, collected from three national epidemiological surveys comprising face-to-face interviews using the Korean version of the Composite International Diagnostic Interview for DSM-IV mental disorders. For each mood or anxiety disorder, the extent to which one mental disorder precedes another was investigated by calculating the proportion of primary AUDs by that of primary mood or anxiety disorder., Results: Regarding alcohol dependence, dysthymic disorder is 5.6 times more likely to occur before alcohol dependence. Moreover, generalized anxiety disorder, social phobia, and specific phobia are 3.6 times, 4.5 times, and 6.3 times more likely to occur before, respectively. Regarding alcohol abuse, specific phobia is 6.3 times more likely to occur before, whereas major depressive disorder is two times more likely to occur after. Moreover, the lag times between primary alcohol abuse and subsequent mood or anxiety disorders were longer than those between primary alcohol dependence and the latter., Limitations: The age of onset might be subject to recall bias. The presence of non-respondents could have influenced the results., Conclusion: We need to recognize that one of the mental disorders could lead to another and consider it in the management of people with AUDs or mood and anxiety disorders., Competing Interests: Declaration of competing interest All authors have no potential conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction : Distal tibial fractures make up approximately 3% to 10% of all tibial fractures or about 1% of lower extremity fractures. MIPO is an appropriate procedure and method to achieve stable metal plate fixation and osseointegration by minimizing soft tissue damage and vascular integrity at the fracture site. MIPO to the medial tibia during distal tibial fractures induces skin irritation due to the thickness of the metal plate, which causes discomfort and pain on the medial side of the distal leg, and if severe, complications such as infection and skin defect may occur. The reverse sural flap is a well-researched approach for covering defects in the lower third of the leg, ankle, and foot. Materials and Methods : Among 151 patients with distal tibia fractures who underwent minimally invasive metal plate fixation, soft tissue was injured due to postoperative complications. We treated 13 cases with necrosis and exposed metal plates by retrograde nasogastric artery flap surgery. For these patients, we collected obligatory patient records, radiological data, and wound photographs of the treatment results and complications of reconstructive surgery. Results : In all the cases, flap survival was confirmed at the final outpatient follow-up. The exposed area of the metal plate was well coated, and there was no plate failure due to complete necrosis. Three out of four women complained of aesthetic dissatisfaction because the volume of the tunnel through which the skin mirror passed and the skin plate itself were thick. In two cases, defatting was performed to reduce the thickness of the plate while removing the metal plate. Conclusions : Metal plate exposure after distal tibial fractures have been treated with minimally invasive metal plate fusion and can be successfully treated with retrograde nasogastric artery flaps, and several surgical techniques are used during flap surgery.

Individuals with end-stage kidney disease (ESKD) on dialysis are at a high risk of developing foot ulcerations and undergoing subsequent lower extremity amputation (LEA), which can exert significant impacts on their quality of life and contribute to rising healthcare costs. We aimed to identify risk factors associated with LEA in patients with ESKD to predict LEA progression and eventually prevent it. We used 18 years (2002-2019) of data from the Korean National Health Insurance Service (KNHIS). Data were collected from patients with ESKD who underwent renal replacement therapy (RRT) and had no history of amputation caused by trauma or toxins. The risk factors were compared between patients with or without LEA. We collected data from 220,838 patients newly diagnosed with ESKD, including 6348 in the LEA group and 214,490 in the non-LEA group. The total incidence of LEA was 2.9%. Older age, male gender, lower income, non-metropolitan residence, diabetes mellitus, dialysis treatment (compared to kidney transplantation), microvascular disease, peripheral vascular disease, endovascular procedure, and endovascular operation were associated with an increased risk of LEA. Thus, individuals with ESKD who are at a higher risk for LEA should be closely monitored, and kidney transplantation should be considered as a preventative measure.

