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Background: While Reddy proposed the H2FPEF diagnostic algorithm to aid in diagnosing heart failure with preserved ejection fraction (HFpEF), certain parameters like age and obesity are not suitable for Asian population, especially given the increasing incidence of HFpEF in younger individuals. Therefore, this study aimed to develop an easy-to-use nomogram with non-invasive indices that can be used in outpatient clinics in Taiwan to quickly estimate the probability of HFpEF and help decide whether further invasive cardiopulmonary exercise test (CPET) is needed., Methods: Outpatients with unexplained dyspnea and fatigue were recruited divided into HFpEF (n = 64) and non-HFpEF (n = 34) groups based on invasive CPET and echocardiography. Multivariate logistic regression analyses identified independent noninvasive variables for developing an HFpEF nomogram. The nomogram's performance was assessed and validated using the concordance index (C-index), area under the curve (AUC), calibration curves, and decision curve analysis., Results: Multivariate logistic regression analyses identified five independent noninvasive variables for developing an HFpEF nomogram, including dyslipidemia (OR = 5.264, p = 0.010), diabetes (OR = 3.929, p = 0.050), left atrial area (OR = 1.130, p = 0.046), hemoglobin <13 g/dL (OR = 5.372, p = 0.010), and NT-proBNP ≥245 pg/mL (OR = 5.108, p = 0.027). The nomogram showed good discriminatory ability (C-index = 0.842) and calibration performance (p = 0.873) and high net benefit (0.1-0.95). Notably, the HFpEF nomogram showed better diagnostic accuracy than the H 2 FPEF score model in predicting Taiwanese HFpEF patients (AUC: 0.873 vs. 0.608, p = 0.0006)., Conclusion: The noninvasive HFpEF nomogram provides a preliminary estimation of the probability of HFpEF in Taiwanese outpatients with unexplained dyspnea and fatigue, which may help the decision-making on further invasive CPET., Competing Interests: Declaration of Competing interest All authors declare that there is no conflict of interest., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background/objective: Orbital diseases often require precise measurements of eyeball volume, optic nerve sheath diameter (ONSD), and apex-to-eyeball distance (AED) for accurate diagnosis and treatment planning. This study aims to automate and optimize these measurements using advanced deep learning segmentation techniques on orbital Computed Tomography (CT) scans., Methods: Orbital CT datasets from individuals of various age groups and genders were used, with annotated masks for the eyeball and optic nerve. A 2D attention U-Net architecture was employed for segmentation, enhanced with slice-level information embeddings to improve contextual understanding. After segmentation, the relevant metrics were calculated from the segmented structures and evaluated for clinical applicability., Results: The segmentation model demonstrated varying performance across orbital structures, achieving a Dice score of 0.8466 for the eyeball and 0.6387 for the optic nerve. Consequently, eyeball-related metrics, such as eyeball volume, exhibited high accuracy, with a root mean square error (RMSE) of 1.28-1.90 cm 3 and a mean absolute percentage error (MAPE) of 12-21% across different genders and age groups. In contrast, the lower accuracy of optic nerve segmentation led to less reliable measurements of optic nerve sheath diameter (ONSD) and apex-to-eyeball distance (AED). Additionally, the study analyzed the automatically calculated measurements from various perspectives, revealing key insights and areas for improvement., Conclusions: Despite these challenges, the study highlights the potential of deep learning-based segmentation to automate the assessment of ocular structures, particularly in measuring eyeball volume, while leaving room for further improvement in optic nerve analysis.

The IL-23-Th17 axis is responsible for neutrophilic inflammation in various inflammatory diseases. Here, we discover a potential pathway to inhibit neutrophilic asthma. In our neutrophil-dominant asthma (NDA) model, single-cell RNA-seq analysis identifies a subpopulation of CD39 + CD9 + interstitial macrophages (IMs) suppressed by IL-23 in NDA conditions but increased by an IL-23 inhibitor αIL-23p19. Adoptively transferred CD39 + CD9 + IMs suppress neutrophil extracellular trap formation (NETosis), a representative phenotype of NDA, and also Th17 cell activation and neutrophilic inflammation. CD39 + CD9 + IMs first attach to neutrophils in a CD9-dependent manner, and then remove ATP near neutrophils that contribute to NETosis in a CD39-dependent manner. Transcriptomic data from asthmatic patients finally show decreased CD39 + CD9 + IMs in severe asthma than mild/moderate asthma. Our results suggest that CD39 + CD9 + IMs function as a potent negative regulator of neutrophilic inflammation by suppressing NETosis in the IL-23-Th17 axis and can thus serve as a potential therapeutic target for IL-23-Th17-mediated neutrophilic asthma., (© 2024. The Author(s).)

Background: Orbital apex syndrome (OAS) is a condition characterised by lesions within the orbital apex, leading to various ophthalmologic symptoms. This study aimed to analyse the clinical characteristics and treatment strategies of OAS with respect to aetiology., Methods: This retrospective analysis utilised data from 5 medical institutions between 2013 and 2022. Patients who were diagnosed with OAS were initially enrolled, but patients who failed to follow up at least 1 month were excluded. The prevalence of initial ophthalmologic symptoms and visual improvement after treatment was compared according to aetiology. Factors related to visual improvement were analysed., Results: Among 73 enrolled patients, the leading aetiology was tumours, followed by fungal infections and inflammation. Visual impairment and proptosis were prevalent in tumour-related OAS cases. Inflammation-related OAS exhibited a higher likelihood of painful eye movements and ophthalmoplegia. Ptosis was most frequently observed in fungal infection-related OAS. Notably, fungal infections emerged as the sole significant factor negatively impacting vision progression. In inflammation-related OAS, the time interval between symptom onset and the administration of steroids was longer in patients without visual improvement, even though there was no statistically significant difference., Conclusions: Tumours were the predominant cause of OAS. Visual impairment was a common manifestation in tumour-related OAS, while fungal infections were strongly associated with a poor visual prognosis. The timely administration of steroids might be helpful for improving vision in patients with inflammation-related OAS. However, further studies are needed to enhance understanding and management of OAS.

Introduction: Angiotensin receptor blockers are widely used antihypertensive drugs in South Korea. In 2021, the Korea Ministry of Food and Drug Safety acknowledged the need for national compensation for a drug-induced liver injury (DILI) after azilsartan use. However, little is known regarding the association between angiotensin receptor blockers and DILI., Objective: We conducted a retrospective cohort study in incident users of angiotensin receptor blockers from a common data model database (1 January, 2017-31 December, 2021) to compare the risk of DILI among specific angiotensin receptor blockers against valsartan., Methods: Patients were assigned to treatment groups at cohort entry based on prescribed angiotensin receptor blockers. Drug-induced liver injury was operationally defined using the International DILI Expert Working Group criteria. Cox regression analyses were conducted to derive hazard ratios and the inverse probability of treatment weighting method was applied. All analyses were performed using R., Results: In total, 229,881 angiotensin receptor blocker users from 20 university hospitals were included. Crude DILI incidence ranged from 15.6 to 82.8 per 1000 person-years in treatment groups, most were cholestatic and of mild severity. Overall, the risk of DILI was significantly lower in olmesartan users than in valsartan users (hazard ratio: 0.73 [95% confidence interval 0.55-0.96]). In monotherapy patients, the risk was significantly higher in azilsartan users than in valsartan users (hazard ratio: 6.55 [95% confidence interval 5.28-8.12])., Conclusions: We found a significantly higher risk of suspected DILI in patients receiving azilsartan monotherapy compared with valsartan monotherapy. Our findings emphasize the utility of real-world evidence in advancing our understanding of adverse drug reactions in clinical practice., (© 2024. The Author(s).)

