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Yeon-Mok Oh,1,* Keu Sung Lee,2,* Yoonki Hong,3,* Sung Chul Hwang,2 Jae Yeol Kim,4 Deog Keom Kim,5 Kwang Ha Yoo,6 Ji-Hyun Lee,7 Tae-Hyung Kim,8 Seong Yong Lim,9 Chin Kook Rhee,10 Hyoung Kyu Yoon,11 Sang Yeub Lee,12 Yong Bum Park,13 Jin Hee Jung,14 Woo Jin Kim,3 Sang-Do Lee,1 Joo Hun Park2 1Department of Pulmonary and Critical Care Medicine and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 2Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, Suwon, Korea; 3Department of Internal Medicine and Environmental Health Center, Kangwon National University, Kangwon National University Hospital, Chuncheon, Korea; 4Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea; 5Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea; 6Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea; 7Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea; 8Division of Pulmonology, Department of Internal Medicine, Hanyang University College of Medicine, Guri, Korea; 9Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea; 10Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St Mary’s Hospital, Catholic University of Korea, Seoul, Korea; 11Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Korea University Anam Hospital, Seoul, Korea; 12Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Korea University Anam Hospital, Seoul, Korea; 13Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul, Korea; 14Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Korea *These authors contributed equally to this work Background: High blood eosinophil count is a predictive biomarker for response to inhaled corticosteroids in prevention of acute exacerbation of COPD, and low blood eosinophil count is associated with pneumonia risk in COPD patients taking inhaled corticosteroids. However, the prognostic role of blood eosinophil count remains underexplored. Therefore, we investigated the associated factors and mortality based on blood eosinophil count in COPD.Methods: Patients with COPD were recruited from 16 hospitals of the Korean Obstructive Lung Disease cohort (n=395) and COPD in Dusty Area cohort (n=234) of Kangwon University Hospital. The two merged cohorts were divided based on blood eosinophil count into three groups: high (≥5%), middle (2%–5%), and low (

Sang-In Park,1,* Howard Lee,1,2,* Jaeseong Oh,1 Kyoung Soo Lim,3 In-Jin Jang,1 Jeong-Ae Kim,4 Jong Hyuk Jung,4 Kyung-Sang Yu1 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, 2Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Clinical Trials Center, Seoul National University Hospital, Seoul, 3Department of Clinical Pharmacology and Therapeutics, CHA University School of Medicine and CHA Bundang Medical Center, Seongnam, 4LG Life Sciences, Ltd, Seoul, Republic of Korea *These authors contributed equally to this work Background: In type 2 diabetes mellitus, fixed-dose combination (FDC) can provide the complementary benefits of correction of multiple pathophysiologic defects such as dysfunctions in glycemic or metabolic control while improving compliance compared with separate tablets taken together. The objective of the study reported here was to compare the pharmacodynamic (PD), pharmacokinetic (PK), and tolerability profiles of gemigliptin and extended-release metformin (metformin XR) between FDC and separate tablets.Methods: A randomized, open-label, single-dose, two-way, two-period, crossover study was conducted in 28 healthy male volunteers. Two FDC tablets of gemigliptin/metformin 25/500 mg or separate tablets of gemigliptin (50 mg ×1) and metformin XR (500 mg ×2) were orally administered in each period. Serial blood samples were collected up to 48 hours post-dose to determine dipeptidyl peptidase 4 (DPP-4) activity using spectrophotometric assay and concentrations of gemigliptin and metformin using tandem mass spectrometry. Geometric mean ratios (GMRs) of FDC to separate tablet formulations and their 90% confidence intervals (CIs) were calculated to compare the PD and PK parameters between the two formulations. Tolerability was assessed throughout the study.Results: The plasma DPP-4 activity–time curves of the FDC and the separate tablets almost overlapped, leading to a GMR (90% CI) of the FDC to separate tablets for the plasma DPP-4 activity and its maximum inhibition of 1.00 (0.97–1.04) and 0.92 (0.82–1.05), respectively. Likewise, all of the GMRs (90% CIs) of FDC to separate tablets for the area under the plasma concentration–time curve and maximum plasma concentration of gemigliptin and metformin fell entirely within the conventional bioequivalence range of 0.80–1.25. Both the FDC and separate tablets were well tolerated.Conclusion: The PD, PK, and tolerability profiles of gemigliptin and metformin XR in FDC and separate tablets were found to be comparable. The FDC tablet of gemigliptin and metformin sustained release can be a convenient therapeutic option in patients with type 2 diabetes mellitus requiring a combination approach. Keywords: dipeptidyl peptidase 4, DPP-4 inhibitor, type 2 diabetes mellitus, T2DM