Patients with end stage kidney disease (ESKD) and a previous acute myocardial infarction (AMI) have less access to KT. Data on ESKD patients with an AMI history who underwent first KT or dialysis between January 2007 and December 2018 were extracted from the Korean National Health Insurance Service. Patients who underwent KT ( n = 423) were chronologically matched in a 1:3 ratio with those maintained on dialysis ( n = 1,269) at the corresponding dates, based on time-conditional propensity scores. The 1, 5, and 10 years cumulative incidences for all-cause mortality were 12.6%, 39.1%, and 60.1% in the dialysis group and 3.1%, 7.2%, and 14.5% in the KT group. Adjusted hazard ratios (HRs) of KT versus dialysis were 0.17 (95% confidence interval [CI], 0.12-0.24; p < 0.001) for mortality and 0.38 (95% CI, 0.23-0.51; p < 0.001) for major adverse cardiovascular events (MACE). Of the MACE components, KT was most protective against cardiovascular death (HR, 0.23; 95% CI, 0.12-0.42; p < 0.001). Protective effects of KT for all-cause mortality and MACE were consistent across various subgroups, including patients at higher risk (e.g., age >65 years, recent AMI [<6 months], congestive heart failure). KT is associated with lower all-cause mortality and MACE than maintenance dialysis patients with a prior AMI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kim, Cho, Kim, Kim, Lee, Huh, Kim, Kang, Yang, Han and Lee.)

Facial expressions play a crucial role in the diagnosis of mental illnesses characterized by mood changes. The Facial Action Coding System (FACS) is a comprehensive framework that systematically categorizes and captures even subtle changes in facial appearance, enabling the examination of emotional expressions. In this study, we investigated the association between facial expressions and depressive symptoms in a sample of 59 older adults without cognitive impairment. Utilizing the FACS and the Korean version of the Beck Depression Inventory-II, we analyzed both "posed" and "spontaneous" facial expressions across six basic emotions: happiness, sadness, fear, anger, surprise, and disgust. Through principal component analysis, we summarized 17 action units across these emotion conditions. Subsequently, multiple regression analyses were performed to identify specific facial expression features that explain depressive symptoms. Our findings revealed several distinct features of posed and spontaneous facial expressions. Specifically, among older adults with higher depressive symptoms, a posed face exhibited a downward and inward pull at the corner of the mouth, indicative of sadness. In contrast, a spontaneous face displayed raised and narrowed inner brows, which was associated with more severe depressive symptoms in older adults. These findings suggest that facial expressions can provide valuable insights into assessing depressive symptoms in older adults.

Objectives: Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by progressive long-term memory loss and cognitive dysfunction. Neuroimaging tests for abnormal amyloid-β (Aβ) deposition are considered the most reliable methods for the diagnosis of AD; however, the cost for such testing is very high and generally not covered by national insurance systems. Accordingly, it is only recommended for individuals exhibiting clinical symptoms of AD supported by clinical cognitive assessments. Recently, it was suggested that dysregulated microRNA-485-3p (miRNA-485-3p) in the brain and cerebrospinal fluid is closely related to pathogenesis of AD. However, a relationship between circulating miRNA-485-3p in salivary exosome-enriched extracellular vesicles (EE-EV) and Aβ deposition in the brain has not been observed., Design & Methods: Using quantitative real-time polymerase chain reaction, we analyzed miRNA-485-3p concentration in salivary EE-EV. We used receiver operating characteristic (ROC) curve analysis to evaluate its predictive value for Aβ positron emission tomography (Aβ-PET) positivity in patients with AD., Results: Our results showed that the miRNA-485-3p concentration in salivary EE-EV isolated from patients with AD was significantly increased compared with that in the healthy controls (p < 0.0001). In the analysis of all participants, the miRNA-485-3p concentration was significantly increased in Aβ-PET-positive participants compared to Aβ-PET-negative participants (p < 0.0001). Further analysis using only AD patients also showed that the miRNA-485-3p concentration was significantly increased in Aβ-PET-positive AD patients vs. Aβ-PET-negative AD patients (p = 0.0063). The ROC curve analysis for differentiating Aβ-PET-positive and negative participants showed that the area under the curve for miRNA-485-3p was 0.9217., Conclusion: These findings suggested that the miRNA-485-3p concentration in salivary EE-EV was closely related to Aβ deposition in the brain and had high diagnostic accuracy for predicting Aβ-PET positivity., 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 Inc. All rights reserved.)