Respiratory viral infection increases host susceptibility to secondary bacterial infections, yet the precise dynamics within airway epithelia remain elusive. Here, we elucidate the pivotal role of CD47 in the airway epithelium during bacterial super-infection. We demonstrated that upon influenza virus infection, CD47 expression was upregulated and localized on the apical surface of ciliated cells within primary human nasal or bronchial epithelial cells. This induced CD47 exposure provided attachment sites for Staphylococcus aureus, thereby compromising the epithelial barrier integrity. Through bacterial adhesion assays and in vitro pull-down assays, we identified fibronectin-binding proteins (FnBP) of S. aureus as a key component that binds to CD47. Furthermore, we found that ciliated cell-specific CD47 deficiency or neutralizing antibody-mediated CD47 inactivation enhanced in vivo survival rates. These findings suggest that interfering with the interaction between airway epithelial CD47 and pathogenic bacterial FnBP holds promise for alleviating the adverse effects of super-infection., (© 2024. The Author(s).)

Although early life colonization of commensal microbes contributes to long-lasting immune imprinting in host tissues, little is known regarding the pathophysiological consequences of postnatal microbial tuning of cutaneous immunity. Here, we show that postnatal exposure to specific skin commensal Staphylococcus lentus (S. lentus) promotes the extent of atopic dermatitis (AD)-like inflammation in adults through priming of group 2 innate lymphoid cells (ILC2s). Early postnatal skin is dynamically populated by discrete subset of primed ILC2s driven by microbiota-dependent induction of thymic stromal lymphopoietin (TSLP) in keratinocytes. Specifically, the indole-3-aldehyde-producing tryptophan metabolic pathway, shared across Staphylococcus species, is involved in TSLP-mediated ILC2 priming. Furthermore, we demonstrate a critical contribution of the early postnatal S. lentus-TSLP-ILC2 priming axis in facilitating AD-like inflammation that is not replicated by later microbial exposure. Thus, our findings highlight the fundamental role of time-dependent neonatal microbial-skin crosstalk in shaping the threshold of innate type 2 immunity co-opted in adulthood., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Pulmonary hypertension (PH) is highly prevalent in patients with heart failure with preserved ejection fraction (HFpEF), and it is a strong predictor of adverse outcomes. We aimed to determine possible echocardiographic parameters to predict the presence of PH in patients with HFpEF., Methods and Results: A total of 113 patients with HFpEF were prospectively enrolled from November 2017 to July 2022. The patients underwent invasive cardiac catheterization and simultaneous echocardiography at rest and during exercise. The parameters indicating right ventricle-pulmonary artery uncoupling, including tricuspid annular plane systolic excursion (TAPSE)/pulmonary artery systolic pressure (PASP) and tricuspid annular systolic velocity (TAS')/PASP were calculated. Receiver operating characteristic curve analysis was used to determine the optimal cut-off points of TAPSE/PASP and TAS'/PASP to differentiate patients with HFpEF with PH from those without PH. Sixty-eight patients with HFpEF with PH and 45 without PH were included. Those with PH had lower TAPSE/PASP and TAS'/PASP at rest and during exercise compared with those without PH. Both resting/stress TAPSE/PASP and TAS'/PASP were correlated with rest/exercise pulmonary capillary wedge pressure and mean pulmonary artery pressure. In multivariable regression analysis, TAPSE/PASP remained a significant predictor of exercise pulmonary capillary wedge pressure and mean pulmonary artery pressure. In receiver operating characteristic curve analysis, the optimal cut-off points of TAPSE/PASP and TAS'/PASP to differentiate patients with HFpEF with PH from those without PH were ≤0.62 and ≤0.47, respectively., Conclusions: Right ventricle-pulmonary artery uncoupling is closely correlated with abnormal rest/exercise hemodynamics (pulmonary capillary wedge pressure and mean pulmonary artery pressure) in patients with HFpEF. TAPSE/PASP and TAS'/PASP can be useful parameters to detect PH in patients with HFpEF.

Purpose: Quetiapine is a drug used to treat schizophrenia, bipolar disorder, and major depressive disorder. However, it can cause mild or severe hepatic adverse events and rarely fatal liver damage. This study was aimed at investigating hepatic toxicity caused by quetiapine use by analyzing the information captured from hospital electronic health records by using the Observational Medical Outcomes Partnership common data model (CDM)., Methods: This was a retrospective observational study involving a nested case-control method. A CDM based on an electronic health record database from five hospitals between January 2009 and May 2020 was used. We analyzed the status of quetiapine use, adverse events, and hepatic impairment., Results: The numbers of patients with non-serious and severe hepatic adverse reactions were 2566 (5.05%) and 835 (1.64%) out of 50 766 patients, respectively. After adjusting for covariates, the odds ratio of hepatic adverse events was 2.35 (95% CI: 2.03-2.72), and the odds ratio of severe hepatic adverse events was 1.76 (95% CI: 1.16-2.66)., Conclusion: Our findings suggest that quetiapine should be cautiously used, and hepatic function should be monitored in patients using quetiapine because it can cause mild or severe hepatic adverse events, complications, and in rare cases, fatal liver damage., (© 2023 John Wiley & Sons Ltd.)

When the lungs are infected with bacteria, alveolar macrophages (AMs) are recruited to the site and play a crucial role in protecting the host by reducing excessive lung inflammation. However, the regulatory mechanisms that trigger the recruitment of AMs to lung alveoli during an infection are still not fully understood. In this study, we identified a critical role for NADPH oxidase 4 (NOX4) in the recruitment of AMs during Staphylococcus aureus lung infection. We found that NOX4 knockout (KO) mice showed decreased recruitment of AMs and increased lung neutrophils and injury in response to S. aureus infection compared to wild-type (WT) mice. Interestingly, the burden of S. aureus in the lungs was not different between NOX4 KO and WT mice. Furthermore, we observed that depletion of AMs in WT mice during S. aureus infection increased the number of neutrophils and lung injury to a similar level as that observed in NOX4 KO mice. Additionally, we found that expression of intercellular adhesion molecule-1 (ICAM1) in NOX4 KO mice-derived lung endothelial cells was lower than that in WT mice-derived endothelial cells. Therefore, we conclude that NOX4 plays a crucial role in inducing the recruitment of AMs by controlling ICAM1 expression in lung endothelial cells, which is responsible for resolving lung inflammation during acute S. aureus infection., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest., (Copyright © 2023. The Korean Association of Immunologists.)

We analyzed whether macular superficial vascular density (SVD) and foveal vascular zone (FAZ) on optical coherence tomography angiography (OCTA) can distinguish between bilateral ametropic and anisometropic amblyopia. We included 42, 33, and 50 eyes in the bilateral ametropic amblyopia, anisometropic amblyopia, and normal control groups, respectively. Using macular swept-source optical coherence tomography angiography, we measured and analyzed the superficial FAZ areas and five sectoral macular SVDs after magnification correction. The anisometropic amblyopic eye group showed significantly increased foveal SVDs (p < 0.001) and significantly decreased superficial FAZ areas (p < 0.001), compared with the remaining groups. Additionally, the bilateral ametropic amblyopia group had significantly decreased nasal SVDs. SVDs and superficial FAZ areas differed among hyperopic amblyopia subtypes. These findings may reflect vascular distribution differences and macular changes in hyperopic amblyopia subtypes compared with normal eyes., (© 2023. Springer Nature Limited.)

