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The effective and efficient treatment of diseases, such as HIV, cancer or hereditary diseases, requires accurate and precise control of the combinatorial drug-dosage and their release. Herein, we introduce a simple photosensitive poly(ethylene glycol) diacrylate (PEGDA) hydrogel based platform for high dynamic range testing of combinatorial cocktail drug screening using three chemical and two protein drug treatments for colon cancer. UV cross linked PEGDA hydrogel droplet arrays on a Teflon patterned glass substrate enable a rapid yet accurate selection and dosage assignment of the drugs. Precisely loaded cocktails of the anticancer drugs were simultaneously released in-parallel with the PEGDA hydrogel chips into 2D or 3D cultured HCT-8 colon cancer cells for combinatorial drug screening. We demonstrate the functionality of our UV gel-Drug Chips 1000 fold range of concentrations for each of the five drugs in 30 seconds to find the optimized drug cocktail using a fractional factorial control system. Our device has low drug consumption, requiring only 12 nL per screening run per droplet. In addition, our UV gel-Drug Chips were employed for find the optimized drug cocktail using a fractional search algorithm. Our cocktail drug response results for both 2D (cell viability is 7.3%) and 3D (cell viability is 10.8%) colon cancer cells were analogous to those found by conventional method (6.8 and 9.3 respectively). In contrast to conventional method, our approach is faster, more effective, less time consuming and requires a lower amounts of drug volume.

Objectives: Emergency medicine (EM) doctors are often required to manage a diverse set of complex challenges; navigating direct patient care, systemic issues and inter-professional interactions. Leadership is well recognised as crucial in optimising both the delivery and the quality of patient care. There is a clear need to gain greater understanding of the reality of EM leadership through exploring doctors' experience and perception of leadership in EM, yet there is a paucity of research focusing on this area. The objective of the present study was to explore the research question: 'What are the experiences and perceptions of leadership by EM doctors?', Methods: This single-site qualitative study was undertaken using semi-structured in-depth individual interviews to collect data. Interviews were audio recorded, transcribed and de-identified. Reflexive thematic analysis was performed by the research team with the aid of DelveTool software., Results: Our sample included nine participants incorporating consultants and registrars. Three major themes were identified: (i) situational tensions, (ii) relational tensions and (iii) leadership style tensions. Each of these was further explored with subthemes discussed separately., Conclusions: Leadership within the ED is complex and multifaceted, with doctors required to navigate many competing tensions. The present study highlighted key areas for future leadership development, including situational awareness, emotional intelligence and a fluid approach to leadership styles. The present study provides an important step towards enhancing the development of targeted leadership training for EM doctors., (© 2024 Australasian College for Emergency Medicine.)

Obesity-mediated hypertension is a worldwide problem. Recent research has indicated that chronic inflammation is associated with the pathogenesis of obese hypertension. Activated immune cells infiltrate target organs, such as arteries, kidneys, and brain, causing end-organ damage and hypertension. Histone deacetylase 6 (HDAC6) regulates the inflammatory cell activity mediating the production of inflammatory cytokines and may play a role in the crosstalk between inflammation and hypertension. In this study, we investigated the roles of HDAC6 in high-fat diet (HFD)-induced kidney inflammation and hypertension. Nine-week-old male C57BL/6 mice were fed either a normal diet (ND) or HFD for 15 weeks. HFD-induced hypertension with increased HDAC6 activities in the kidney and bone marrow-derived macrophages (BMDM). When HFD group reached the hypertensive phase, each group of mice was intraperitoneally injected with vehicle or selective HDAC6 inhibitor Tubacin (1 mg/kg/day) for 14 days. Tubacin treatment lowered blood pressure (BP) of HFD-fed mice to the normal level with successful inhibition of HDAC6 activity. Immunohistochemical staining of F4/80, which is known as a macrophage marker, revealed that HFD promoted macrophage infiltration into the kidney. Consequently, pro-inflammatory factors TNFα and IL-6 gene expressions in the kidney were increased by HFD. Tubacin canceled HFD-induced macrophage infiltration and inflammation in the kidney. HDAC6 gene silencing and Tubacin treatment in Raw 264.7 cells also blocked the chemoattractant-stimulated cell migration in vitro. The results reveal the novel role of HDAC6 in BMDM migration, kidney inflammation, and high BP induced by HFD providing HDAC6 inhibitors as a therapeutic option for obesity-mediated hypertension., Competing Interests: Declaration of competing interest We have nothing to declare., (Copyright © 2024. Published by Elsevier Inc.)

Motile cilia are crucial for maintaining healthy bodily functions by facilitating fluid transport and removing foreign substances or debris from the body. The dysfunction of motile cilia leads to ciliopathy. In particular, damage to the motile cilia of the airways can cause or worsen respiratory disease, making it an attractive target for therapeutic interventions. However, there are no treatments to induce motile ciliogenesis. Forkhead box transcription factor J1 (FOXJ1), the master regulator, has been implicated in motile cilia formation. Mice lacking the Foxj1 gene show loss of axoneme, a key component of cilia, that further highlights the importance of FOXJ1 in motile cilia formation. This prompted us to identify new small molecules that could induce motile ciliogenesis. A phenotype-based high-throughput screening (HTS) in a Tg(foxj1a:eGFP) zebrafish model was performed and a novel hit compound was identified. Among the synthesized compounds, compound 16c effectively enhanced motile ciliogenesis in a transgenic zebrafish model. To further test the efficacy of compound 16c on a mammalian airway system consisting of multiciliated cells (MCCs), ex vivo mice tracheal epithelial cell culture was adopted under an air-liquid interface system (ALI). Compound 16c significantly increased the number of MCCs by enhancing motile ciliogenesis. In addition, compound 16c exhibited good liver microsomal stability, in vivo PK profiles with AUC, and oral bioavailability. There was no significant inhibition of CYP and hERG, and no cell cytotoxicity was shown. In an elastase-induced COPD (chronic obstructive pulmonary disease) mouse model, compound 16c effectively prevented the development and onset of COPD. Taken together, compound 16c has great promise as a therapeutic agent for treating and alleviating motile ciliopathies., 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 Masson SAS. All rights reserved.)

Background/Objective: This study aimed to compare the functional outcomes, such as knee muscle strength, dynamic postural stability, pain scores, and physical activity, in patients with knee osteoarthritis (OA) on stair climbing training with and without interferential electrotherapy (IFE) for 12 weeks. Methods: A total of 40 knee OA patients with Kellgren-Lawrence (K-L) grade ≤ 2 were enrolled (20 stair-climbing training with IFE vs. 20 stair-climbing training without IFE). The knee quadriceps and hamstring muscle strengths were measured using an isokinetic device. The dynamic postural stability was assessed using postural stabilometry. The pain score was evaluated using the visual analog scale (VAS). Physical activity was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Results: The WOMAC score was significantly different ( p < 0.019) between stair-climbing training with and without IFE in patients with knee OA, while knee muscle strength, dynamic postural stability, or pain score were not (all p > 0.05). Conclusion: Stair-climbing training with IFE was more beneficial for physical activity recovery than stair-climbing training without IFE. Therefore, clinicians and therapists should be aware that stair climbing, which can be practiced in daily life for the management of patients with knee OA, and the addition of IFE may improve physical activity.