Polyglycolic acid (PGA) is a promising polymer in the packaging field owing to its excellent hydrolysis, heat resistance, and gas barrier properties, but it is limited in application due to its poor toughness. For this reason, a covalently bonded chain extender is introduced to increase compatibility with flexible polymers. However, covalent bonds are unfavorable for application to degradable plastics because of the energy required for reverse reactions. Therefore, we intended to effectively control the ductility of blending plastics by using a novel ionic chain extender with a relatively weaker non-covalent bond than the existing covalent bond. Polycaprolactone (PCL), which has biodegradability and flexibility, was selected as a blending polymer. For comparison, a covalently reactive chain extender (G-CE) and a non-covalently ionic chain extender (D-CE) were synthesized and compounded with blending plastics. Each chain extender improved the compatibility between PGA and PCL, and the ductility of the PGA/PCL blending plastics was more greatly enhanced with non-covalently bonded D-CE than with covalently bonded G-CE. At this time, the ductility of the PGA/PCL(90/10) blending plastic without CE was 7.2%, the ductility of blending plastic with D-CE (10D) was 26.6%, and the ductility of blending plastic with G-CE (10G) was 18.6%. Therefore, it was confirmed that the novel ionic chain extender inducing non-covalent bonds improves the compatibility between PGA and PCL and is more advantageous in enhancing ductility through a reversible reaction.

Polymer-based nanocomposites are desirable materials for next-generation dielectric capacitors. 2D dielectric nanosheets have received significant attention as a filler. However, randomly spreading the 2D filler causes residual stresses and agglomerated defect sites in the polymer matrix, which leads to the growth of an electric tree, resulting in a more premature breakdown than expected. Therefore, realizing a well-aligned 2D nanosheet layer with a small amount is a key challenge; it can inhibit the growth of conduction paths without degrading the performance of the material. Here, an ultrathin Sr 1.8 Bi 0.2 Nb 3 O 10 (SBNO) nanosheet filler is added as a layer into poly(vinylidene fluoride) (PVDF) films via the Langmuir-Blodgett method. The structural properties, breakdown strength, and energy storage capacity of a PVDF and multilayer PVDF/SBNO/PVDF composites as a function of the thickness-controlled SBNO layer are examined. The seven-layered (only 14 nm) SBNO nanosheets thin film can sufficiently prevent the electrical path in the PVDF/SBNO/PVDF composite and shows a high energy density of 12.8 J cm -3 at 508 MV m -1 , which is significantly higher than that of the bare PVDF film (9.2 J cm -3 at 439 MV m -1 ). At present, this composite has the highest energy density among the polymer-based nanocomposites under the filler of thin thickness., (© 2023 The Authors. Small published by Wiley-VCH GmbH.)

Background: Low body mass index (BMI) or underweight status in late life is associated with an increased risk of dementia or Alzheimer's disease (AD). However, the relationship between late-life BMI and prospective longitudinal changes of in-vivo AD pathology has not been investigated., Methods: This prospective longitudinal study was conducted as part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE). A total of 194 cognitive normal older adults were included in the analysis. BMI at baseline was measured, and two-year changes in brain Aβ and tau deposition on PET imaging were used as the main outcomes. Linear mixed-effects (LME) models were used to examine the relationships between late-life BMI and longitudinal change in AD neuropathological biomarkers., Results: A lower BMI at baseline was significantly associated with a greater increase in tau deposition in AD-signature region over 2 years (β, -0.018; 95% CI, -0.028 to -0.004; p = .008), In contrast, BMI was not related to two-year changes in global Aβ deposition (β, 0.0002; 95% CI, -0.003 to 0.002, p = .671). An additional exploratory analysis for each sex showed lower baseline BMI was associated with greater increases in tau deposition in males (β, -0.027; 95% CI, -0.046 to -0.009; p = 0.007), but not in females., Discussion: The findings suggest that lower BMI in late-life may predict or contribute to the progression of tau pathology over the subsequent years in cognitively unimpaired older adults., (© 2023. The Author(s).)

Introduction: The study aims to test whether an increase in memory load could improve the efficacy in detection of Alzheimer's disease and prediction of the Mini-Mental State Examination (MMSE) score., Methods: Speech from 45 mild-to-moderate Alzheimer's disease patients and 44 healthy older adults were collected using three speech tasks with varying memory loads. We investigated and compared speech characteristics of Alzheimer's disease across speech tasks to examine the effect of memory load on speech characteristics. Finally, we built Alzheimer's disease classification models and MMSE prediction models to assess the diagnostic value of speech tasks., Results: The speech characteristics of Alzheimer's disease in pitch, loudness, and speech rate were observed and the high-memory-load task intensified such characteristics. The high-memory-load task outperformed in AD classification with an accuracy of 81.4% and MMSE prediction with a mean absolute error of 4.62., Discussion: The high-memory-load recall task is an effective method for speech-based Alzheimer's disease detection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bae, Seo, Ko, Ham, Kim and Lee.)