Background: Allergic inflammation affects the epithelial cell populations resulting in goblet cell hyperplasia and decreased ciliated cells. Recent advances in single-cell RNA sequencing (scRNAseq) have enabled the identification of new cell subtypes and genomic features of single cells. In this study, we aimed to investigate the effect of allergic inflammation in nasal epithelial cell transcriptomes at the single-cell level., Methods: We performed scRNAseq in cultured primary human nasal epithelial (HNE) cells and in vivo nasal epithelium. The transcriptomic features and epithelial cell subtypes were determined under IL-4 stimulation, and cell-specific marker genes and proteins were identified., Results: We confirmed that cultured HNE cells were similar to in vivo epithelial cells through scRNAseq. Cell-specific marker genes were utilized to cluster the cell subtypes, and FOXJ1 + -ciliated cells were sub-classified into multiciliated and deuterosomal cells. PLK4 and CDC20B were specific for deuterosomal cells, and SNTN, CPASL, and GSTA2 were specific for multiciliated cells. IL-4 altered the proportions of cell subtypes, resulting in a decrease in multiciliated cells and loss of deuterosomal cells. The trajectory analysis revealed deuterosomal cells as precursor cells of multiciliated cells and deuterosomal cells function as a bridge between club and multiciliated cells. A decrease in deuterosomal cell marker genes was observed in nasal tissue samples with type 2 inflammation., Conclusion: The effects of IL-4 appear to be mediated through the loss of the deuterosomal population, resulting in the reduction in multiciliated cells. This study also newly suggests cell-specific markers that might be pivotal for investigating respiratory inflammatory diseases., (© 2023 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Rapid and low-cost diagnosis of coronavirus disease 2019 (COVID-19) is essential to identify infected subjects, particularly asymptomatic cases, primarily to arrest the spread of the disease through local transmission. Antibody-based chromatographic serological tests, as an alternative to the RT-PCR technique, offer only limited help due to high false positives. We propose to exploit our cholesteric liquid crystal biosensor platform for one-step, wash-free, rapid detection of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus directly with minimal sample pre-processing. As mentioned above, cholesteric liquid crystals are an effective and innovative approach to healthcare as a rapid test for the diagnosis of COVID-19 and other diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lin, Chung, Chuang, Wang, Lai, Hsu, Lin and Hsiao.)

We sought to establish an unsupervised algorithm with a three-dimensional (3D) variational autoencoder model (VAE) for the detection of abnormal extraocular muscles in small datasets of orbital computed tomography (CT) images. 334 CT images of normal orbits and 96 of abnormal orbits diagnosed as thyroid eye disease were used for training and validation; 24 normal and 11 abnormal orbits were used for the test. A 3D VAE was developed and trained. All images were preprocessed to emphasize extraocular muscles and to suppress background noise (e.g., high signal intensity from bones). The optimal cut-off value was identified through receiver operating characteristic (ROC) curve analysis. The ability of the model to detect muscles of abnormal size was assessed by visualization. The model achieved a sensitivity of 79.2%, specificity of 72.7%, accuracy of 77.1%, F1-score of 0.667, and AUROC of 0.801. Abnormal CT images correctly identified by the model showed differences in the reconstruction of extraocular muscles. The proposed model showed potential to detect abnormalities in extraocular muscles using a small dataset, similar to the diagnostic approach used by physicians. Unsupervised learning could serve as an alternative detection method for medical imaging studies in which annotation is difficult or impossible to perform., (© 2023. The Author(s).)

Recently, deep learning-based segmentation models have been widely applied in the ophthalmic field. This study presents the complete process of constructing an orbital computed tomography (CT) segmentation model based on U-Net. For supervised learning, a labor-intensive and time-consuming process is required. The method of labeling with super-resolution to efficiently mask the ground truth on orbital CT images is introduced. Also, the volume of interest is cropped as part of the pre-processing of the dataset. Then, after extracting the volumes of interest of the orbital structures, the model for segmenting the key structures of the orbital CT is constructed using U-Net, with sequential 2D slices that are used as inputs and two bi-directional convolutional long-term short memories for conserving the inter-slice correlations. This study primarily focuses on the segmentation of the eyeball, optic nerve, and extraocular muscles. The evaluation of the segmentation reveals the potential application of segmentation to orbital CT images using deep learning methods.

The aim of this paper is to explore the usage and impact of the Internet-of-Things-based Smart Home Technology (IoT-SHT) in Malaysia. Face-to-face interviews were conducted with a total of eleven IoT-SHT users who had a minimum of 2-year usage experience. The semi-structured interview consisted of six questions which were compartmentalised into two sections. Common themes were identified through constant comparison of the inductive data in the coding process. The in-depth interview uncovered six uses of IoT-SHT. Mainly, it was used for real-time remote control, surveillance, sensing, home automation, entertainment, and family communication. It seems clear that the IoT-SHT helped people to save time, changed their lives, improved security, safety, environment condition, fun, convenience, and comfort within the home ground. It also facilitated better health tracking, family care, and energy conservation. Psychologically, the IoT-SHT also enhanced one's image, offered better companionship, and improved the sense of belongingness, and closeness within the family. This study fills the research gap by providing insights into how the IoT-SHT was used, thereby benefiting users in Malaysia. With the arrival of industrial revolution 4.0, a comprehensive knowledge on the usage of IoT is pertinent. The findings of this study may also serve as a foundation for future research in IoT-SHT adoption. Practically, this study accelerates IoT-SHT diffusion by providing insights to vendors in designing better IoT products and services, based on the popular usages and impactful benefits., Supplementary Information: The online version contains supplementary material available at 10.1007/s10209-022-00937-0., Competing Interests: Conflict of interestAll authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript., (© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) 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.)

Purpose: To explore the possibility of using glucagon-like peptide-1 receptor agonist (GLP-1RA) as a new treatment for neuroinflammation, by analyzing retinal pathological changes in an optic nerve crush rat model., Methods: Eight-week-old male Sprague-Dawley rats were divided into lixisenatide (LIX, n = 10), traumatic control (T-CON, n = 10), and normal control (n = 5) groups. The optic nerves of left eyes in the LIX and T-CON groups were crushed in a standardized manner. The LIX group was treated with subcutaneous injections of lixisenatide (200 μg/kg/day) for 5 days. One week after initiating treatment, quantitative polymerase chain reaction, Western blot, and immunohistochemistry analyses were performed on the retinal tissues of each group to identify inflammatory markers., Results: The LIX group showed significantly lower mRNA levels of interleukin 1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), thioredoxin interacting protein (TXNIP), and glial fibrillary acidic protein (GFAP) than the T-CON group. Also, the LIX group exhibited decreased TXNIP and GFAP expression compared with the T-CON group, and similar expression to the normal control group, according to Western blot analysis. Significantly increased immunohistochemistry staining of Brn3a and decreased TUNEL staining were seen in the LIX group compared with the T-CON group, indicating that lixisenatide contributes to retinal ganglion cell survival in cases of acute optic nerve injury., Conclusions: Neuroinflammation was significantly reduced in lixisenatide-treated retinas compared with untreated retinas in our acute optic nerve injury rat model. The neuroprotective effect of lixisenatide indicates that it can serve a new treatment option against clinically intractable traumatic optic neuropathy., Competing Interests: Declaration of competing interest None declared., (Copyright © 2022. Published by Elsevier B.V.)