Background: Flight attendants face various risk factors in their working environments, particularly occupational exposure to cosmic radiation. This study aimed to assess cancer risk among air transportation industry workers, including flight attendants, in Korea by constructing a cohort using national health registry-based data and analyzing cancer incidence risk., Methods: We used the Korea National Health Insurance Service database from 2002 to 2021 to construct a cohort of 37,011 workers in the air transportation industry. Cancer incidence was defined using the tenth version of the International Classification of Diseases. We calculated the age- and sex-specific standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) by applying the cancer incidence rate of the general population between 2002 and 2019., Results: Approximately 5% of the cohort developed cancer. Overall, the cancer incidence in the cohort was similar to or lower than that of the general population, with the SIRs for all cancers being lower. However, significantly higher SIRs were observed for nasopharyngeal cancer (SIR, 3.21; 95% CI, 1.71-5.48) and non-Hodgkin lymphoma (SIR, 1.57; 95% CI, 1.02-2.32) in male workers and breast and genital cancer (SIR, 1.51; 95% CI, 1.34-1.70) and thyroid cancer (SIR, 1.25; 95% CI, 1.05-1.47) in female workers., Conclusions: The lower overall cancer incidence among air transportation industry workers observed in this study could indicate the "healthy worker effect"; however, the incidences of certain cancers were higher than those in the general population. Given that these workers are exposed to multiple occupational and lifestyle-related risk factors, including cosmic radiation, further studies are necessary to determine radiation-induced cancer risk while considering potential confounding factors., (© 2024. The Author(s).)

Flavonols effectively scavenge the reactive nitrogen species (RNS) and reactive oxygen species (ROS) and act as immune-enhancing, anti-inflammatory, anti-diabetic, and anti-carcinogenic agents. Here, we explored the comparative antioxidant and anti-inflammatory properties of plant-originating flavonols, like quercetin, rutin, and troxerutin against acetylsalicylic acid. Quercetin and rutin showed a high ability to remove active ROS, but troxerutin and acetylsalicylic acid exhibited little such function. In RAW 264.7 cells, quercetin, rutin, and troxerutin did not exhibit cellular toxicity at low concentrations. In addition, quercetin, rutin, and troxerutin considerably (p < 0.05) lowered the protein expression of cyclooxygenase 2 (COX-2) as compared to acetylsalicylic acid in cells inflamed with lipopolysaccharides (LPS). Additionally, in inflamed cells, quercetin and rutin significantly down-regulated the nitrogen oxide (NO) level (p < 0.05) at higher concentrations, whereas Troxerutin did not reduce the NO level. In addition, Troxerutin down-regulated the pro-inflammatory protein markers, such as TNF-α, COX-2, NF-κB, and IL-1β better than quercetin, rutin, and acetylsalicylic acid. We observed that troxerutin exhibited a significantly greater anti-inflammatory effect than acetylsalicylic acid did. Acetylsalicylic acid did not significantly down-regulated the expression of COX-2 and TNF-α (p < 0.05) compared to troxerutin. Hence, it can be concluded that the down-regulation of NO levels and the expression of COX-2 and TNF-α proteins could be mechanisms of action for the natural compounds quercetin, rutin, and troxerutin in preventing inflammation., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Human induced pluripotent stem cells (iPSCs) can be differentiated into neurons, providing living human neurons to model brain diseases. However, it is unclear how different types of molecules work together to regulate stem cell and neuron biology in healthy and disease states. In this study, we conducted integrated proteomics, lipidomics, and metabolomics analyses with confident identification, accurate quantification, and reproducible measurements to compare the molecular profiles of human iPSCs and iPSC-derived neurons. Proteins, lipids, and metabolites related to mitosis, DNA replication, pluripotency, glycosphingolipids, and energy metabolism were highly enriched in iPSCs, whereas synaptic proteins, neurotransmitters, polyunsaturated fatty acids, cardiolipins, and axon guidance pathways were highly enriched in neurons. Mutations in the GRN gene lead to the deficiency of the progranulin (PGRN) protein, which has been associated with various neurodegenerative diseases. Using this multiomics platform, we evaluated the impact of PGRN deficiency on iPSCs and neurons at the whole-cell level. Proteomics, lipidomics, and metabolomics analyses implicated PGRN's roles in neuroinflammation, purine metabolism, and neurite outgrowth, revealing commonly altered pathways related to neuron projection, synaptic dysfunction, and brain metabolism. Multiomics data sets also pointed toward the same hypothesis that neurons seem to be more susceptible to PGRN loss compared to iPSCs, consistent with the neurological symptoms and cognitive impairment from patients carrying inherited GRN mutations.

Background: The reliability of presepsin as a biomarker of sepsis may be reduced in patients with acute kidney injury (AKI) requiring continuous kidney replacement therapy (CKRT). This study analyzed the utility of plasma presepsin values in predicting mortality in patients with AKI requiring CKRT, particularly those with sepsis-associated AKI., Methods: This single-center retrospective study included 57 patients who underwent CKRT, with plasma presepsin measurements, from April 2022 to March 2023; 35 had sepsis-associated AKI. The predictive values of plasma presepsin, as well as Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores, for 28-day mortality were analyzed using receiver operating characteristic curves. Multivariate Cox regression analysis was performed to identify risk factors for 28-day mortality in the sepsis-associated AKI subgroup., Results: Overall, plasma presepsin showed a lower area under the curve value (0.636; 95% confidence interval [CI], 0.491-0.781) than the APACHE II (0.663; 95% CI, 0.521-0.804) and SOFA (0.731; 95% CI, 0.599-0.863) scores did. However, in sepsis-associated AKI, the area under the curve increased to 0.799 (95% CI, 0.653-0.946), which was higher than that of the APACHE II (0.638; 95% CI, 0.450-0.826) and SOFA (0.697; 95% CI, 0.519-0.875) scores. In the multivariate Cox regression analysis, a high presepsin level was an independent risk factor for 28-day mortality in sepsis-associated AKI (hazard ratio, 3.437; p = 0.03)., Conclusion: Presepsin is a potential prognostic marker in patients with sepsis-associated AKI requiring CKRT.

This study aimed to compare functional outcomes sequentially up to 1 year after combined anterior cruciate ligament reconstruction (ACLR) and anterolateral ligament reconstruction (ALLR) and isolated ACLR. Fifty patients who underwent ACLR with versus without ALLR were analyzed at four different time points (preoperatively and 3, 6, and 12 months postoperatively). For the functional outcomes, muscle strength and acceleration time (AT) were measured using an isokinetic dynamometer. Proprioception was evaluated using joint position sense and dynamic postural stability. Patient-reported outcomes were measured using the Tampa Scale for Kinesiophobia (TSK-11) scores. Functional performance was assessed using single-leg hop distance (SLHD) and Limb Symmetry Index. In the operated knees, quadriceps (at 6 months postoperatively, p = 0.003) and hamstring (at 6 and 12 months postoperatively, p < 0.001) strength were significantly higher in the combined ACLR and ALLR group than the isolated ACLR group. The TSK-11 (at 6 and 12 months postoperatively, p < 0.001) was significantly lower in the combined ACLR and ALLR group than the isolated ACLR group. SLHD was significantly higher in the combined ACLR and ALLR group than the isolated ACLR group (at 6 months, p = 0.022 and at 12 months, p = 0.024). The addition of ALLR to primary ACLR yielded better muscle performance, fear of movement, and functional performance than isolated ACLR., (© 2024. The Author(s).)

Periprosthetic joint infections (PJIs) pose a significant challenge in orthopedic surgery, particularly total joint arthroplasty (TJA), due to the potential for implant failure and increased patient morbidity. Early and accurate detection of PJIs is crucial for timely intervention and better patient prognosis. Herein, we successfully screened a high-affinity aptamer targeting alpha-defensin complex human neutrophil protein 1-3 (HNP 1-3; potential PJI biomarkers in synovial fluid [SF]) for the first time using systematic evolution of ligands by exponential enrichment (SELEX) on an integrated microfluidic platform. The compact microfluidic device enabled efficient screening, with each round completed within <2 h, comprising five rounds of positive selection, two rounds of negative selection, and one round of competitive selection. A novel one-aptamer-one-antibody assay was further developed from the optimal aptamer screened, and it could accurately quantify HNP 1-3 in SF within 3 h with only ∼50 μL of SF. The assay demonstrated strong binding affinity and specificity for the target protein in SF. Thirteen PJI SF samples were accurately diagnosed and the assay was accurate over a wide dynamic range (0.32-100 mg/L). This study has showcased a rapid and accurate diagnostic tool for PJI detection, which should see widespread use in the clinic, holding promise for potential analytical applications in orthopedic surgery and improving patient care.