Background: Preoperative verification of fracture morphology is essential for determining the definitive fixation strategy in the management of a pilon fracture. This study aimed to determine the correlation between fibular injury patterns and fracture morphologies and introduce clinical implications., Methods: Computed tomography scans of 96 pilon fractures were retrospectively analyzed and divided into three types: intact fibula, simple fracture, and multifragment fracture. The principal fracture line and comminution zones were illustrated on a plafond template and diagrammatized on a 6 × 6 grid using PowerPoint software as fracture mapping. Correlations between fibular injury patterns and fracture morphologies, including comminution zones and principal fracture lines, were analyzed., Results: The thickest comminution zone was most often located in the anterolateral quadrant. According to fibular injury patterns, the comminution zone of the multifragment group was placed two grids more lateral than that of other groups. Lateral exits of the principal fracture line in the multifragment group were much more concentrated within the fibular incisura., Conclusions: In pilon fractures, a more complex fibular fracture pattern was related to the valgus position. Moreover, the articular fracture pattern of pilon fractures differed according to coronal angulation and fibular fracture pattern. These differences should influence the operative approach and placement of the plate., Competing Interests: CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported., (Copyright © 2023 by The Korean Orthopaedic Association.)

High blood adiponectin has been associated with Alzheimer's disease (AD) dementia and related cognitive decline. We aimed to investigate the association between serum adiponectin level and in vivo AD pathologies. Cross-sectional and longitudinal study designs for the data of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease, an ongoing prospective cohort study that began in 2014. A total of 283 cognitively normal older adults between 55 and 90 years of age were included in community and memory clinic setting. Participants underwent comprehensive clinical assessments, measurement of serum adiponectin level, and multimodal brain imaging, including Pittsburgh compound-B positron emission tomography (PET), AV-1451 PET, fluorodeoxyglucose (FDG)-PET, and MRI at baseline and 2-year follow-up. Serum adiponectin level was positively associated with global beta-amyloid protein (Aβ) retention and change therein over 2 years, but not with other AD neuroimaging markers including tau deposition, AD-related neurodegeneration, and white matter hyperintensities. Blood adiponectin level is associated with increased brain amyloid deposition, which suggests that adiponectin may be a potential target for therapeutic and preventive strategies against AD.

The ongoing COVID-19 has not only caused millions of deaths worldwide, but it has also led to economic recession and the collapse of public health systems. The vaccines and antivirals developed in response to the pandemic have improved the situation markedly; however, the pandemic is still not under control with recurring surges. Thus, it is still necessary to develop therapeutic agents. In our previous studies, we designed and synthesized a series of novel 2-anilinoquinazolin-4(3H)-one derivatives, and demonstrated inhibitory activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and MERS-CoV in vitro. We then conducted in vivo studies using modified compounds that are suitable for oral administration. These compounds demonstrated no toxicity in rats and inhibited viral entry. Here, we investigated the in vivo efficacy of these drug candidates against SARS-CoV-2. Three candidate drugs, 7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4(3H)-one (1), N-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N-(3,5-dichlorophenyl)acetamide (2), and N-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N-(3,5-difluorophenyl)acetamide (3) were administered orally to hACE2 transgenic mice at a dose of 100 mg/kg. All three drugs improved survival rate and reduced the viral load in the lungs. These results show that the derivatives possess in vivo antiviral efficacy similar to that of molnupiravir, which is currently being used to treat COVID-19. Overall, our data suggest that 2-anilinoquinazolin-4(3H)-one derivatives are promising as potential oral antiviral drug candidates against SARS-CoV-2 infection., (© 2023 Wiley Periodicals LLC.)

Competing Interests: The authors have nothing to disclose.