As an enveloped virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) delivers its viral genome into host cells via fusion of the viral and cell membranes. Here, we show that ANO6/TMEM16F-mediated cell surface exposure of phosphatidylserine is critical for SARS-CoV-2 entry and that ANO6-selective inhibitors are effective against SARS-CoV-2 infections. Application of the SARS-CoV-2 Spike pseudotyped virus (SARS2-PsV) evokes a cytosolic Ca 2+ elevation and ANO6-dependent phosphatidylserine externalization in ACE2/TMPRSS2-positive mammalian cells. A high-throughput screening of drug-like chemical libraries identifies three different structural classes of chemicals showing ANO6 inhibitory effects. Among them, A6-001 displays the highest potency and ANO6 selectivity and it inhibits the single-round infection of SARS2-PsV in ACE2/TMPRSS2-positive HEK 293T cells. More importantly, A6-001 strongly inhibits authentic SARS-CoV-2-induced phosphatidylserine scrambling and SARS-CoV-2 viral replications in Vero, Calu-3, and primarily cultured human nasal epithelial cells. These results provide mechanistic insights into the viral entry process and offer a potential target for pharmacological intervention to protect against coronavirus disease 2019 (COVID-19)., Competing Interests: Declaration of interests M.G.L., J.M.L., and W.N. are inventors on a pending patent related to this work filed by Yonsei University Office of Research Affairs/University Industry Foundation. The authors declare no other competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aim: This study aimed to assess the effects of daily sedation interruption on the mechanical ventilation duration and relevant outcomes in mechanically ventilated patients in the intensive care unit (ICU)., Background: Previously, three meta-analyses on the association of daily sedation interruption with the mechanical ventilation duration have reported conflicting findings, and these did not support current guideline recommendations that daily sedation interruption can be routinely used in mechanically ventilated adult ICU patients., Design: This was a systematic review and meta-analysis of randomized controlled studies., Data Sources: Data were from PubMed, Embase, Cochrane Library, CINAHL, ProQuest dissertation and theses, Airiti Library, China National Knowledge Infrastructure, Wanfang Data Chinese, Science Direct and PsycINFO databases., Review Methods: Two reviewers independently assessed, extracted and appraised the included studies. Then, pooled estimates were calculated using a random-effects model., Results: In total, 45 studies involving 5493 participants were included. Compared with controls, daily sedation interruption significantly reduced the mechanical ventilation duration, ICU stay length, sedation duration, and tracheostomy and ventilator-associated pneumonia risks (all p ≤ 0.001). Moreover, the Acute Physiology and Chronic Health Evaluation II score and study quality were significant moderators., Conclusion: Daily sedation interruption could substantially reduce the duration of mechanical ventilation, particularly when it was applied to patients with high disease severity., (© 2021 John Wiley & Sons Australia, Ltd.)

A novel device for cholesteric liquid crystal (LC; CLC)-based biosensing chips for detecting heme oxygenase (HO)-1 within the cerebrospinal fluid (CSF) was invented. In the CLC device, the reorientation of the LCs was strongly influenced by the alignment layer surface and adjacent LCs. When the substrate was coated with the alignment layer, the CLCs oriented homeotropically in a focal conic state. Once HO-1 was immobilized onto the orientation sheet-coated substrate, the CLC changed from a focal conic state to a bright planar state by disrupting the CLCs. The concentration of HO-1 within CSF was shown to be an effective outcome indicator for patients with a spontaneous subarachnoid hemorrhage. We showed that the CLC immunoassaying can be used to measure HO-1 with a lower detection limit of about 10 ng/mL. The linear range was 10 ng/mL to 1 mg/mL. An easy-to-use, rapid-detection, and label-free CLC immunoassay device is proposed.

A mnemonic-opto-synaptic transistor (MOST) that has triple functions is demonstrated for an in-sensor vision system. It memorizes a photoresponsivity that corresponds to a synaptic weight as a memory cell, senses light as a photodetector, and performs weight updates as a synapse for machine vision with an artificial neural network (ANN). Herein the memory function added to a previous photodetecting device combined with a photodetector and a synapse provides a technical breakthrough for realizing in-sensor processing that is able to perform image sensing and signal processing in a sensor. A charge trap layer (CTL) was intercalated to gate dielectrics of a vertical pillar-shaped transistor for the memory function. Weight memorized in the CTL makes photoresponsivity tunable for real-time multiplication of the image with a memorized photoresponsivity matrix. Therefore, these multi-faceted features can allow in-sensor processing without external memory for the in-sensor vision system. In particular, the in-sensor vision system can enhance speed and energy efficiency compared to a conventional vision system due to the simultaneous preprocessing of massive data at sensor nodes prior to ANN nodes. Recognition of a simple pattern was demonstrated with full sets of the fabricated MOSTs. Furthermore, recognition of complex hand-written digits in the MNIST database was also demonstrated with software simulations., (© 2022. The Author(s).)

Background: Atrial fibrillation (AF) is prevalent in patients with type 2 diabetes mellitus (T2DM). Obesity commonly accompanies T2DM, and increases the risk of AF. However, the dose-relationship between body mass index (BMI) and AF risk has seldom been studied in patients with diabetes., Methods: This cohort study utilized a database from National Taiwan University Hospital, a tertiary medical center in Taiwan. Between 2014 and 2019, 64,339 adult patients with T2DM were enrolled for analysis. BMI was measured and categorized as underweight (BMI < 18.5), normal (18.5 ≤ BMI < 24), overweight (24 ≤ BMI < 27), obesity class 1 (27 ≤ BMI < 30), obesity class 2 (30 ≤ BMI < 35), or obesity class 3 (BMI ≥ 35). Multivariate Cox regression and spline regression models were employed to estimate the relationship between BMI and the risk of AF in patients with T2DM., Results: The incidence of AF was 1.97 per 1000 person-years (median follow-up, 70.7 months). In multivariate Cox regression, using normal BMI as the reference group, underweight (HR 1.52, 95% CI 1.25-1.87, p < 0.001) was associated with a significantly higher risk of AF, while overweight was associated with significantly reduced risk of AF (HR 0.82, 95% CI 0.73-0.89, p < 0.001). Kaplan-Meier analysis showed AF risk was highest in the underweight group, followed by obesity class 3, while the overweight group had the lowest incidence of AF (log-rank test, p < 0.001). The cubic restrictive spline model revealed a "J-shaped" or "L-shaped" relationship between BMI and AF risk., Conclusions: Underweight status confers the highest AF risk in Asian patients with T2DM., (© 2021. The Author(s).)

(1) Background: Empathy affects an individual's decision to participate in volunteering, and volunteering, in turn, influences mental health. Intriguingly, studies have been limited in exploring underlying mechanisms and boundary conditions for the relationship between empathy and mental health. Furthermore, volunteering studies have overlooked the multi-dimensionality of empathy. Therefore, this study seeks to contribute to extant literature by investigating the mediating effect of volunteering for the relationships between cognitive and affective empathy and mental health and the moderating effect of gender for the relationship between empathy and volunteering. (2) Methods; Data were collected using a survey in South Korea and consisted of 301 full-time employees who voluntarily engaged in their corporate volunteer programs. Furthermore, they voluntarily participated in the study. The hypotheses were tested with path analysis and a group comparison was also conducted. (3) Results: Volunteering was found to mediate the relationships between cognitive empathy and affective empathy with mental health. In addition, gender moderated the relationship between empathy and volunteering. (4) Conclusions: As the study found empathy to increase individuals' engaging in volunteering activities which then improved mental health, the study supports extant theoretical frameworks on empathy and volunteering. Moreover, the study found gender differences on empathy and volunteering; thereby supporting and contributing to extant literature.