This study aimed to compare functional outcomes including knee muscle strength in the quadriceps and hamstrings, and proprioception, assessed through dynamic postural stability (overall stability index [OSI]) and self-reported outcomes in the operated and non-operated knees between anterior cruciate ligament reconstruction (ACLR) with meniscal repair for unstable (root and radial tears) and stable (longitudinal, horizontal, and bucket handle tears) meniscal tears. A total of 76 patients were randomly selected (41 with ACLR with meniscal repair for unstable meniscal tears and 35 with ACLR with meniscal repair for stable meniscal tears) at three different time points (preoperative, 6 months, and 12 months). Repeated measures analysis of variance was used to investigate the differences in outcomes for between-subject and within-subject factors. In the operated knees, there were no significant differences for functional outcomes between the two groups (all p > 0.05). In the non-operated knees, a significant difference was observed for the OSI between the two groups, which was significantly higher in ACLR with meniscal repair for unstable meniscal tears than for stable meniscal tears at 6 months ( p < 0.001). Multiple linear regression analysis showed that age ( p = 0.027), preoperative OSI in the operated knees ( p = 0.005), and postoperative OSI in the operated knees at 6 months ( p = 0.002) were significant and independent predictors for OSI in the non-operated knees at 6 months postoperatively. Therefore, while no differences were observed in functional outcomes between the two groups in the operated knees, dynamic postural stability was poorer at 6 months postoperatively in the non-operated knees of patients with ACLR with meniscal repair for unstable meniscal tears. Furthermore, a significant correlation was observed between preoperative/postoperative dynamic postural stability in the operated knees and postoperative dynamic postural stability in the non-operated knees. Hence, we recommend incorporating balance exercises for both knees in post-surgical rehabilitation, particularly for patients with unstable meniscal tears., Competing Interests: The authors declare no conflicts of interest regarding this article.

Cardiovascular diseases (CVDs) claimed the lives of nearly 21 million people worldwide in 2021, accounting for 30% of global deaths. However, one in five CVD patients is unaware that they have the disease, emphasizing the need for accurate biomarker monitoring. Herein we developed an integrated microfluidic system (IMS) for rapid quantification of four CVD biomarkers, including N-terminal pro B-type natriuretic peptide (NT-proBNP), fibrinogen, cardiac troponin I (cTnI), and C-reactive protein (CRP)- via aptamer-coated interdigitated electrodes (IDE) with integrated circuits (IC) and a self-driven IMS for sample treatment. The device was composed of plasma filtration, metering, and fluidic delay modules, and the former could extract 45% of plasma from a 20-μL blood sample; the metering module could quantify 5 μL of plasma within 90 s. Subsequently, the plasma was transported to a detection chamber, where IC-based IDE sensors made measurements within 5 min. The entire 15-min process allowed us to evaluate biomarkers across a wide dynamic range: NT-proBNP (0.1-10,000 pg/mL), fibrinogen (50-1,000 mg/dL), cTnI (0.1-10,000 pg/mL), and CRP (0.5-9 mg/L). Given that spiked blood samples were measured with reasonable accuracy (>80%), the IMS could see utility in CVD risk assessment and personalized medicine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

We reported a microfluidic system for sorting of extracellular vesicles (EVs), which can house DNAs, RNAs, lipids, proteins, and metabolites that are important in intercellular communication. Their presence within bodily fluids has demonstrated potential in both clinical diagnostic and therapeutic applications. Furthermore, EVs exhibit distinct subtypes categorized by their sizes, each endowed with unique biophysical properties. Despite several existing techniques for EV isolation and purification, diminished purity and prolonged processing times still hamper clinical utility; comprehensive capture of EVs remains an ongoing pursuit. To address these challenges, we devised an innovative method for automated sorting of nano-scale EVs employing optically-induced dielectrophoresis on an integrated microfluidic chip. With this approach, EVs of three distinct size categories (small: 100-150 nm, medium-sized: 150-225 nm, and large: 225-350 nm) could be isolated at a purity of 86%. This new method has substantial potential in expediting EV research and diagnostics.

Cholangiocarcinoma (CCA) is an aggressive cancer that originates from the epithelial cells lining the bile ducts. Due to its location deep within the body and nonspecific symptoms in the early stages, it is often diagnosed at the advanced stage, thus leading to worse prognosis. Circulating tumor cells within liquid biopsies ( i.e. blood) have been considered as promising biomarkers for CCA diagnosis, though current methods for profiling them are not satisfactory in terms of sensitivity and specificity. Herein we developed a new cancer cell probing and immuno-tracking assay known as "CAPTURE", which was performed on an integrated microfluidic system (IMS) to automate CCA diagnosis from bile with a sample amount of only 1 mL. The assay utilized magnetic beads surface-coated with two affinity reagents, a nucleic acid aptamer (HN16) and a glycosaminoglycan (SCH 45-mix), for capturing cancer cells in bile; the "gold standard" anti-epithelial cell adhesion molecule was used as a comparison. In a single-blind test of 54 CCA-positive (+) and 102 CCA-negative (-) clinical samples, sensitivities and specificities of 96 and 80%, respectively, were documented with the CAPTURE assay on-bench. An IMS composed of a centrifugal module for sample pretreatment and a CAPTURE module for cell capture and staining was integrated with a new "vertical integration module" for detecting cancer cells from bile without human intervention. Furthermore, a novel micro-tier structure within the centrifugal module was designed to block passage of gallbladder stones with diameters >1 mm, thereby preventing their interference during the subsequent CAPTURE assay. Improved sensitivity and specificity (100 & 83%, respectively) by using three affinity reagents were achieved on the IMS when using 26 clinical bile samples, confirming its clinical bio-applicability for CCA diagnosis. This approach could be therefore used for early-stage CCA diagnostics, ideally enabling effective treatment, as well as reducing potential for relapse.

Competing Interests: Conflict of interest D.L.B. discloses the following relationships—Advisory Board: AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Stasys; Board of Directors: AngioWave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Consultant: Broadview Ventures; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and US national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Takeda. All other authors declare that there is no conflict of interest relevant to this work.

During a disease survey in October 2019, leaf spot symptoms with a yellow halo were observed on Korean angelica ( Anglica gigas ) plants grown in fields in Pyeongchang, Gangwon Province, Korea. Incidence of diseased leaves of the plants in the investigated fields ranged from 10% to 60%. Morphological and cultural characteristics of two single-spore isolates from the leaf lesions indicated that they belonged to the genus Didymella. Molecular phylogenetic analyses using combined sequences of LSU, ITS, TUB2 , and RPB2 regions showed distinct clustering of the isolates from other Didymella species. In addition, the morphological and cultural characteristics of the isolates were somewhat different from those of closely related Didymella spp. Therefore, the novelty of the isolates was proved based on the investigations. Pathogenicity of the novel Didymella species isolates was confirmed on leaves of Korean angelica plants via artificial inoculation. This study reveals that Didymella gigantis sp. nov. causes leaf spot in Korean angelica., Competing Interests: No potential conflict of interest was reported by the authors., (© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of the Korean Society of Mycology.)