Objectives: This study aimed to investigate the predictive efficacy of shear-wave elastography, superb microvascular imaging (SMI), and CEUS for allograft rejection in kidney transplants without graft dysfunction., Methods: From January 2021 to November 2021, 72 consecutive patients who underwent both allograft biopsy and ultrasound were evaluated. Blood test results were obtained within a week of the ultrasound examinations, which were performed before the protocol biopsy. Resistive index (RI), tissue viscoelasticity, vascular index, and quantitative CEUS parameters were measured. Patients were divided based on biopsy results into the rejection and non-rejection groups., Results: Among the 72 patients, 21 patients had pathological characteristics of acute rejection. RI of allograft was significantly higher in the rejection group (p = 0.007), compared to the non-rejection group. There were no significant between-group differences in vascular indices of SMI, mean elasticity, and mean viscosity. Meanwhile, among the parameters obtained by the time-intensity curve on CEUS, the cortical and medullary ratios of average contrast signal intensity, peak enhancement, wash-in area AUC, wash-in perfusion index, wash-out AUC, and wash-in and wash-out AUC were significantly different between the two groups (p < 0.05). In the receiver operating characteristic curve analysis for predicting allograft rejection, the AUC was 0.853 for the combination of six CEUS parameters, RI, and blood urea nitrogen., Conclusions: Among non-invasive quantitative ultrasound measurements, CEUS parameters are the most useful for diagnosing subclinical allograft rejection. Furthermore, the combination of CEUS parameters, RI, and blood urea nitrogen may be helpful for the early detection of renal allograft rejection., Key Points: • Among non-invasive quantitative ultrasound measurements, CEUS parameters are the most useful for the diagnosis of subclinical allograft rejection. • On CEUS, the C/M ratios of MeanLin, PE, WiAUC, WiPI, WoAUC, and WiWoAUC are significantly lower in the rejection group; the combination of these showed reliable predictive performance for rejection. • The combination of CEUS parameters, RI, and BUN has a high predictive capability for subclinical allograft rejection., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to threaten human health and create socioeconomic problems worldwide. A library of 200,000 small molecules from the Korea Chemical Bank (KCB) were evaluated for their inhibitory activities against SARS-CoV-2 in a phenotypic-based screening assay to discover new therapeutics to combat COVID-19. A primary hit of this screen was the quinolone structure-containing compound 1. Based on the structure of compound 1 and enoxacin, which is a quinolone-based antibiotic previously reported to have weak activity against SARS-CoV-2, we designed and synthesized 2-aminoquinolone acid derivatives. Among them, compound 9b exhibited potent antiviral activity against SARS-CoV-2 (EC 50  = 1.5 µM) without causing toxicity, while having satisfactory in vitro PK profiles. This study shows that 2-aminoquinolone acid 9b provides a promising new template for developing anti-SARS-CoV-2 entry inhibitors., 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 Ltd.. All rights reserved.)

Objective: The aims of our study were to identify distinct trajectories of cognitive function using the group-based trajectory model. We also investigate which demographic factors act as risk factors for cognitive decline in each group., Methods: The data from the Seoul National University Hospital Healthcare System Gangnam Center, from 2005 to 2019. The number of study subjects was 637. We used a group-based model to identify cognitive function trajectories. Multinomial logistic regression was employed to define risk factors for cognitive function decline., Results: The cognitive function trajectories among adults over 40 years of age were heterogeneous. We identified four trajectories: high (27.3%), medium (41.0%), low (22.7%), and rapid decline (9.1%). Older age, male, low educational level, bad dietary habits, diabetes mellitus, technical worker, and lower income increased the likelihood of a cognitive function decline., Conclusion: A younger age, a higher educational level, professional worker, good dietary habits, no diabetes mellitus, and no obesity improved cognitive function. A combination of these factors can improve "cognitive reserve" and delay cognitive decline. Interventions to prevent cognitive decline are needed after identification of high-risk groups for cognitive decline.