Allopurinol is the first-line agent for patients with gout, including those with moderate-to-severe chronic kidney disease. However, increased thyroid-stimulating hormone (TSH) levels are observed in patients with long-term allopurinol treatment. This large-scale, nested case-control, retrospective observational study analysed the association between allopurinol use and increased TSH levels. A common data model based on an electronic medical record database of 19,200,973 patients from seven hospitals between January 1997 and September 2020 was used. Individuals aged > 19 years in South Korea with at least one record of a blood TSH test were included. Data of 59,307 cases with TSH levels > 4.5 mIU/L and 236,508 controls matched for sex, age (± 5), and cohort registration date (± 30 days) were analysed. An association between the risk of increased TSH and allopurinol use in participants from five hospitals was observed. A meta-analysis (I 2  = 0) showed that the OR was 1.51 (95% confidence interval: 1.32-1.72) in both the fixed and random effects models. The allopurinol intake group demonstrated that increased TSH did not significantly affect free thyroxine and thyroxine levels. After the index date, some diseases were likely to occur in patients with subclinical hypothyroidism and hypothyroidism. Allopurinol administration may induce subclinical hypothyroidism., (© 2021. The Author(s).)

Development of adjacent segment pathology leading to secondary operation is a matter of concern after anterior cervical discectomy and fusion (ACDF). Some studies have reported anatomic difference between races, but no epidemiological data on prevalence of clinical adjacent segment pathology (cASP) among races or continents has been published. The purpose of this study was to compare the prevalence of cASP that underwent surgery after monosegmental ACDF among continents by meta-analysis. MEDLINE, EMBASE, and Cochrane Library with manual searching in key journals, reference lists, and the National Technical Information Service were searched from inception to December 2018. Twenty studies with a total of 2009 patients were included in the meta-analysis. We extracted the publication details, sample size, and prevalence of cASP that underwent surgery. A total of 15 papers from North America, three from Europe, and two from Asia met the inclusion criteria. A total number of 2009 patients underwent monosegmental ACDF, and 113 patients (5.62%) among them had cASP that underwent surgery. The rate of cASP that underwent surgery was 4.99% in the North America, 3.65% in the Europe, 6.34% in the Asia, and there were no statistically significant differences ( p = 0.63). The current study using the method of meta-analysis revealed that there were no significant differences in the rate of cASP that underwent surgery after ACDF among the continents.

Employees withholding their opinions is pervasive in organizations. However, the individual outcomes of employee silence have not been frequently investigated. Previous studies have found that there are detrimental effects of employee silence and building on this research stream, the study viewed perceived stress as an underlying mechanism linking employee silence to task performance and deviant behavior. Moreover, this study explored the moderating effect of interpersonal trust in the relationship between employee silence and perceived stress. Using a sample of 231 white-collar employees from China, this study found perceived stress to mediate the relationships between employee silence and task performance and deviant behavior. Also, coworker trust was found to moderate the relationship between employee silence and perceived stress. As coworker trust moderated the relationship, supplementary analyses further found mediated moderation for the model.

Magnesium metal and its alloys are being developed as effective orthopedic implants; however, the mechanisms underlying the actions of magnesium on bones remain unclear. Cystic fibrosis, the most common genetic disease in Caucasians caused by the mutation of CFTR, has shown bone disorder as a key clinical manifestation, which currently lacks effective therapeutic options. Here we report that implantation of magnesium-containing implant stimulates bone formation and improves bone fracture healing in CFTR-mutant mice. Wnt/β-catenin signaling in the bone is enhanced by the magnesium implant, and inhibition of Wnt/β-catenin by iCRT14 blocks the magnesium implant to improve fracture healing in CFTR-mutant mice. We further demonstrate that magnesium ion enters osteocytes, increases intracellular cAMP level and activates ATF4, a key transcription factor known to regulate Wnt/β-catenin signaling. In vivo knockdown of ATF4 abolishes the magnesium implant-activated β-catenin in bones and reverses the improved-fracture healing in CFTR-mutant mice. In addition, oral supplementation of magnesium activates ATF4 and β-catenin as well as enhances bone volume and density in CFTR-mutant mice. Together, these results show that magnesium implantation or supplementation may serve as a potential anabolic therapy for cystic fibrosis-related bone disease. Activation of ATF4-dependent Wnt/β-catenin signaling in osteocytes is identified as a previously undefined mechanism underlying the beneficial effect of magnesium on bone formation., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

Intestinal Behçet's disease (BD) and Crohn's disease (CD) present similar manifestations, but there are no specific diagnostic tests to differentiate them. We used a proteomic approach to discover novel diagnostic biomarkers specific to intestinal BD. Colon mucosa tissue samples were obtained from patients with intestinal BD or CD using colonoscopy-guided biopsy of the affected bowel. Peptides from seven intestinal BD and seven CD patients were extracted and labeled using tandem mass tag (TMT) reagents. The labeled peptides were identified and quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The proteins were further validated using immunohistochemical (IHC) analysis with tissue samples and an ELISA test with serum samples from 20 intestinal BD and 20 CD patients. Using TMT/LC-MS/MS-based proteomic quantification, we identified 39 proteins differentially expressed between intestinal BD and CD. Beta-2 glycoprotein 1 (APOH) and maltase-glucoamylase (MGAM) showed higher intensity in the IHC staining of intestinal BD tissues than in CD tissues. The serum MGAM level was higher in intestinal BD patients. Proteomic analysis revealed that some proteins were differentially expressed in patients with intestinal BD compared with those with CD. Differential MGAM expression in intestinal BD suggests its role as a potential novel diagnostic biomarker.

Selenoproteins containing selenium in the form of selenocysteine are critical for bone remodeling. However, their underlying mechanism of action is not fully understood. Herein, we report the identification of selenoprotein W (SELENOW) through large-scale mRNA profiling of receptor activator of nuclear factor (NF)-κΒ ligand (RANKL)-induced osteoclast differentiation, as a protein that is downregulated via RANKL/RANK/tumour necrosis factor receptor-associated factor 6/p38 signaling. RNA-sequencing analysis revealed that SELENOW regulates osteoclastogenic genes. SELENOW overexpression enhances osteoclastogenesis in vitro via nuclear translocation of NF-κB and nuclear factor of activated T-cells cytoplasmic 1 mediated by 14-3-3γ, whereas its deficiency suppresses osteoclast formation. SELENOW-deficient and SELENOW-overexpressing mice exhibit high bone mass phenotype and osteoporosis, respectively. Ectopic SELENOW expression stimulates cell-cell fusion critical for osteoclast maturation as well as bone resorption. Thus, RANKL-dependent repression of SELENOW regulates osteoclast differentiation and blocks osteoporosis caused by overactive osteoclasts. These findings demonstrate a biological link between selenium and bone metabolism.

