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Insomnia is one of the most common sleep disorders, affecting 10-15% of the global population. Because classical remedies used to treat insomnia have various side effects, new therapeutics for insomnia are attracting attention. In the present study, we found that N 2 -Ethyl-N 4 -(furan-2-ylmethyl) quinazoline-2,4-diamine (AR-001) has adenosine A 1 receptor agonistic activity and exhibits hypnotic efficacy by decreasing sleep onset latency and increasing total sleep time in a pentobarbital-induced sleep model. This hypnotic effect of AR-001 was significantly inhibited by the adenosine A 1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). As a result of immunohistochemistry, AR-001 was shown to increase neural activity in the sleep-promoting region, ventrolateral preoptic nucleus (VLPO), and decrease neural activity in the wake-promoting region, basal forebrain (BF), and lateral hypothalamus (LH), and that these effects of AR-001 were significantly inhibited by DPCPX treatment. In addition, AR-001 increased adenosine A 1 receptor mRNA levels in the hypothalamus. In conclusion, this study suggests that AR-001 has a hypnotic effect, at least partially, through adenosine A 1 receptor and may have therapeutic potential for insomnia., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Yi-Sook Jung reports financial support was provided by GRRC program of Gyeonggi province (GRRCAjou2023-B01). Hye Jin Jee reports was provided by Korea Initiative for fostering University of Research and Innovation Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. NRF2021M3H1A104892211). Yi-Sook Jung reports financial support was provided by Ministry of Food and Drug Safety, Republic of Korea (21153MFDS602). If there are other authors, they 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Sleep is one of the most essential physiological phenomena for maintaining health. Sleep disturbances, such as insomnia, are often accompanied by psychiatric or physical conditions such as impaired attention, anxiety, and stress. Medication used to treat insomnia have concerns about potential side effects with long-term use, so interest in the use of alternative medicine is increasing. In this study, we investigated the hypnotic effects of β-lapachone (β-Lap), a natural naphthoquinone compound, using pentobarbital-induced sleep test, immunohistochemistry, real-time PCR, and western blot in mice. Our results indicated that β-Lap exerts a significant hypnotic effect by showing a decrease in sleep onset latency and an increase in total sleep time in pentobarbital-induced sleep model. The results of c-Fos immunostaining showed that β-Lap decreased neuronal activity in the basal forebrain and lateral hypothalamus, which are wakefulness-promoting brain regions, while increasing in the ventrolateral preoptic nucleus, a sleep-promoting region; all these effects were significantly abolished by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an adenosine A 1 receptor (A 1 R) antagonist. Western blot analysis showed that β-Lap increased extracellular signalregulated kinase phosphorylation and nuclear factor-kappa B translocation from the cytoplasm to the nucleus; these effects were inhibited by DPCPX. Additionally, β-Lap increased the mRNA levels of A 1 R. Taken together, these results suggest that β-Lap exerts hypnotic effects, potentially through A 1 R.

Insomnia is a common sleep disorder with significant societal and economic impacts. Current pharmacotherapies for insomnia are often accompanied by side effects, necessitating the development of new therapeutic drugs. In this study, the hypnotic effects and mechanisms of Sedum kamtschaticum 30% ethanol extract (ESK) and one of its active compounds, myricitrin, were investigated using pentobarbital-induced sleep experiments, immunohistochemistry (IHC), receptor binding assays, and enzyme-linked immunosorbent assay (ELISA). The pentobarbital-induced sleep experiments revealed that ESK and myricitrin reduced sleep latency and prolonged total sleep time in a dose-dependent manner. Based on c-Fos immunostaining, ESK, and myricitrin enhanced the GABAergic neural activity in sleep-promoting ventrolateral preoptic nucleus (VLPO) GABAergic. By measuring the level of GABA released from VLPO GABAergic neurons, ESK and myricitrin were found to increase GABA release in the hypothalamus. These effects were significantly inhibited by SCH. Moreover, ESK exhibited a concentration-dependent binding affinity for the adenosine A 2A receptors (A 2A R). In conclusion, ESK and myricitrin have hypnotic effects, and their underlying mechanisms may be related to the activation of A 2A R.