Aim: The neurobiological substrates underlying the relationship of circadian rest-activity rhythm (RAR) alteration with accelerated late-life cognitive decline are not clearly understood. In the present study, the longitudinal relationship of objectively measured circadian RAR with in vivo Alzheimer disease (AD) pathologies and cerebrovascular injury was investigated in older adults without dementia., Methods: The present study included 129 participants without dementia who participated in the KBASE (Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease) cohort. All participants underwent actigraphy at baseline and two consecutive [ 11 C] Pittsburgh compound-B positron emission tomography (PET), [ 18 F] fluorodeoxyglucose-PET, magnetic resonance imaging, and Mini-Mental State Examination (MMSE) at baseline and at a 2-year follow-up assessment. The associations of circadian RAR with annualized change in neuroimaging measures including global amyloid-beta retention, AD-signature region cerebral glucose metabolism (AD-CM), and white matter hyperintensity volume were examined., Results: Delayed acrophase at baseline was significantly associated with greater annualized decline of AD-CM over a 2-year period, but not with that of other neuroimaging measures. In contrast, other circadian RAR parameters at baseline had no association with annualized change of any neuroimaging measures. Annualized decline of AD-CM was also significantly positively associated with the annual change in MMSE scores. Furthermore, a mediation analysis showed that greater reduction in AD-CM mediated the effect of delayed acrophase at baseline on faster decline of MMSE score., Conclusion: The findings indicate that delayed acrophase in late life may cause or predict hypometabolism at AD-signature brain regions, which underlies cognitive decline in the near future., (© 2022 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Aims: Chronic kidney disease (CKD) increases risk of cardiovascular disease (CVD). Less is known about how CVD associates with future risk of kidney failure with replacement therapy (KFRT)., Methods and Results: The study included 25 903 761 individuals from the CKD Prognosis Consortium with known baseline estimated glomerular filtration rate (eGFR) and evaluated the impact of prevalent and incident coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) events as time-varying exposures on KFRT outcomes. Mean age was 53 (standard deviation 17) years and mean eGFR was 89 mL/min/1.73 m2, 15% had diabetes and 8.4% had urinary albumin-to-creatinine ratio (ACR) available (median 13 mg/g); 9.5% had prevalent CHD, 3.2% prior stroke, 3.3% HF, and 4.4% prior AF. During follow-up, there were 269 142 CHD, 311 021 stroke, 712 556 HF, and 605 596 AF incident events and 101 044 (0.4%) patients experienced KFRT. Both prevalent and incident CVD were associated with subsequent KFRT with adjusted hazard ratios (HRs) of 3.1 [95% confidence interval (CI): 2.9-3.3], 2.0 (1.9-2.1), 4.5 (4.2-4.9), 2.8 (2.7-3.1) after incident CHD, stroke, HF and AF, respectively. HRs were highest in first 3 months post-CVD incidence declining to baseline after 3 years. Incident HF hospitalizations showed the strongest association with KFRT [HR 46 (95% CI: 43-50) within 3 months] after adjustment for other CVD subtype incidence., Conclusion: Incident CVD events strongly and independently associate with future KFRT risk, most notably after HF, then CHD, stroke, and AF. Optimal strategies for addressing the dramatic risk of KFRT following CVD events are needed., Competing Interests: Conflict of interest: P.B.M. reports grants and personal fees from Boehringer Ingelheim; personal fees and non-financial support from Napp, Astrazeneca; personal fees from GSK, Pharmacosmos, and Astellas, outside the submitted work. J.J.C. is a Statistical Editor for the European Heart Journal. K.M. reports grants from NIDDK, during the conduct of the study; grants and personal fees from Kyowa Kirin, personal fees from Akebia, Kowa, and Fukuda Denshi, outside the submitted work. M.E.G. reports grants from National Kidney Foundation and from Kidney Disease Improving Global Outcomes outside the submitted work. J.C. reports grants from National Institute of Health and National Kidney Foundation during the conduct of the study; consulting at Healthy.io and scientific advisor to SomaLogic outside the submitted work. J.Ch. reports grants from National Health and Medical Research Council of Australia and grants and personal fees from Servier International outside the submitted work. L.C. reports consulting from CSL Vifor, honorarium for giving a talk from Fresenius Medical Care, and grants from NIH-NIDDK outside the submitted work. A.R.C. reports personal fees from Novartis, Amgen, Reata; grants from Novo Nordisk, Bayer, outside the submitted work. D.d.Z. reports personal fees from Merck during the conduct of the study, Bayer, Boehringer Ingelheim, and Travere outside the submitted work. M.E. reports