Purpose: To determine whether microfracture with bone marrow aspirate concentrate (BMAC) improves functional outcome and cartilage regeneration better than microfracture alone in patients undergoing high tibial osteotomy (HTO) for medial unicompartmental osteoarthritis (OA)., Methods: Among 436 patients treated with HTO for medial unicompartmental OA with varus deformity between 2010 and 2016, clinical outcomes were retrospectively compared between the microfracture alone group (group I, 43 cases) and microfracture with BMAC augmentation group (group II, 48 cases). Of these, 64 patients underwent a second-look arthroscopic assessment. Clinical outcomes were compared based on the Knee Society Score (KSS), International Knee Documentation Committee (IKDC) subjective score, and Western Ontario and McMaster Universities Arthritis Index (WOMAC). Cartilage regeneration was assessed according to Koshino's staging system and the International Cartilage Repair Society (ICRS) Cartilage Repair Assessment (CRA) grading system., Results: At the last follow-up, there were no significant intergroup differences in terms of KSS for pain and function (p > 0.05). Moreover, WOMAC scores were similar between the two groups (p > 0.05). Regarding second-look arthroscopy findings, according to Koshino's staging system, there was no significant intergroup difference in terms of defect coverage (p = 0.187). However, group II showed a significantly better mean CRA score than group I (p = 0.035)., Conclusion: There were no significant differences in clinical outcomes and cartilage regeneration between the groups. However, the CRA score was significantly higher with BMAC augmentation and microfracture than microfracture alone. Therefore, BMAC augmentation had a synergistic effect for a better cartilage regeneration, although studies with a longer follow-up might help to confirm whether microfracture with BMAC augmentation would ensure better clinical outcomes than microfracture alone for the treatment of knee OA.

Background: Cartilage repair performed as a single-stage procedure is an important advancement in the treatment of full-thickness cartilage injury and has potential for widespread clinical use., Purpose: To investigate the short-term outcomes and cartilage regeneration after implantation of allogeneic human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in patients who received high tibial osteotomy (HTO) for symptomatic medial knee osteoarthritis., Methods: Patients underwent treatment of full-thickness chondral injury in the osteoarthritic knee with HTO and implantation of hUCB-MSCs and were followed prospectively for a minimum of one year. Ninety-three patients were followed for a mean 1.7 years (range, 1.0-3.5). Median cartilage lesion size was 6.5 cm 2 (range, 2.0-12.8). Clinical outcomes were examined with patient-reported scoring instruments that consisted of the International Knee Documentation Committee (IKDC) subjective score, Western Ontario and McMaster University Osteoarthritis Index (WOMAC) score, Knee Society Score (KSS), and Hospital for Special Surgery (HSS) score. Cartilage regeneration was evaluated using the International Cartilage Repair Society (ICRS) cartilage repair assessment grading (CRA) system and the Koshino regeneration staging system in 49 patients who underwent second look arthroscopic assessment when their HTO plates were removed., Results: At final follow-up, the median IKDC subjective score had significantly improved from 39.0 to 71.3; the WOMAC score from 44.5 to 11.0; the KSS pain and function scores from 29.8 to 43.2 and 61.0 to 81.2, respectively; and the HSS from 61.6 to 82.7 (p < 0.05). Pre-operative examination showed ICRS grade IV cartilage injury in all knees, and cartilage regeneration at 2nd look arthroscopy showed improvements (8.2% of patients improved to ICRS grade I, 69.3% to grade II, and 22.5% to grade III). Moreover, Koshino stage was B in 24.5% and C in 75.5% of patients (p < 0.05)., Conclusion: Allogeneic hUCB-MSC implantation combined with HTO for medial knee osteoarthritis was safe and showed signs of cartilage status improvement. Furthermore, randomized controlled studies with a control group are necessary to determine the real effectiveness and indications of this new combined procedure for patients with osteoarthritis.

Background: Delirium is a critical and highly prevalent problem among critically ill patients. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC) are the most recommended assessment tools for detecting intensive care unit (ICU) delirium., Objectives: To synthesize the current evidence and compared the diagnostic accuracy of the two tools in the detection of delirium in adults in ICUs., Design: Systematic review and meta-analysis., Data Source: A comprehensive search of the following electronic databases was performed using PubMed, Embase, CINAHL and ProQuest Dissertations and Theses A&I. The date range searched was from database inception to April 26, 2019., Review Methods: Two researchers independently identified articles, systematically abstracted data and evaluated the sensitivity and specificity of the CAM-ICU or the ICDSC against standard references. Bivariate diagnostic statistical analysis with a random-effects model was performed to summarize the pooled sensitivity and specificity of the two tools., Results: In total, 29 CAM-ICU and 12 ICDSC studies were identified. The pooled sensitivity was 0.84 and 0.83 and pooled specificity was 0.95 and 0.87 for the CAM-ICU and the ICDSC, respectively. The CAM-ICU had higher summary specificity than the ICDSC did (p = 0.04). The percentage of hypoactive delirium, ICU type, use of mechanical ventilation, number of participants, and female percentage moderated the accuracy of the tools. Most of the domains of patient selection, index test, reference standards, and flow and timing were rated as having a low or unclear risk of bias., Conclusions: Although both the CAM-ICU and the ICDSC are accurate assessment tools for screening delirium in critically ill patients, the CAM-ICU is superior in ruling out patients without ICU delirium and detecting delirium in patients in the medical ICU and those receiving mechanical ventilation. Further investigations are warranted to validate our findings. The study protocol is registered at PROSPERO (CRD42020133544)., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In general, reverse shoulder arthroplasty revision is performed using the same implant for both the humerus and glenoid components. However, the authors of the present case used different implants from what was used previously for treating instability with scapular notching and glenoid aseptic loosening and report the case., Competing Interests: Conflict of interest None., (Copyright © 2020 Korean Shoulder and Elbow Society.)

Simple clavicle fractures can achieve satisfactory results through conservative treatment, and the less frequency of nonunion. Non-union or malunion can occur in displaced clavicle fractures or comminuted shaft fractures. Treatment of displaced comminuted clavicle shaft fractures is performed by holding together the free fragments with interfragmentary screws or wires and fixing them to the clavicle with a plate. Therefore, we performed interfragmentary fixation using open reduction and internal fixation with bioresorbable screws (Mg-Ca alloy, Resomet bioresorbable bone screw; U&I Corp.) and bioresorbable wires (Mg-Ca alloy, Resomet bioresorbable K-wire and pin, U&I Corp.) for displaced comminuted clavicle fractures (Robinson type 2B) and additionally used a metal plate. We expected decreased irritation and infection due to absorption after surgery. We report four cases that were treated in this way., Competing Interests: Conflict of interest None., (Copyright © 2020 Korean Shoulder and Elbow Society.)

While a clear operating field during endoscopy is essential for accurate diagnosis and effective surgery, fogging or biofouling of the lens can cause loss of visibility during these procedures. Conventional cleaning methods such as the use of an irrigation unit, anti-fogging surfactant, or particle-based porous coatings infused with lubricants have been used but proven insufficient to prevent loss of visibility. Herein, a mechanically robust anti-fogging and anti-biofouling endoscope lens was developed by forming a lubricant-infused directly engraved nano-/micro-structured surface (LIDENS) on the lens. This structure was directly engraved onto the lens via line-by-line ablation with a femtosecond laser. This directly engraved nano/microstructure provides LIDENS lenses with superior mechanical robustness compared to lenses with conventional particle-based coatings, enabling the maintenance of clear visibility throughout typical procedures. The LIDENS lens was chemically modified with a fluorinated self-assembled monolayer (F-SAM) followed by infusion of medical-grade perfluorocarbon lubricants. This provides the lens with high transparency (> 70%) along with superior and long-lasting repellency towards various liquids. This excellent liquid repellency was also shown to be maintained during blood dipping, spraying, and droplet condensation experiments. We believe that endoscopic lenses with the LIDENS offer excellent benefits to endoscopic surgery by securing clear visibility for stable operation.