Background: There is limited evidence regarding the association between muscle strength and metabolic dysfunction-associated fatty liver disease (MAFLD)., Aim: To investigate the association between muscle strength and MAFLD in the general population in Korea., Methods: This nationwide representative cross-sectional study included 31649 individuals aged ≥ 19 years who participated in the Korea National Health and Nutrition Examination Survey between 2015 and 2018. Odds ratios (ORs) and 95% confidence intervals (95%CIs) for MAFLD according to sex-specific quartiles of muscle strength, defined by relative handgrip strength, were calculated using multivariable logistic regression analysis. Additionally, multivariable logistic regression analysis was used to assess the association between muscle strength and probable liver fibrosis in patients with MAFLD., Results: Of all the participants, 29.3% had MAFLD. The prevalence of MAFLD was significantly higher in the lower muscle strength quartile groups for all participants, sexes, and age groups ( P < 0.001). A 1.92-fold (OR = 1.92, 95%CI: 1.70-2.16) and 3.12-fold (OR = 3.12, 95%CI: 2.64-3.69) higher risk of MAFLD was observed in the lowest quartile (Q1) group than in the other groups (Q2-Q4) and the highest quartile (Q4) group, respectively. The ORs of MAFLD were significantly increased in the lower muscle strength quartile groups in a dose-dependent manner ( P for trend < 0.001). These associations persisted in both sexes. An inverse association between muscle strength and the risk of MAFLD was observed in all subgroups according to age, obesity, and diabetes mellitus. In patients with MAFLD, the odds of severe liver fibrosis were higher in Q1 (OR = 1.83, 95%CI: 1.25-2.69) than in other groups (Q2-Q4)., Conclusion: Among Korean adults, low muscle strength was associated with an increased risk of MAFLD and liver fibrosis in patients with MAFLD., Competing Interests: Conflict-of-interest statement: The authors disclose no conflicts., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Mortality from cardiovascular diseases in Asian populations is considerable. Menopause is a risk-enhancing factor for cardiovascular disease, but it is unclear whether menopause is an independent risk factor for cardiovascular disease and mortality in Asian women., Methods and Results: A total of 1 159 405 postmenopausal women, who had participated in the health examinations of the Korean National Health Insurance Service in 2009, were analyzed, and their reproductive histories were taken. A multivariable Cox proportional hazard model assessed the hazard ratios (HRs) of myocardial infarction (MI), ischemic stroke, and all-cause mortality, according to the history of premature menopause and age at menopause. After an average 10-year follow-up, there were 31 606, 45 052, and 77 680 new cases of MI, ischemic stroke, and all-cause mortality, respectively. The women with premature menopause exhibited increased risks of MI (HR, 1.40 [95% CI, 1.31-1.50]), ischemic stroke (HR, 1.24 [95% CI, 1.17-1.31]), and all-cause mortality (HR, 1.19 [95% CI, 1.14-1.24]) when compared with women with menopause aged ≥50 years. The highest risk was evident with menopause between the ages of 30 and 34 years (HR for MI, 1.52 [95% CI, 1.30-1.78]; HR for ischemic stroke, 1.29 [95% CI, 1.12-1.48]; HR for all-cause mortality, 1.33 [95% CI, 1.20-1.47]) when compared with women with menopause aged ≥50 years., Conclusions: Earlier age at menopause was associated with increased risks for MI, ischemic stroke, and all-cause mortality. Future guidelines and risk assessment tools should consider menopause as an independent risk factor of cardiovascular disease in Korean women.

Background: Total joint arthroplasty (TJA) has significantly improved the quality of life for millions suffering from end-stage arthritis. However, periprosthetic joint infections (PJI) remain a serious complication, necessitating extensive interventions and prolonged antimicrobial treatments. The aging population is expected to lead to a rise in TJA cases, subsequently increasing the incidence of PJI, particularly in the elderly who face higher mortality rates. Current diagnostic methods for suspected PJI, such as radiographs and biochemical markers like CRP and ESR, exhibit limited sensitivity. Therefore, there is a critical need for a specific synovial fluid biomarker assay to enhance PJI diagnosis using specific SF-based assay., Results: This study introduces a novel microfluidic chip with a paper-based aptamer-sandwich assay for the quantitative detection of HNP 1, a crucial PJI biomarker, in synovial fluid. The assay leverages the advantages of aptamers over antibodies, demonstrating high selectivity and affinity for target molecules. The integration of a nitrocellulose (NC) membrane onto the microfluidic platform represents a significant advancement, reducing background signals and simplifying the assay procedure without intricate procedure and pre-treatment. The NC membrane-based microfluidic device offers rapid, cost-effective, and highly sensitive detection of HNP 1, with a limit of detection of 0.5 mg L -1 . The microfluidic device demonstrates exceptional performance, detecting up to four clinical samples in approximately 42 min on a single chip with 100 % accuracy, as confirmed by analysis of 12 clinical samples and comparison with "gold-standard". Moreover, the assay exhibits a wide dynamic range of 0.5-100 mg L-1, underscoring its potential as a powerful tool for PJI diagnosis in clinical settings., Significance: This work introduces a paper-based microfluidic system tailored for rapid HNP 1 detection using synovial fluid near joint region (and not serum via blood) for better diagnosis. The innovative paper-based aptamer-sandwich assay yields results within 42-min. Significantly, it boasts a wide dynamic range, detecting levels from an impressive 0.5 mg L-1, crucial in the 2.6 mg L-1 threshold region. This heightened sensitivity and expansive detection capability establish our assay as a leader in PJI diagnostics, promising unmatched precision and efficiency in clinical applications., 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.)

Frequent screening for thyroid cancer has been suggested as a probable explanation for the observed high risk of thyroid cancer in nuclear power plant (NPP) areas. We aimed to compare thyroid cancer screening rates of residents living near NPPs to those of the general population. This study utilized data from two national survey-based studies in 2016 and in 2014, respectively, for residents (n = 1,200) living in administrative districts within 5 km of NPP sites as the interest group, and the general population (n = 228,712) including distant-living residents (n = 19,100) in administrative districts within 30 km of NPP sites as reference groups. We observed an increase in screening rates in residents near NPPs, which may lead to a higher possibility of thyroid cancer detection. Therefore, further epidemiological studies investigating radiation-induced thyroid cancer risk among residents near NPPs should be carefully designed and interpreted considering possible detection bias., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

During disease surveys of Angelica acutiloba plants in Korea, leaf spot symptoms were observed in a field in Andong in July 2019, and stem rot symptoms in vinyl greenhouses in Yangpyeong in April 2020. Incidence of leaf spot and stem rot of the plants ranged from 10 to 20% and 5 to 30%, respectively. Morphological and cultural characteristics of fungal isolates from the leaf spot and stem rot symptoms fitted into those of the genus Phoma . Molecular phylogenetic analyses of two single-spore isolates from the symptoms using concatenated sequences of LSU, ITS, TUB2, and RPB2 genes authenticated an independent cluster from other Didymella (anamorph: Phoma ) species. Moreover, the isolates showed different morphological and cultural characteristics in comparison to closely related Didymella species. These discoveries confirmed the novelty of the isolates. Pathogenicity of the novel Didymella species isolates was substantiated on leaves and stems of A. acutiloba through artificial inoculation. Thus, this study reveals that Didymella acutilobae sp. nov. causes leaf spot and stem rot in Angelica acutiloba., Competing Interests: No potential conflict of interest was reported by the authors., (© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of the Korean Society of Mycology.)