Background: To examine the effectiveness and safety of a data sharing and comprehensive management platform for institutionalized older patients., Methods: We applied information technology-supported integrated health service platform to patients who live at long-term care hospitals (LTCHs) and nursing homes (NHs) with cluster randomized controlled study. We enrolled 555 patients aged 65 or older (461 from 7 LTCHs, 94 from 5 NHs). For the intervention group, a tablet-based platform comprising comprehensive geriatric assessment, disease management, potentially inappropriate medication (PIM) management, rehabilitation program, and screening for adverse events and warning alarms were provided for physicians or nurses. The control group was managed with usual care. Co-primary outcomes were (1) control rate of hypertension and diabetes, (2) medication adjustment (PIM prescription rate, proportion of polypharmacy), and (3) combination of potential quality-of-care problems (composite quality indicator) from the interRAI assessment system which assessed after 3-month of intervention., Results: We screened 1119 patients and included 555 patients (control; 289, intervention; 266) for analysis. Patients allocated to the intervention group had better cognitive function and took less medications and PIMs at baseline. The diabetes control rate (OR = 2.61, 95% CI 1.37-4.99, p = 0.0035), discontinuation of PIM (OR = 4.65, 95% CI 2.41-8.97, p < 0.0001), reduction of medication in patients with polypharmacy (OR = 1.98, 95% CI 1.24-3.16, p = 0.0042), and number of PIMs use (ꞵ =  - 0.27, p < 0.0001) improved significantly in the intervention group. There was no significant difference in hypertension control rate (OR = 0.54, 95% CI 0.20-1.43, p = 0.2129), proportion of polypharmacy (OR = 1.40, 95% CI 0.75-2.60, p = 0.2863), and improvement of composite quality indicators (ꞵ = 0.03, p = 0.2094). For secondary outcomes, cognitive and motor function, quality of life, and unplanned hospitalization were not different significantly between groups., Conclusions: The information technology-supported integrated health service effectively reduced PIM use and controlled diabetes among older patients in LTCH or NH without functional decline or increase of healthcare utilization., Trial Registration: Clinical Research Information Service, KCT0004360. Registered on 21 October 2019., (© 2024. The Author(s).)

Mental and financial hardship during the COVID-19 pandemic in New York City was severe, but how vulnerable groups have been disproportionately impacted is incompletely understood. In partnership with community stakeholders, we administered a web-based survey to a convenience sample of New York City residents (18 + years) from May 2020 to April 2021 to evaluate their financial and emotional stressors. We analyzed outcomes by race, ethnicity, and education level. A total of 1854 adults completed the survey across three consecutive non-overlapping samples. Fifty-five percent identified other than non-Latinx White. Sixty-four percent reported emotional stress; 38%, 32%, and 32% reported symptoms of anxiety, depression, and post-traumatic stress disorder respectively; and 21% reported a large adverse financial impact. The leading unmet needs were mental health and food services (both 19%), and health services (18%). Need for both resources grew over time. Adverse financial impact directly correlated with presence of all four adverse mental health outcomes above. In multivariate analysis, non-White race and lack of college degree were associated with adverse financial impact, whereas LGBT identity and lack of college degree were associated with mental health impact. Throughout the COVID-19 pandemic, participants in this research demonstrated a large and growing mental and financial strain, disproportionately associated with lower education level, non-White race, and LGBT status. Our findings suggest an urgent need to differentially target COVID-19 mental health and resource support in New York City to persons in these vulnerable communities., (© 2024. W. Montague Cobb-NMA Health Institute.)