Purpose: To investigate the effect of prostaglandin F2α (PGF2α), latanoprost, travoprost, bimatoprost, and tafluprost on human orbital preadipocyte differentiation and intracellular lipid storage, and to reveal the potential mechanisms by which topical prostaglandin analogs induce orbital fat volume reduction and cause deep superior sulcus syndrome.Methods: Human orbital adipose precursors were treated in vitro for 24 h (day 1) with PGF2α, latanoprost, travoprost, bimatoprost, and tafluprost in their commercial formulations (1:100 dilution). Expressions of adipogenic transcription factor, peroxisome proliferator-activated receptor-gamma (PPARγ), and CCAAT-enhancer-binding protein α (C/EBPα) were determined by real-time reverse transcription-polymerase chain reaction (RT-PCR) at day 7. At 14 days, cells were stained with oil red O, intracellular lipid accumulation was evaluated by lipid absorbance, and adipocyte expression marker [Lipoprotein lipase (LPL)] was determined by real-time RT-PCR.Results: Our results showed that PGF2α and topical prostaglandin analogs down-regulated the expression of PPARγ and C/EBPα, and inhibited accumulation of intra-cytoplasmic lipid droplets and expression of LPL compared with the untreated control. Comparison between the 4 drugs showed that latanoprost had the weakest antiadipogenic effect, and bimatoprost induced the most significant reduction of adipogenesis.Conclusion: Latanoprost, travoprost, bimatoprost, and tafluprost inhibited human preadipocyte differentiation and intracellular lipid accumulation. Morphologic and metabolic changes in orbital adipocytes caused by PGF2α analogs are a possible pathophysiologic explanation of superior eyelid deepening in patients with glaucoma. [ABSTRACT FROM AUTHOR]

Background: Most ductal carcinoma in situ (DCIS) of the breast is asymptomatic and usually manifests as calcifications in screening mammography. On the other hand, little is known about ultrasonographic (US) features of asymptomatic DCIS, for US is rarely used for the diagnosis and evaluation of DCIS because of low sensitivity in detecting microcalcifications. Purpose: To evaluate US detection and characterization of DCIS in asymptomatic women and correlate these imaging findings with the histopathologic features. Material and Methods: This retrospective study evaluated mammographic and US images of 60 DCIS cases from 59 asymptomatic women. US was performed in knowledge of mammographic findings. The following histopathologic parameters were analyzed: Van Nuys classification, architectural pattern, and presence of microinvasion. Image detectability and US features were correlated with these histopathologic parameters. Results: Of the 54 cases (90.0%) detected on mammography, 48 cases (88.9%) had microcalcifications only, 5 (9.3%) had microcalcifications with associated density, and 1 (1.9%) had soft tissue density alone. Of the 38 cases (63.3%) identified by US, 29 cases (76.3%) had a mass with or without microcalcifications, six (15.8%) had microcalcifications only, and three (7.9%) had other findings. US identified lesions were associated with higher Van Nuys groups, microinvasion and comedocarcinoma (P = 0.044, P = 0.024, and P = 0.032, respectively). The most common US finding was a not-circumscribed, oval mass with parallel orientation and normal acoustic transmission. Microcalcifications were seen on US in 31 (81.6%) of the 38 US visible cases; this finding showed a trend of association with Van Nuys group 2 and 3 but was not statistically significant (P = 0.063). Conclusion: When DCIS was identified on US, it was associated with more aggressive histopathologic type. However, mammographic correlation is essential to differentiate benign from malignant lesion in cases seen by US; US findings of asymptomatic DCIS had a low suspicion of malignancy. [ABSTRACT FROM AUTHOR]