Tryptophan hydroxylase 1 (TPH1) has emerged as a target for the treatment of metabolic diseases including obesity and fatty liver disease. A series of xanthine derivatives were synthesized and evaluated for their TPH1 inhibition. Among the synthesized compounds, compound 40 showed good in vitro activity and liver microsomal stability. Docking studies revealed that compound 40 showed better binding to TPH1 via key intermolecular interactions involving the xanthine scaffold, imidazo-thiazolyl ring, and hydroxyl-containing phenacyl moiety. In addition, compound 40 effectively suppressed the adipocyte differentiation of 3 T3-L1 cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Variants of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) have evolved such that it may be challenging for diagnosis and clinical treatment of the pandemic coronavirus disease-19 (COVID-19). Compared with developed SARS-CoV-2 diagnostic tools recently, aptamers may exhibit some advantages, including high specificity/affinity, longer shelf life (vs. antibodies), and could be easily prepared. Herein an integrated microfluidic system was developed to automatically carry out one novel screening process based on the systematic evolution of ligands by exponential enrichment (SELEX) for screening aptamers specific with SARS-CoV-2. The new screening process started with five rounds of positive selection (with the S1 protein of SARS-CoV-2). In addition, including non-target viruses (influenza A and B), human respiratory tract-related cancer cells (adenocarcinoma human alveolar basal epithelial cells and dysplastic oral keratinocytes), and upper respiratory tract-related infectious bacteria (including methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae), and human saliva were involved to increase the specificity of the screened aptamer during the negative selection. Totally, all 10 rounds could be completed within 20 h. The dissociation constant of the selected aptamer was determined to be 63.0 nM with S1 protein. Limits of detection for Wuhan and Omicron clinical strains were found to be satisfactory for clinical applications (i.e. 4.80 × 10 1 and 1.95 × 10 2 copies/mL, respectively). Moreover, the developed aptamer was verified to be capable of capturing inactivated SARS-CoV-2 viruses, eight SARS-CoV-2 pseudo-viruses, and clinical isolates of SARS-CoV-2 viruses. For high-variable emerging viruses, this developed integrated microfluidic system can be used to rapidly select highly-specific aptamers based on the novel SELEX methods to deal with infectious diseases in the future., 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.)

Adipose tissues are central in controlling metabolic homeostasis and failure in their preservation is associated with age-related metabolic disorders. The exact role of mature adipocytes in this phenomenon remains elusive. Here we describe the role of adipose branched-chain amino acid (BCAA) catabolism in this process. We found that adipocyte-specific Crtc2 knockout protected mice from age-associated metabolic decline. Multiomics analysis revealed that BCAA catabolism was impaired in aged visceral adipose tissues, leading to the activation of mechanistic target of rapamycin complex (mTORC1) signaling and the resultant cellular senescence, which was restored by Crtc2 knockout in adipocytes. Using single-cell RNA sequencing analysis, we found that age-associated decline in adipogenic potential of visceral adipose tissues was reinstated by Crtc2 knockout, via the reduction of BCAA-mTORC1 senescence-associated secretory phenotype axis. Collectively, we propose that perturbation of BCAA catabolism by CRTC2 is critical in instigating age-associated remodeling of adipose tissue and the resultant metabolic decline in vivo., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Aims: Protease-activated receptor 2 (PAR2), a type of G protein-coupled receptor (GPCR), plays a significant role in pathophysiological conditions such as inflammation. A synthetic peptide SLIGRL-NH 2 (SLIGRL) can activate PAR2, while FSLLRY-NH 2 (FSLLRY) is an antagonist. A previous study showed that SLIGRL activates both PAR2 and mas-related G protein-coupled receptor C11 (MrgprC11), a different type of GPCR expressed in sensory neurons. However, the impact of FSLLRY on MrgprC11 and its human ortholog MRGPRX1 was not verified. Hence, the present study aims to verify the effect of FSLLRY on MrgprC11 and MRGPRX1., Methods: The calcium imaging technique was applied to determine the effect of FSLLRY in HEK293T cells expressing MrgprC11/MRGPRX1 or dorsal root ganglia (DRG) neurons. Scratching behavior was also investigated in wild-type and PAR2 knockout mice after injecting FSLLRY., Key Findings: It was surprisingly discovered that FSLLRY specifically activates MrgprC11 in a dose-dependent manner, but not other MRGPR subtypes. Furthermore, FSLLRY also moderately activated MRGPRX1. FSLLRY stimulates downstream pathways including Gα q/11 , phospholipase C, IP 3 receptor, and TRPC ion channels to evoke an increase in the intracellular calcium levels. The molecular docking analysis predicted that FSLLRY interacts with the orthosteric binding pocket of MrgprC11 and MRGPRX1. Finally, FSLLRY activated primary cultures of mouse sensory neurons, and induced scratching behaviors in mice., Significance: The present study has revealed that FSLLRY is capable of triggering itch sensation through activation of MrgprC11. This finding highlights the importance of considering the unexpected activation of MRGPRs in future therapeutic approaches aimed at the inhibition of PAR2., Competing Interests: Declaration of competing interest The authors state no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Lipid accumulation in macrophages is a prominent phenomenon observed in atherosclerosis. Previously, intimal foamy macrophages (FM) showed decreased inflammatory gene expression compared to intimal non-foamy macrophages (NFM). Since reprogramming of lipid metabolism in macrophages affects immunological functions, lipid profiling of intimal macrophages appears to be important for understanding the phenotypic changes of macrophages in atherosclerotic lesions. While lipidomic analysis has been performed in atherosclerotic aortic tissues and cultured macrophages, direct lipid profiling has not been performed in primary aortic macrophages from atherosclerotic aortas. We utilized nanoflow ultrahigh-performance liquid chromatography-tandem mass spectrometry to provide comprehensive lipid profiles of intimal non-foamy and foamy macrophages and adventitial macrophages from Ldlr -/- mouse aortas. We also analyzed the gene expression of each macrophage type related to lipid metabolism. FM showed increased levels of fatty acids, cholesterol esters, phosphatidylcholine, lysophosphatidylcholine, phosphatidylinositol, and sphingomyelin. However, phosphatidylethanolamine, phosphatidic acid, and ceramide levels were decreased in FM compared to those in NFM. Interestingly, FM showed decreased triacylglycerol (TG) levels. Expressions of lipolysis-related genes including Pnpla2 and Lpl were markedly increased but expressions of Lpin2 and Dgat1 related to TG synthesis were decreased in FM. Analysis of transcriptome and lipidome data revealed differences in the regulation of each lipid metabolic pathway in aortic macrophages. These comprehensive lipidomic data could clarify the phenotypes of macrophages in the atherosclerotic aorta., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest., (Copyright © 2023. The Korean Association of Immunologists.)

The diagnosis of periprosthetic joint infection (PJI) remains a labor-intensive and challenging issue, with life-threatening complications associated with misdiagnoses. Superior diagnostic approaches are therefore urgently needed, and synovial biomarkers are gaining substantial attention in this capacity. A new aptamer-based sandwich assay was developed where the aptamer probes specific to one such biomarker, alpha-defensin human neutrophil protein 1 (HNP 1), was integrated herein into a new microfluidic platform. The magnetic beads coated with the primary aptamer probe were able to bind the target protein with high affinity and high specificity in synovial fluid and a fluorescent-labelled secondary aptamer were further used to quantify HNP 1 in a sandwich approach. Up to four clinical samples with low volume (∼50 μL each) in a much faster assay including detection within <60 min with 100% accuracy (with totally 13 clinical samples without the need of sample pretreatment) through the use of the aptamer-based sandwich assay were automatically detected on a single chip. The wide dynamic range of this compact device, 0.5-100 mg/L, highlights its utility for future PJI diagnostics in the clinic., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Post-arthroplasty periprosthetic joint infection (PJI) is a serious ailment that can be difficult to diagnose. Herein, we developed a novel integrated microfluidic system (IMS) capable of detecting two common PJI biomarkers, alpha defensin human neutrophil peptide 1 (HNP-1) and C-reactive protein (CRP), from synovial fluid (SF). A magnetic bead-based one-aptamer-one-antibody assay was carried out automatically within 45 min on a single chip for simultaneous detection of both biomarkers at concentration ranges of 0.01-50 (HNP-1) and 1-100 (CRP) mg/L. It is the first report for utilizing these two biomarkers as targets to establish the new one-aptamer-one-antibody assay to detect PJI on-chip, and the aptamers demonstrated high specificity to their SF targets. As 20 clinical samples were correctly diagnosed with our IMS (verified by a common gold standard kit), it could serve as a promising tool for PJI diagnostics.