institutional grants from Astellas pharma, AstraZeneca, and Vifor Pharma; honoraria form Astellas pharma, AstraZeneca, Baxter healthcare, and Fresenius Medical Care; support for attending meetings from Baxter healthcare, participation on a DSMB or Advisory Board for Astellas pharma, AstraZeneca, and Vifor pharma, and a leadership or fiduciary role on the Steering Committee of the Swedish Renal Registry, outside the submitted work. O.M.G. reports personal fees from Akebia, Amgen, AstraZeneca, Reata, Ardelyx, and QED, outside the submitted work. H.J.L.H. reports grants and honoraria for steering committee to his institution from Abbvie; grants and honoraria for steering committee and payments for advisory boards to his institution from AstraZeneca; honoraria for steering committee and payments for advisory boards from Bayer; grants and honoraria for steering committee and payments for advisory boards to his institution from Boehringer Ingelheim; honoraria for steering committee to his institution from CSL Behring, Chinook, Dimerix, Gilead; grants and honoraria for steering committee to his institution from Janssen, honoraria for steering committee to his institution from Eli Lilly, Merck, Mitsubishi Tanabe; grants and honoraria for steering committee to his institution from Novo Nordisk; and honoraria for steering committee to his institution from Travere Pharmaceuticals outside the submitted work. W.G.H. reports SHARP was funded by Merck & Co., Inc., Whitehouse Station, NJ USA, during the conduct of the study; he received grants from Boehringer Ingelheim and Eli Lilly; grants and fellowship from MRC UK, and fellowship from Kidney Research UK outside the submitted work. R.W.M. reports grants from NIHR and Kidney Research UK during the conduct of the study. G.N.N. reports personal fees, non-financial support, and other support (Scientific Cofounder, have equity/stock options, royalties and consulting) from Renalytix; personal fees and non-financial support from Pensieve Health; non-financial support and other support (Scientific Cofounder, have equity/stock options) from Nexus I Connect, Sole proprietor of Data2Wisdom LLC; personal fees from Variant Bio, Qiming Capital, Cambridge Consulting, Daiichi Sankyo, and Menarini Health, outside the submitted work. M.R. reports grants from NIH during the conduct of the study. N.S. reports being a current employee of GSK and employed at AMGA at the time of this study. B.S. reports grants from AstraZeneca, GlaxoSmithKline, and Fresenius Medical Care outside the submitted work. D.C.W. reports personal fees from AstraZeneca during the conduct of the study; personal fees from Amgen, Astellas, Bayer, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Janssen, Mundipharma, Merck Sharp and Dohme, Tricida, Vifor and Zydus; and personal fees from AstraZeneca outside the submitted work. J.v.d.B. reports being an employee and stakeholder of Binnovate Digital Health BV outside the submitted work. All other co-authors have nothing to disclose. Some of the data reported here have been supplied by the United States Renal Data System. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the US Government., (© The Author(s) 2023. 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Background: Low bone mass is common in malnourished patients with chronic kidney disease (CKD) and can lead to a higher risk of fractures. Elderly and CKD patients have the same risk factors for protein-energy wasting, sarcopenia, and osteoporosis. Here, we investigated the association between phase angle (PhA) and bone mineral density (BMD) in dialysis-naïve patients with CKD stage 5 (CKD5) and identified a statistical relationship between PhA and age, which affects bone density. Methods: Bio-impedance spectroscopy for evaluating body composition and PhA and dual-energy X-ray absorptiometry for determining the BMD were simultaneously performed in 167 consecutive patients (mean age, 59.65 ± 13.98 years; women, 40.1%). Two-way analysis of variance (ANOVA) was conducted to assess the potential interaction effect of PhA and age on femoral neck BMD (FN-BMD). Results: Our results showed that PhA and age were independently associated with FN-BMD and T-score in multiple linear regressions analyses. A significant interaction effect of PhA and age on FN-BMD was found on two-way ANOVA ( p = 0.028). The average BMD values for the first and second tertiles of the PhA were higher in the young versus elderly group, whereas patients in the elderly group had higher BMD in the third tertiles. Conclusions: A relationship was noted between PhA and BMD in patients with advanced-stage CKD. The effect of PhA level on FN-BMD differed between elderly and young patients. Our study suggested that higher PhA levels could be a marker explaining the maintenance of good bone health in elderly patients with CKD5. Further longitudinal analyses are needed to determine whether PhA predicts the risk of CKD-MBD-related fractures during CKD progression.