Background: A high-flexion posterior-stabilized rotating-platform mobile-bearing prosthesis was designed in an attempt to improve the range of motion after total knee arthroplasty without compromising the theoretical advantages of the posterior-stabilized rotating-platform mobile-bearing system. The aim of this study was to compare the outcomes of standard and high-flexion posterior-stabilized rotating-platform mobile-bearing total knee arthroplasties.Methods: One hundred and seventy knees were randomly allocated to receive either a standard (n = 85) or a high-flexion (n = 85) posterior-stabilized rotating-platform mobile-bearing prosthesis and were followed prospectively for a minimum of two years. Ranges of motion, functional outcomes determined with use of standard scoring systems, and radiographic measurements were assessed. In addition, patients' abilities to perform activities requiring deep knee flexion and patient satisfaction were evaluated with use of questionnaires.Results: The average postoperative maximal flexion was 130° for the knees with the standard design and 128° for those with the high-flexion design, and the difference was not significant. The two prosthetic designs also did not differ significantly with regard to the Knee Society scores; Hospital for Special Surgery (HSS) scores; or the scores on the pain, stiffness, and function subscales of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). In addition, the numbers of knees able to perform deep-flexion-related activities and the rates of patient satisfaction were similar in the two study groups.Conclusions: This prospective randomized study revealed no significant differences between standard and high-flexion posterior-stabilized rotating-platform mobile-bearing total knee prostheses in terms of clinical or radiographic outcomes or range of motion at a minimum of two years postoperatively. [ABSTRACT FROM AUTHOR]

Objective: Previous studies have reported that vitamin D deficiency increased the risk of Alzheimer's disease (AD) dementia in older adults. However, little is known about how vitamin D is involved in the pathophysiology of AD. Thus, this study aimed to examine the association and interaction of serum vitamin D levels with in vivo AD pathologies including cerebral beta-amyloid (Aβ) deposition and neurodegeneration in nondemented older adults., Methods: 428 Nondemented older adults were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease, a prospective cohort that began in 2014. All participants underwent comprehensive clinical assessments, measurement of serum 25-hydroxyvitamin D (25[OH]D), and multimodal brain imaging including Pittsburgh compound B (PiB) positron emission tomography and magnetic resonance imaging. Global PiB deposition was measured for the Aβ biomarker. Intracranial volume-adjusted hippocampal volume (HVa) was used as a neurodegeneration biomarker., Results: Overall, serum 25(OH)D level was not associated with either Aβ deposition or HVa after controlling for age, sex, apolipoprotein E ε4 positivity, and vascular risk factors. However, serum 25(OH)D level had a significant moderating effect on the association between Aβ and neurodegeneration, with lower serum 25(OH)D level significantly exacerbating cerebral Aβ-associated hippocampal volume loss (B = 34.612, p = 0.008)., Conclusion: Our findings indicate that lower serum vitamin D levels may contribute to AD by exacerbating Aβ-associated neurodegeneration in nondemented older adults. Further studies to explore the potential therapeutic effect of vitamin D supplementation on the progression of AD pathology will be necessary.