Extracorporeal shockwave therapy (ESWT) can induce wound healing by increasing tissue microcirculation. However, studies on the effect of ESWT on enhancing tissue microcirculation in diabetic foot ulcer (DFU), particularly on when the microcirculation increases after ESWT application, are still lacking. Therefore, we aimed to examine the effectiveness of ESWT in promoting microcirculation in DFU patients in a time-dependent manner. We included 50 feet of 25 patients with type 2 diabetes mellitus and Wagner grade I to II DFU in this study. The affected feet were used as the ESWT group and the unaffected contralateral feet were used as the control group. ESWT was performed in 3 sessions per week for a total of 3 weeks. Transcutaneous partial oxygen pressure (TcPO2) was used to evaluate the tissue microcirculation. The TcPO2 level (>43 mm Hg) in the ESWT group was recovered by the 2nd week of treatment, and statistical significance (P < .05) was demonstrated at the same time. From the 2nd week of ESWT, a significant increase in TcPO2 was observed in Wagner grade I and II DFU. These findings imply that the ESWT may improve microcirculation in patients with Wagner grades I to II DFU. However, this impact requires at least 2 weeks or more than 6 sessions. For better comparison, further studies with larger clinical groups and extended period are needed., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Patellofemoral pain syndrome (PFPS) is a common cause of anterior knee pain, and therapeutic exercises are recommended. During the COVID-19 pandemic, despite recommendations on the importance of telerehabilitation, insufficient studies have investigated functional outcomes between supervised rehabilitation and telerehabilitation in patients with PFPS. This study aimed to compare the muscle strength, muscle activation time, and patient-reported outcomes between supervised rehabilitation and telerehabilitation in female patients with PFPS. A total of 61 patients (supervised, n = 30; telerehabilitation, n = 31) participated. Muscle strength and activation time of the quadriceps and hamstrings were measured using an isokinetic device. Hip muscle strength was evaluated using a hand-held dynamometer. Patient-reported outcomes were measured using the visual analog scale (VAS) for pain, Kujala Anterior Knee Pain Scale (AKPS) for functional ability, and Tampa scale for kinesiophobia (TSK-11). No significant differences were found in muscle strength, muscle activation time, or patient-reported outcomes of the involved knees between the two groups ( p > 0.05). In addition, the rate of change in all parameters did not significantly differ between the two groups ( p > 0.05). Telerehabilitation, such as a home-exercise program supervised by physical therapists, may be as effective as supervised rehabilitation in improving functional outcomes in female patients with PFPS.

Five types of odor-emitting exhaust gases from medical waste were selected, and their adsorption capacity and desorption efficiency were investigated using activated carbon. The selected gases included polar gases (hydrogen sulfide (H2S) and ammonia (NH3)) and non-polar gases (acetaldehyde (AA), methyl mercaptan (MM), and trimethylamine (TMA))). Commercial activated carbon with a specific surface area of 2276 m2/g was used as the adsorbent. For the removal of odor from medical waste, we investigated: (1) the effective adsorption capacity of a single gas (<1 ppm), (2) the effect of the adsorbed NH3 gas concentration and flow rate, and (3) the desorption rate using NH3 gas. The values of the effective adsorption capacity of the single gas were in the following order: H2S < NH3 < AA < MM < TMA, at 0.2, 4.2, 6.3, 6.6, and 35.7 mg/g, respectively. The results indicate that polar gases have a lower effective adsorption capacity than that of non-polar gases, and that the size of the gas molecules and effective adsorption capacity exhibit a proportional relationship. The effective adsorption performance of NH3 gas showed an increasing trend with NH3 concentration. Therefore, securing optimal conditions for adsorption/desorption is imperative for the highly efficient removal of odor from medical waste.

Objectives: This study investigated recent trends in the prevalence of obesity among Korean adolescents and explored socioeconomic disparities in obesity., Methods: This study used annual self-reported data on height, weight, and socioeconomic information from the Korea Youth Risk Behavior Web-based Survey from 2006 to 2020. With a 95.8% response rate, the sample consisted of 818,210 adolescents. Obesity prevalence was calculated according to 4 socioeconomic indicators (household income, father's educational attainment, mother's educational attainment, and urbanicity). Socioeconomic inequality was quantified using the relative index of inequality (RII)., Results: The overall prevalence of obesity increased, doubling from 5.9% in 2006 to 11.7% in 2020. Boys and high school students showed a higher prevalence. The RIIs in household income and parental educational attainments significantly increased with time, indicating a growing inequality in obesity. Socioeconomic disadvantages had a greater influence on obesity among girls. The most recent RII values for boys were 1.25 for income, 1.79 for the father's education, and 1.45 for the mother's education, whereas the corresponding values for girls were 2.49, 3.17, and 2.62, respectively., Conclusions: These findings highlight growing inequalities in adolescent obesity according to household income and parental educational attainments, especially for girls and middle schoolers.

Indoor environment quality (IEQ) evaluation can help improve building satisfaction and productivity of residents. However, for more efficient analysis, it is necessary to gain a large amount of data on the differences between specific groups, such as building and resident work types. In this study, we conducted an IEQ evaluation for administrators and researchers, which are occupational groups of a research institute. The evaluation was conducted using quantitative and qualitative methods to find the relationships between IEQ satisfaction and work productivity for each job type. Our results showed that light environment and office layout were correlated with the work productivity of administrators, and light environment, office layout, thermal comfort, and sound environment were correlated with the work productivity of researchers. In addition, there was a significant difference in layout and thermal comfort items between administrators and researchers. Therefore, this study revealed significant differences in the effect of IEQ evaluation on work productivity between different occupations in a research institute.

Quercetin (Qu) is a dietary antioxidant and a member of flavonoids in the plant polyphenol family. Qu has a high ability to scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS) molecules; hence, exhibiting beneficial effects in preventing obesity, diabetes, cancer, cardiovascular diseases, and inflammation. However, quercetin has low bioavailability due to poor water solubility, low absorption, and rapid excretion from the body. To address these issues, the usage of Qu nanosuspensions can improve physical stability, solubility, and pharmacokinetics. Therefore, we developed a Qu and polyethylene glycol nanosuspension (Qu-PEG NS) and confirmed its interaction by Fourier transform infrared analysis. Qu-PEG NS did not show cytotoxicity to HaCaT and RAW 264.7 cells. Furthermore, Qu-PEG NS effectively reduced the nitrogen oxide (NO) production in lipopolysaccharide (LPS)-induced inflammatory RAW 264.7 cells. Additionally, Qu-PEG NS effectively lowered the levels of COX-2, NF-κB p65, and IL-1β in the LPS-induced inflammatory RAW 264.7 cells. Specifically, Qu-PEG NS exhibited anti-inflammatory properties by scavenging the ROS and RNS and mediated the inhibition of NF-κB signaling pathways. In addition, Qu-PEG NS had a high antioxidant effect and antibacterial activity against Escherichia coli and Bacillus cereus . Therefore, the developed novel nanosuspension showed comparable antioxidant, anti-inflammatory, and antibacterial functions and may also improve solubility and physical stability compared to raw quercetin., Competing Interests: The authors declare no conflict of interest.