The cellular entry of severe respiratory syndrome coronavirus-2 (SARS-CoV-2) is mediated by interaction with the human angiotensin-converting enzyme 2 (ACE2), a receptor that is expressed on both lung and intestinal epithelial cells. We performed a quantitative proteomic analysis to investigate the expression of possible receptors for SARS-CoV-2 in the intestinal mucosa of 23 patients with chronic colitis. ACE2 expression was low and remained unaltered in the gut of patients with ulcerative colitis (UC), Crohn's disease (CD), intestinal Behćet's disease (BD), and intestinal tuberculosis (TB), when compared with that of healthy individuals. Additionally, the expression levels of some probable co-receptors, including dipeptidyl peptidase 4 (DPP4), aminopeptidase N (AMPN), and glutamyl aminopeptidase (AMPE), were unchanged in the affected UC, CD, intestinal BD, and intestinal TB colon mucosa samples. In conclusion, gut inflammation associated with chronic colitis does not mediate a further increase in the cellular entry of SARS-CoV-2., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2020.)

Background : Social interactions among employees are essential for individual performance as they provide various job-related information and feedback as well as social and emotional support. Tasks have become interdependent among organizational members, allowing teamwork to generally become an organizational norm. Consequently, it is pertinent that employees maintain favorable working relationships with other organizational members because workplace ostracism has become an organizational concern. Although recent studies have examined numerous psychological mechanisms that associate ostracism with workplace outcomes, studies have been limited in exploring practical facets that link the relationship. Thus, this study examined the mediating effect of team-member exchange for workplace ostracism and task performance and the moderating effect of task interdependence in influencing the relationship. Methods : Data were collected using a two-wave design and sampled 242 full-time employees in South Korea. The hypotheses were tested with hierarchical regression analyses. Results : Team-member exchange was found to mediate the relationship between workplace ostracism and task performance and task interdependence moderated the mediated relationship. Conclusions : The results suggest that being ostracized negatively influences the quality of the relationship between team-members which then affects individual performance. In addition, the conditional indirect effect for ostracism on task performance was significant when task interdependence was high, while not significant when it was low, thus moderating the mediated relationship.

Background: Mutations in ADCK4 (aarF domain containing kinase 4) generally manifest as steroid-resistant nephrotic syndrome and induce coenzyme Q 10 (CoQ 10 ) deficiency. However, the molecular mechanisms underlying steroid-resistant nephrotic syndrome resulting from ADCK4 mutations are not well understood, largely because the function of ADCK4 remains unknown., Methods: To elucidate the ADCK4's function in podocytes, we generated a podocyte-specific, Adck4 -knockout mouse model and a human podocyte cell line featuring knockout of ADCK4 . These knockout mice and podocytes were then treated with 2,4-dihydroxybenzoic acid (2,4-diHB), a CoQ 10 precursor analogue, or with a vehicle only. We also performed proteomic mass spectrometry analysis to further elucidate ADCK4's function., Results: Absence of Adck4 in mouse podocytes caused FSGS and albuminuria, recapitulating features of nephrotic syndrome caused by ADCK4 mutations. In vitro studies revealed that ADCK4-knockout podocytes had significantly reduced CoQ 10 concentration, respiratory chain activity, and mitochondrial potential, and subsequently displayed an increase in the number of dysmorphic mitochondria. However, treatment of 3-month-old knockout mice or ADCK4-knockout cells with 2,4-diHB prevented the development of renal dysfunction and reversed mitochondrial dysfunction in podocytes. Moreover, ADCK4 interacted with mitochondrial proteins such as COQ5, as well as cytoplasmic proteins such as myosin and heat shock proteins. Thus, ADCK4 knockout decreased the COQ complex level, but overexpression of ADCK4 in ADCK4-knockout podocytes transfected with wild-type ADCK4 rescued the COQ5 level., Conclusions: Our study shows that ADCK4 is required for CoQ 10 biosynthesis and mitochondrial function in podocytes, and suggests that ADCK4 in podocytes stabilizes proteins in complex Q in podocytes. Our study also suggests a potential treatment strategy for nephrotic syndrome resulting from ADCK4 mutations., (Copyright © 2020 by the American Society of Nephrology.)

Selenoprotein P (SELENOP), secreted from the liver, functions as a selenium (Se) supplier to other tissues. In the brain, Se homeostasis is critical for physiological function. Previous studies have reported that SELENOP co-localizes with the apolipoprotein E receptor 2 (ApoER2) along the blood-brain barrier (BBB). However, the mechanism underlying SELENOP transportation from hepatocytes to neuronal cells remains unclear. Here, we found that SELENOP was secreted from hepatocytes as an exosomal component protected from plasma kallikrein-mediated cleavage. SELENOP was interacted with apolipoprotein E (ApoE) through heparin-binding sites of SELENOP, and the interaction regulated the secretion of exosomal SELENOP. Using in vitro BBB model of transwell cell culture, exosomal SELENOP was found to supply Se to brain endothelial cells and neuronal cells, which synthesized selenoproteins by a process regulated by ApoE and ApoER2. The regulatory role of ApoE in SELENOP transport was also observed in vivo using ApoE -/- mice. Exosomal SELENOP transport protected neuronal cells from amyloid β (Aβ)-induced cell death. Taken together, our results suggest a new delivery mechanism for Se to neuronal cells by exosomal SELENOP.