Objective: We intended to investigate the relationships between visual sensory impairment (VSI) or auditory sensory impairment (ASI) and brain pathological changes associated with cognitive decline in older adults., Methods: We primarily tried to examine whether each sensory impairment is related to Alzheimer's disease (AD) pathology, specifically beta-amyloid (Aβ) deposition, through both cross-sectional and longitudinal approaches in cognitively unimpaired older adults. Self-report questionnaires on vision and hearing status were administered at the baseline. Neuroimaging scans including brain [ 11 C] Pittsburgh Compound B PET and MRI, as well as clinical assessments, were performed at baseline and 2-year follow-up., Results: Cross-sectional analyses showed that the VSI-positive group had significantly higher Aβ deposition than the VSI-negative group, whereas there was no significant association between ASI positivity and Aβ deposition. Longitudinal analyses revealed that VSI positivity at baseline was significantly associated with increased Aβ deposition over 2 years (β = 0.153, p = 0.025), although ASI positivity was not (β = 0.045, p = 0.518). VSI positivity at baseline was also significantly associated with greater atrophic changes in AD-related brain regions over the 2-year follow-up period (β = -0.207, p = 0.005), whereas ASI positivity was not (β = 0.024, p = 0.753). Neither VSI nor ASI positivity was related to cerebrovascular injury, as measured based on the white matter hyperintensity volume., Conclusion: The findings suggest that VSI is probably related to AD-specific pathological changes, which possibly mediate the reported relationship between VSI and cognitive decline. In contrast, ASI appears not associated with AD pathologies but may contribute to cognitive decline via other mechanisms.

Purpose: PET/CT and MRI can accurately diagnose dementia but are expensive and inconvenient for patients. Therefore, we aimed to generate synthetic fluid-attenuated inversion recovery (FLAIR) images from 18 F-FDG PET and CT images of the human brain using a generative adversarial network (GAN)-based deep learning framework called the CypixGAN, which combined the CycleGAN framework with the L1 loss function of the pix2pix., Patients and Methods: Data from 143 patients who underwent PET/CT and MRI were used for training (n = 79), validation (n = 20), and testing (n = 44) the deep learning frameworks. Synthetic FLAIR images were generated using the pix2pix, CycleGAN, and CypixGAN, and white matter hyperintensities (WMHs) were then segmented. The performance of CypixGAN was compared with that of the other frameworks., Results: The CypixGAN outperformed the pix2pix and CycleGAN in generating synthetic FLAIR images with superior visual quality. Peak signal-to-noise ratio and structural similarity index (mean ± standard deviation) estimated using the CypixGAN (20.23 ± 1.31 and 0.80 ± 0.02, respectively) were significantly higher than those estimated using the pix2pix (19.35 ± 1.43 and 0.79 ± 0.02, respectively) and CycleGAN (18.74 ± 1.49 and 0.78 ± 0.02, respectively) ( P < 0.001). WMHs in synthetic FLAIR images generated using the CypixGAN closely resembled those in ground-truth images, as indicated by the low absolute percentage volume differences and high dice similarity coefficients., Conclusions: The CypixGAN generated high-quality FLAIR images owing to the preservation of spatial information despite using unpaired images. This framework may help improve diagnostic performance and cost-effectiveness of PET/CT when MRI scan is unavailable., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Alzheimer's disease (AD) pathogenesis has been associated with the gut microbiome and its metabolites, though the specific mechanisms have remained unclear. In our study, we used a multi-omics approach to identify specific microbial strains and metabolites that could potentially mitigate amyloidopathy in 5xFAD mice, a widely used model for AD research. Among the microbial strains tested, three showed promising results in reducing soluble amyloid-beta (Aβ) levels. Plasma metabolomics analysis revealed an enrichment of tryptophan (Trp) and indole-3-lactic acid (ILA) in mice with reduced soluble Aβ levels, suggesting a potential preventative role. The administration of a combined treatment of Trp and ILA prevented both Aβ accumulation and cognitive impairment in the 5xFAD mice. Our investigation into the mechanism revealed that ILA's effect on reducing Aβ levels was mediated through the activation of microglia and astrocytes, facilitated by the aryl hydrocarbon receptor (AhR) signaling pathway. These mechanisms were verified through experiments in 5xFAD mice that included an additional group with the administration of ILA alone, as well as in vitro experiments using an AhR inhibitor. Clinical data analysis revealed a greater abundance of Lactobacillus reuteri in the gut of healthy individuals compared to those at early stages of Aβ accumulation or with mild cognitive impairment. Additionally, human post-mortem brain analyses showed an increased expression of genes associated with the AhR signaling pathway in individuals without AD, suggesting a protective effect against AD progression. Our results indicate that ILA from gut microbes could inhibit the progression of amyloidopathy in 5xFAD mice through activation of AhR signaling in the brain., 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 Inc.)