The properties of wheat dough according to salt level and type of mixer were investigated, and parameters derived from each analysis were comprehensively compared. Mixolab analysis showed that water absorption decreased with salt level while the dough strength increased. In the Mixolab C2 stage, related with thermal strength, C2 temperature and time had stronger correlation with other dough strength parameters than C2 torque. Thickness increase of gluten strand was dominant in the doughs prepared by vertical mixer (VMD) than in those prepared by Mixolab device (MLD), for the same salt level. In large deformation, increase in resistance to extension by salt level was much greater in VMD than in MLD. In small deformation, relationships of salt level with G', G'' and power-law exponent (n) were linear and non-linear in MLD and VMD, respectively. Since MLD could not perfectly reflect VMD, properties of dough should be considered in multiple ways for its comprehensive understanding., Competing Interests: Conflict of interestThe authors declare no conflict of interest., (© The Korean Society of Food Science and Technology 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Rapid, sensitive and accurate diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of great need for effective quarantining and treatment. Real-time reverse-transcription polymerase chain reaction requiring thermocyling has been commonly used for diagnosis of SARS-CoV-2 though it may take two to 4 h before lengthy sample pretreatment process and require bulky apparatus and well-trained personnel. Since multiple reverse transcription loop-mediated isothermal amplification (multiple RT-LAMP) process without thermocycling is sensitive, specific and fast, an electromagnetically-driven microfluidic chip (EMC) was developed herein to lyse SARS-CoV-2 viruses, extract their RNAs, and perform qualitative analysis of three marker genes by on-chip multiple RT-LAMP in an automatic format within 82 min at a limit of detection of only ∼5000 copies per reaction (i.e. 200 virus/ μL). This compact EMC may be especially promising for SARS-CoV-2 diagnostics in resource-limited countries., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Neuromorphic devices have been extensively studied to overcome the limitations of a von Neumann system for artificial intelligence. A synaptic device is one of the most important components in the hardware integration for a neuromorphic system because a number of synaptic devices can be connected to a neuron with compactness as high as possible. Therefore, synaptic devices using silicon-based memory, which are advantageous for a high packing density and mass production due to matured fabrication technologies, have attracted considerable attention. In this study, a segmented transistor devoted to an artificial synapse is proposed for the first time to improve the linearity of the potentiation and depression (P/D). It is a complementary metal oxide semiconductor (CMOS)-compatible device that harnesses both non-ohmic Schottky junctions of the source and drain for improved weight linearity and double-layered nitride for enhanced speed. It shows three distinct and unique segments in drain current-gate voltage transfer characteristics induced by Schottky junctions. In addition, the different stoichiometries of Si x N y for a double-layered nitride is utilized as a charge trap layer for boosting the operation speed. This work can bring the industry potentially one step closer to realizing the mass production of hardware-based synaptic devices in the future.

With recent rapid increases in Cu resistivity, RC delay has become an important issue again. Co, which has a low electron mean free path, is being studied as beyond Cu metal and is expected to minimize this increase in resistivity. However, extrinsic time-dependent dielectric breakdown has been reported for Co interconnects. Therefore, it is necessary to apply a diffusion barrier, such as the Ta/TaN system, to increase interconnect lifetimes. In addition, an ultrathin diffusion barrier should be formed to occupy as little area as possible. This study provides a thermodynamic design for a self-forming barrier that provides reliability with Co interconnects. Since Cr, Mn, Sn, and Zn dopants exhibited surface diffusion or interfacial stable phases, the model constituted an effective alloy design. In the Co-Cr alloy, Cr diffused into the dielectric interface and reacted with oxygen to provide a self-forming diffusion barrier comprising Cr 2 O 3 . In a breakdown voltage test, the Co-Cr alloy showed a breakdown voltage more than 200% higher than that of pure Co. The 1.2 nm ultrathin Cr 2 O 3 self-forming barrier will replace the current bilayer barrier system and contribute greatly to lowering the RC delay. It will realize high-performance Co interconnects with robust reliability in the future., (© 2022. The Author(s).)

In the context of an ageing population, the burden of disease and medicine use is also expected to increase. As such, medicine safety and preventing avoidable medicine-related harm are major public health concerns, requiring further research. Potentially suboptimal medicine regimens is an umbrella term that captures a range of indicators that may increase the risk of medicine-related harm, including polypharmacy, underprescribing and high-risk prescribing, such as prescribing potentially inappropriate medicines. This narrative review aims to provide a background and broad overview of the patterns and implications of potentially suboptimal medicine regimens among older adults. Original research published between 1990 and 2021 was searched for in MEDLINE, using key search terms including polypharmacy, inappropriate prescribing, potentially inappropriate medication lists, medication errors, drug interactions and drug prescriptions, along with manual checking of reference lists. The review summarizes the prevalence, risk factors and clinical outcomes of polypharmacy, underprescribing and potentially inappropriate medicines. A synthesis of the evidence regarding the longitudinal patterns of polypharmacy is also provided. With an overview of the existing literature, we highlight a number of key gaps in the literature. Directions for future research may include a longitudinal investigation into the risk factors and outcomes of extended polypharmacy, research focusing on the patterns and implications of underprescribing and studies that evaluate the applicability of tools measuring potentially inappropriate medicines to study settings., Plain Language Summary: A review on potentially inappropriate medicine regimens Medicine use in older age is common. Older adults with more than one chronic condition are likely to use multiple medicines to manage their health. However, there are times when taking multiple medicines may be unsafe and the number of medicines, or the combination of medicines used, may increase the risk of poor health outcomes. The term medicine regimens is used to describe all the medicines an individual takes. There are several ways to measure when a medicine regimen may be inappropriate and, therefore, potentially harmful. Much research has been published looking into potentially inappropriate medicine regimens. To bring together the current research, this review provides a background on the different measures of potentially inappropriate medicine regimens. It also summarizes how many people may experience potentially inappropriate medicine regimens, the impact it is having on their health and who may be at greater risk. In doing so, we found a number of gaps in the existing evidence, indicating that our understanding of potentially inappropriate medicine regimens is incomplete. This review highlights gaps in knowledge that can be addressed by future research. With an improved understanding of potentially inappropriate medicine regimens, we may be able to better identify those at greater risk to prevent or minimize the impact of poorer health outcomes related to unsafe medicine use., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Prof. Christopher Etherton-Beer is an Editorial Board member of Therapeutic Advances in Drug Safety., (© The Author(s), 2022.)

Background: This study aimed to evaluate the association of hypertension with incident infective endocarditis (IE) by investigating the incidence of IE according to blood pressure levels using the National Health Insurance Service database., Methods: The data of 4 080 331 individuals linked to the health screening database in 2009 were retrieved (males, 55.08%; mean age, 47.12±14.13 years). From 2009 to 2018, the risk factors for the first episode of IE were investigated. Hypertension was categorized into normotension, prehypertension, hypertension, and hypertension with medication. The Cox proportional hazard model assessed the effect of blood pressure level during the health screening exam on incident IE., Results: During the 9-year follow-up, 812 (0.02%) participants were diagnosed with IE. The incidence rates of IE in the normotension, prehypertension, hypertension, and hypertension with medication groups were 0.9, 1.4, 2.6, and 6.0 per 100 000 person-years, respectively. Those with prehypertension, hypertension, and hypertension with medication were correlated with an increased risk of IE in a dose-response manner compared with the normotension group (hazard ratio, 1.33 [95% CI, 1.06-1.68]; hazard ratio, 1.98 [1.48-2.66]; hazard ratio, 2.56 [2.02-3.24], respectively, all P <0.001)., Conclusions: In a large national cohort study with an average follow-up of 9 years, increased blood pressure was identified as a risk factor for incident IE in a dose-dependent manner. Hypertension increases the public health care burden by acting as a risk factor for rare infective heart diseases.

Extracellular vesicles (EVs) are cell-derived membrane-bound particles, including exosomes and microvesicles that differ in cellular origin, content, and lipid composition. This study reports that exosomes and microvesicles can be simultaneously separated by size using flow field-flow fractionation (FlFFF) employed with field programming and that the detection of low-concentration EV species can be significantly improved using multiangle light scattering (MALS). The efficiency of ultracentrifugation (UC) and ultrafiltration (UF) in isolating EVs from the culture media of DU145 cells was compared, and the results showed that UF retrieves more EVs than UC. Two size fractions (small and large) of both exosomes and microvesicles were collected during the FlFFF runs and examined using Western blotting to confirm each EV, and transmission electron microscopy was performed for size analysis. Sizes were compared using the root-mean-square radius obtained from the MALS calculation. The collected fractions were further examined using nanoflow ultrahigh-performance liquid chromatography-electrospray ionization-tandem mass spectrometry for the size-dependent lipidomic profiles of exosomes and microvesicles, showing that lipids were more enriched in the fraction containing large exosomes than in that containing small exosomes; however, an opposite trend was observed with microvesicles. The present study demonstrated that UF followed by FlFFF-MALS can be utilized for the size separation of exosomes and microvesicles without sequential centrifugation, which is useful for monitoring the changes in the size distribution of EVs depending on the biological status along with generating size-dependent lipidomic profiles.