This study explored the anti-inflammatory effects of a glucagon-like peptide-1 receptor agonist (GLP-1RA), known as lixisenatide, on the eyes of early type 2 diabetic mice. Diabetic (db/db) mice were divided into three groups: GLP-1RA [lixisenatide (LIX)], insulin (INS) with controlled hyperglycemia based on the glucose concentration of lixisenatide, and diabetic control (D-CON). Nondiabetic control mice (db/dm) were also characterized for comparison. After 8 weeks of treatment, mRNA levels of inflammatory markers, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, immunohistochemical staining; Western blot of glial fibrillary acidic protein (GFAP) and thioredoxin-interacting protein; and retinal thickness were assessed in the central and peripheral neurosensory retina. LIX showed decreased immunohistochemical staining for both thioredoxin-interacting protein and GFAP in the central and peripheral neurosensory retina compared with D-CON and INS, and decreased expression of these proteins in the neurosensory retina and immunohistochemical staining in the optic nerve head for GFAP compared with D-CON. The inner nuclear layer in the peripheral retina in LIX was only thinner than those of D-CON and INS. In an early type 2 diabetic mouse model, lixisenatide treatment showed superior anti-inflammatory effects on the retina and optic nerve head independent of hyperglycemia. Thus, the neuroprotective effects of lixisenatide treatment in the peripheral inner nuclear layer should be evaluated in early type 2 diabetic retinopathy., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Microbial communities of the mouse gut have been extensively studied; however, their functional roles and regulation are yet to be elucidated. Metagenomic and metatranscriptomic analyses may allow us a comprehensive profiling of bacterial composition and functions of the complex gut microbiota. The present study aimed to investigate the active functions of the microbial communities in the murine cecum by analyzing both metagenomic and metatranscriptomic data on specific bacterial species within the microbial communities, in addition to the whole microbiome., Results: Bacterial composition of the healthy mouse gut microbiome was profiled using the following three different approaches: 16S rRNA-based profiling based on amplicon and shotgun sequencing data, and genome-based profiling based on shotgun sequencing data. Consistently, Bacteroidetes, Firmicutes, and Deferribacteres emerged as the major phyla. Based on NCBI taxonomy, Muribaculaceae, Lachnospiraceae, and Deferribacteraceae were the predominant families identified in each phylum. The genes for carbohydrate metabolism were upregulated in Muribaculaceae, while genes for cofactors and vitamin metabolism and amino acid metabolism were upregulated in Deferribacteraceae. The genes for translation were commonly enhanced in all three families. Notably, combined analysis of metagenomic and metatranscriptomic sequencing data revealed that the functions of translation and metabolism were largely upregulated in all three families in the mouse gut environment. The ratio of the genes in the metagenome and their expression in the metatranscriptome indicated higher expression of carbohydrate metabolism in Muribaculum, Duncaniella, and Mucispirillum., Conclusions: We demonstrated a fundamental methodology for linking genomic and transcriptomic datasets to examine functional activities of specific bacterial species in a complicated microbial environment. We investigated the normal flora of the mouse gut using three different approaches and identified Muribaculaceae, Lachnospiraceae, and Deferribacteraceae as the predominant families. The functional distribution of these families was reflected in the entire microbiome. By comparing the metagenomic and metatranscriptomic data, we found that the expression rates differed for different functional categories in the mouse gut environment. Application of these methods to track microbial transcription in individuals over time, or before and after administration of a specific stimulus will significantly facilitate future development of diagnostics and treatments., Competing Interests: The authors have declared that no competing interests exist.

No previously suggested biomarkers of nasal mucosal inflammation have been practically applied in clinical fields, and nasal epithelium-derived secreted proteins as biomarkers have not specifically been investigated. The goal of this study was to identify secreted proteins that dynamically change during the differentiation from basal cells to fully differentiated cells and examine whether nasal epithelium-derived proteins can be used as biomarkers of nasal mucosal inflammation, such as chronic rhinosinusitis. To achieve this goal, we analyzed two secretomes using the isobaric tag for relative and absolute quantification technique. From in vitro secretomes, we identified the proteins altered in apical secretions of primary human nasal epithelial cells according to the degree of differentiation; from in vivo secretomes, we identified the increased proteins in nasal lavage fluids obtained from patients 2 weeks after endoscopic sinus surgery for chronic sinusitis. We then used a parallel approach to identify specific biomarkers of nasal mucosal inflammation; first, we selected apolipoprotein E as a nasal epithelial cell-derived biomarker through screening proteins that were upregulated in both in vitro and in vivo secretomes, and verified highly secreted apolipoprotein E in nasal lavage fluids of the patients by Western blotting. Next, we selected periostin as an inflammatory mediator-inducible biomarker from in vivo secretomes, the secretion of which was not induced under in vitro culture conditions. We demonstrated that those two nasal epithelium-derived proteins are possible biomarkers of nasal mucosal inflammation.

Objectives: Human epidermal growth factor receptor-2 (HER2) and 3 (HER3) belong to the epidermal growth factor receptor (EGFR) family of transmembrane receptor tyrosine kinases. In this study, we assessed HER2/HER3 expression levels in specimens of epithelial ovarian cancer and determined their correlation with clinical features of ovarian cancer., Methods: Tissue microarrays (TMAs) were prepared from paraffin blocks of 105 ovarian tumour samples. HER2, HER3, PI3K, Akt, p-Akt, mTOR, p-mTOR, S6, and p-S6 expression levels were investigated using immunohistochemistry (IHC). HER2 and HER3 amplifications were determined using in situ hybridization (ISH). The correlation between HER2/3 expression and disease outcome of the patients including surgical outcome, progression-free survival (PFS) and overall survival (OS) was analysed., Results: HER2 positivity was 3.8% by IHC and 5.7% by ISH, whereas that of HER3 was 12.4% and 8.6%, respectively. HER2 status by either IHC or ISH was not related to PFS (p=0.128, 0.168, respectively) and OS (p=0.245, 0.164, respectively). However, the HER3 status determined using fluorescence ISH was associated with poor PFS (p=0.035 on log rank test), which was a significant risk factor even after adjusting other possible risk factors in multivariate analysis (hazard ratio=2.377 [1.18-7.49], p=0.021). Expressions of Akt, p-mTOR, and S6 were also related with poor progression (p=0.008, 0.049, 0.014, respectively)., Conclusion: HER3 is possibly an independent marker for poor prognosis in individuals with ovarian cancer, as the HER3 signalling pathway is distinct from that of HER2. The possibility of targeted therapy for patients with HER3 alteration in ovarian cancer should be evaluated., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2019. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

Background/objectives: To analyze the surgical and sensory outcomes of intermittent exotropia according to refractive errors and the factors associated with surgical success., Subjects/methods: A total of 326 children were divided into three groups according to preoperative refractive error; hyperopic eyes with SE ≥+2D (hyperopic group), eyes with SE between -1D and +2D (emmetropic group), and myopic eyes with SE ≤-1D (myopic group). The surgical outcomes and the sensory outcomes measured by near and distant stereoacuity were compared among the three groups., Results: The surgical success rate in hyperopic group was significantly lower compared to myopic group at last follow-up (P = 0.012). Preoperative near stereopsis was not different among three groups, however, the distance stereopsis was significantly deteriorated in the hyperopic group compared to the other two groups (Titmus; P = 0.168, FD2; P < 0.001, DR; P = 0.048). There was postoperative improvement in both near and distant stereopsis in all three groups (Titmus; P = 0.009, FD2; P = 0.021, DR; P = 0.036) and no significant difference was found in the postoperative distant stereopsis among the three groups., Conclusions: Preoperative refractive error is a prognostic factor of surgical success in patients with intermittent exotropia. Patients with hyperopia achieved less favorable surgical outcome compared to myopic patients. The preoperative distant stereoacuity was decreased in hyperopic patients compared to myopic patients, which eventually improved after surgery and showed no significant difference at postoperative measurements.

Purpose: To investigate the relationship between macular thickness and axial length (AL) in myopic eyes., Methods: We included 441 myopic eyes in this study and measured macular thickness at the fovea and in other macular regions, using optical coherence tomography. We got thickness difference indices (TDIs) which by definition are the values of thickness difference obtained by subtracting the foveal thickness from that of each macula sector to evaluate macular contour. We then analyzed the relationships between AL and foveal thickness and AL and the TDIs of each macular sector., Results: In polynomial regression analyses, foveal thickness slope was relatively flat up to an AL of 25.5 mm and began to rise from 25.5-26.0 mm. The TDIs were also relatively flat up to AL of 25.5mm and started to show steepened negative slopes from around AL of 25.5 mm. When grouping myopia participants as high myopia or non-high myopia based on AL of 25.5mm, all macular indices of the high myopia group showed significant correlation with AL (all p values <0.01). But all indices of non-high myopia group had no significant correlation with AL., Conclusions: Average macular thickness profiles showed that appreciable changes started at an AL of 25.5mm., Competing Interests: The authors declare that they have no conflicts of interest.