Diabetes is a chronic disease with significant complications, necessitating regular treatment and checkups, which can be costly and time-consuming for patients. To address this, we developed the Sliding Microneedle (MN)-Lateral flow immunoassay strip (LFIAs) device that combines the advantages of MNs and LFIAs to detect IL-6, an independent biomarker for diabetes complications. This device offers rapid and highly sensitive detection of IL-6 by extracting interstitial fluid (ISF) through MNs and transferring it to LFIAs. The stainless MN, embedded in the 3D-printed Sliding MN-LFIAs device, was inserted into the skin at a 20° angle, minimizing blood contamination risk. With a filter paper attached to the MN surface, the device collected 4.65 ± 0.05 μL of ISF containing IL-6 within 90 s. The ISF was then transferred to the LFIAs using a running buffer. After a 15-min reaction, silver enhancement (SE) treatment was applied, allowing for the highly sensitive and specific detection of IL-6 at 10 2  pg/mL concentrations. The Sliding MN-LFIAs device successfully distinguished between normal and diabetic rat models, demonstrating its potential as an effective tool for detecting diabetes complications quickly and affordably., 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.)

Objective: To investigate the highest opportunity skin puncture point and needle orientation according to facial asymmetry and classification., Methods: Computed tomography of 136 patients was analyzed. Horizontal and vertical angles and distances from the canthal-tragal line were investigated to determine the puncture point and needle's angle., Result: All patients' average points were 7.39 (±2.85) mm anterior to the tragus and 3.44 (±4.18) mm below the canthal-tragal line with an angle of 8.53 (±6.90)° anteriorly and 32.26 (±7.23)° superiorly. Regarding asymmetry, there was a statistical difference in horizontal angle, depth, and canthal-tragal distance between the deviated and non-deviated sides. Especially, vertical distances were 4.44 (±4.66) mm and 2.59 (±4.11) mm in the deviated and non-deviated sides, respectively ( p < 0.001)., Conclusion: In closed-mouth, the puncture point was closer to the tragus and lower than the conventional point. The point in the deviated side should be considered lower than the non-deviated side.

Background: Nutrition is largely affected in bipolar disorder (BD), however, there is a lack of understanding on the relationship between dietary categories, BD, and the prevalence of metabolic syndrome. The objective of this study is to examine dietary trends in BD and it is hypothesized that diets with increased consumption of seafood and high-fiber carbohydrates will be correlated to improved patient outcomes, and a lower frequency of metabolic syndrome., Methods: This retrospective cohort study includes two French cohorts. The primary cohort, FACE-BD, includes 268 stable BD patients. The second cohort, I-GIVE, includes healthy controls, both stable and acute BD and schizophrenia patients. Four dietary categories were assessed: meat, seafood, low-fiber and high-fiber carbohydrates. Dietary data from two food frequency questionnaires were normalized using min-max scaling and assessed using various statistical analyses., Results: In our primary cohort, the increased high-fiber carbohydrate consumption was correlated to lower prevalence of metabolic syndrome and improved mood. Low-fiber carbohydrate consumption is associated with higher BMI, while higher seafood consumption was correlated to improved mood and delayed age of onset. Results were not replicated in our secondary cohort., Limitations: Our populations were small and two different dietary questionnaires were used; thus, results were used to examine similarities in trends., Conclusions: Overall, various dietary trends were associated with metabolic syndrome, BMI, lactate, mood and age of onset. Improving our understanding of nutrition in BD can provide mechanistic insight, clinically relevant nutritional guidelines for precision medicine and ultimately improve the quality of lives for those with BD., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)