An integrated microfluidic platform (IMP) utilizing real-time reverse-transcription loop-mediated isothermal amplification (RT-LAMP) was developed here for detection and quantification of three genes of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; i.e., coronavirus diseases 2019 (COVID-19)): RNA-dependent RNA polymerase, the envelope gene, and the nucleocapsid gene for molecular diagnosis. The IMP comprised a microfluidic chip, a temperature control module, a fluidic control module that collectively carried out viral lysis, RNA extraction, RT-LAMP, and the real-time detection within 90 min in an automatic format. A limit of detection of 5 × 10 3 copies/reaction for each gene was determined with three samples including synthesized RNAs, inactive viruses, and RNAs extracted from clinical samples; this compact platform could be a useful tool for COVID-19 diagnostics., Competing Interests: There is no conflict of interests for this article., (© 2022 Elsevier B.V. All rights reserved.)

Ovarian cancer (OvCa) is among the most severe gynecologic cancers, yet individuals may be asymptomatic during its early stages. Routine, early screening for genetic abnormalities associated with OvCa could improve prognoses, and this can be achieved by detecting mutant genes in cell-free DNA (cfDNA). Herein, we developed an integrated microfluidic chip (IMC) that could extract cfDNA from plasma and automatically detect and quantify mutations in the OvCa biomarker BRCA 1. The cfDNA extraction module relied on a vortex-type micromixer to mix cfDNA with magnetic beads surface-coated with cfDNA probes and could isolate 76% of molecules from a 200 μL plasma sample in 45 min. The cfDNA quantification module, which comprised a micropump that evenly distributed 4.5 μL of purified cfDNA into the on-chip, allele-specific quantitative polymerase chain reaction (qPCR) zones, was capable of quantifying mutant genes within 90 min. By automating the cfDNA extraction and qPCR processes, this IMC could be used for clinical screening for OvCa-associated mutations.

Fatty liver index (FLI) is a simple and useful index that evaluates non-alcoholic fatty liver disease (NAFLD), particularly in large epidemiologic studies. Heart failure (HF) is becoming a burden to public health as the global trend toward an aging society continues. Thus, we investigated the effect of FLI on the incidence of HF using large cohort data from the Korean National Health Insurance health database. Methods and Results: A total of 7,958,538 subjects aged over 19 years without baseline HF (men = 4,142,264 and women = 3,816,274) were included. Anthropometric and biochemical measurements were evaluated. FLI scores were calculated and FLI ≥ 60 was considered as having NAFLD. Hazard ratios (HRs) and 95% confidence intervals (CIs) for HF incidence were analysed using multivariable time-dependent Cox proportional hazard models. During a mean follow up of 8.26 years, 17,104 participants developed HF. The FLI components associated with the incidence of HF and FLI showed a causal relationship with HF; the FLI ≥ 60 group had a higher HR for HF (HR 1.493; 95% CIs 1.41−1.581) than the FLI < 30 group. Subgroup analysis showed that fatty liver (FLI ≥ 60) with age ≥ 65 years or women displayed higher HR for HF than fatty liver with age < 65 or men, respectively. An increase in FLI score significantly increased the HR for HF except for those with a FLI score change from <30 to 30−60. Conclusion: NAFLD defined by FLI and increase in FLI score were associated with the incidence of HF. Further detailed prospective studies are needed.

Graduate and continuing medical education programs have transitioned to a competency-based medical education model, in which abilities necessary for the practice of medicine, called competencies, are defined as learning outcomes. Each competency contains milestones that describe stages of development from novice to master and provide criteria for assessing learners along this continuum. Assessments in competency-based medical education are formative and are intended to assist learners in achieving the next stage in mastery rather than render a final evaluation. Although written examinations are typically used to evaluate learners, assessments measuring the performance of skills, such as direct observation or patient registries, provide stronger evidence of achievement of learning outcomes. Once assessments identify strengths and areas of improvement in a learner, effective feedback is critical in assisting their professional development. Feedback should be routine, timely, nonthreatening, specific, and encourage self-assessment. The "ask-tell-ask" feedback method follows this framework by asking for the learner's self-assessment first, telling the observer's own assessment next, and then finally asking for the learner's questions and action plan to address the issues raised. Effective assessment and feedback in competency-based medical education assists learners in their continued professional development and aims to provide evidence of their impact on the health status of patients and communities., (Published by Elsevier Inc.)

Background: We recently analyzed the joint capsule adjacent to the medial meniscus and found that the perimeniscal joint capsule has collagen fiber orientation similar to that of circumferential meniscal fibers, potentially playing a role in preventing extrusion., Purpose: To analyze the meniscal extrusion prevention potential of the circumferential rim augmentation suture around the perimeniscal capsule in a rabbit root tear model and analyze the biomechanical function in a porcine cadaveric knee., Study Design: Controlled laboratory study., Methods: Rabbit medial meniscus root tear models were divided into 3 experimental groups: root tear, root tear and suture repair, and root tear and circumferential rim augmentation suture. As for the circumferential rim augmentation suture procedure, a suture was placed to circumscribe the outer rim of the medial meniscus and passed through bone tunnels located at the tibial insertion of each root. After 4 and 8 weeks, meniscal extrusion was analyzed by micro-computed tomography, gross morphology, and histologic analysis of the medial femoral cartilage. For biomechanical analysis, porcine knees were divided into groups similar to rabbit experiments. Tibiofemoral contact parameters were assessed using a pressure mapping sensor system after applying a load of 200 N on the knee joint., Results: The root tear and circumferential rim augmentation suture group showed less meniscal extrusion, less gap within the tear site, and less cartilage degeneration compared with other groups after 4 and 8 weeks of surgery in the rabbit root tear model. Biomechanical analysis showed the root tear and circumferential rim augmentation suture group had larger contact area and lower peak contact pressure compared with root tear and root tear and suture repair groups., Conclusion: The circumferential rim augmentation suture reduced the degree of meniscal extrusion while restoring meniscal function, potentially preventing progression of arthritis in a rabbit root tear model and porcine knee biomechanical analysis., Clinical Relevance: The circumferential rim augmentation suture may be a novel augmentation option during root tear treatment.

Saliva is a readily accessible and clinically useful biofluid that can be used to develop disease biomarkers because of a variety of biologically active molecules in it that are also found in blood. However, even though saliva sampling is simple and non-invasive, few studies have investigated the use of salivary lipids as biomarkers, and the extraction of lipids from saliva needs to be examined thoroughly. In the present study, methods (i.e., saliva sample volume, 0.1-1.0 mL) for the extraction and analysis of salivary lipids by nanoflow ultrahigh performance liquid chromatography-tandem mass spectrometry (nUHPLC-ESI-MS/MS) were evaluated according to the matrix effect, extraction recovery, and number of quantifiable lipids. A total of 780 lipids were identified in a pooled saliva sample from 20 healthy volunteers, and 372 lipids without differentiating acyl chain structures were quantified, along with comprehensive information on salivary lipid composition and individual lipid levels. Even though extraction recovery was maintained at saliva sample volumes as low as 0.2 mL, the matrix effect and limit of detection (LOD) were relatively large with 1.0 mL. Considering the matrix effect, LOD, and number of quantifiable lipids (>limit of quantitation), the minimum volume of saliva sufficient for lipidomic analysis using nUHPLC-ESI-MS/MS was determined to be 0.5 mL., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)