Background/aim: Chronic kidney disease (CKD) is one of the most common causes of mortality in wild non-domestic felidae. The molecular mechanism regulating renal fibrosis in nephropathy is not fully understood especially in the felidae. This study aimed to elucidate senescence marker protein 30 (SMP30) expression patterns and its relationship with epithelial-mesenchymal transition (EMT) by immunostaining in two necropsied Siberian tigers (Panthera tigris altaica) with CKD., Materials and Methods: Two kidney samples from male Siberian tigers were fixed and tissue sections were stained for histopathological assay., Results: In CKD, renal tubular epithelial cells lost their tubular structures surrounded by severe interstitial fibrosis and were detached from the basement membrane. These damaged cells resembled the morphology of mesenchymal cells and showed much lower SMP30 expression compared with intact tubular epithelial cells. These cells also expressed vimentin, which is specifically expressed by mesenchymal cells, and through double staining, it was observed that vimentin was expressed in the tubular epithelial cells where SMP30 was not expressed. In addition, double-positive expression of pan-cytokeratin (pan-CK) and vimentin was found in damaged epithelial cells with mesenchymal features., Conclusion: We demonstrated possible evidence to understand the role of SMP30 as a new pivotal factor and the possibility of decreased SMP30 as a potential indicator of EMT at the end stage of CKD., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Dementia is a clinical syndrome characterized by progressive impairment of cognitive and functional abilities. As currently applied treatments for dementia can only delay the progression of dementia and cannot fundamentally cure it, much attention is being paid to reducing its incidence by preventing the associated risk factors. Cardiovascular and metabolic diseases are well-known risk factors for dementia, and many studies have attempted to prevent dementia by treating these risk factors. Growing evidence suggests that sex-based factors may play an important role in the pathogenesis of dementia. Therefore, a deeper understanding of the differences in the effects of drugs based on sex may help improve their effectiveness. In this study, we reviewed sex differences in the impact of therapeutics targeting risk factors for dementia, such as cardiovascular and metabolic diseases, to prevent the incidence and/or progression of dementia.

Recent developments in genome sequencing have expanded the knowledge of genetic factors associated with late-onset Alzheimer's disease (AD). Among them, genetic variant ε4 of the APOE gene (APOE4) confers the greatest disease risk. Dysregulated glucose metabolism is an early pathological feature of AD. Using isogenic ApoE3 and ApoE4 astrocytes derived from human induced pluripotent stem cells, we find that ApoE4 increases glycolytic activity but impairs mitochondrial respiration in astrocytes. Ultrastructural and autophagy flux analyses show that ApoE4-induced cholesterol accumulation impairs lysosome-dependent removal of damaged mitochondria. Acute treatment with cholesterol-depleting agents restores autophagic activity, mitochondrial dynamics, and associated proteomes, and extended treatment rescues mitochondrial respiration in ApoE4 astrocytes. Taken together, our study provides a direct link between ApoE4-induced lysosomal cholesterol accumulation and abnormal oxidative phosphorylation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Ischemia-reperfusion (IR) injury, a leading cause of acute kidney injury (AKI), is still without effective therapies. Succinate accumulation during ischemia followed by its oxidation during reperfusion leads to excessive reactive oxygen species (ROS) and severe kidney damage. Consequently, the targeting of succinate accumulation may represent a rational approach to the prevention of IR-induced kidney injury. Since ROS are generated primarily in mitochondria, which are abundant in the proximal tubule of the kidney, we explored the role of pyruvate dehydrogenase kinase 4 (PDK4), a mitochondrial enzyme, in IR-induced kidney injury using proximal tubule cell-specific Pdk4 knockout (Pdk4 ptKO ) mice. Knockout or pharmacological inhibition of PDK4 ameliorated IR-induced kidney damage. Succinate accumulation during ischemia, which is responsible for mitochondrial ROS production during reperfusion, was reduced by PDK4 inhibition. PDK4 deficiency established conditions prior to ischemia resulting in less succinate accumulation, possibly because of a reduction in electron flow reversal in complex II, which provides electrons for the reduction of fumarate to succinate by succinate dehydrogenase during ischemia. The administration of dimethyl succinate, a cell-permeable form of succinate, attenuated the beneficial effects of PDK4 deficiency, suggesting that the kidney-protective effect is succinate-dependent. Finally, genetic or pharmacological inhibition of PDK4 prevented IR-induced mitochondrial damage in mice and normalized mitochondrial function in an in vitro model of IR injury. Thus, inhibition of PDK4 represents a novel means of preventing IR-induced kidney injury, and involves the inhibition of ROS-induced kidney toxicity through reduction in succinate accumulation and mitochondrial dysfunction., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Objectives: Coronavirus disease 2019 (COVID-19) is associated with mortality in persons with comorbidities. The aim of this study was to evaluate in-hospital outcomes in patients with COVID-19 with and without epilepsy., Methods: We conducted a retrospective study of patients with COVID-19 admitted to a multicenter health system between March 15, 2020, and May 17, 2021. Patients with epilepsy were identified using a validated International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM)/ICD-10-CM case definition. Logistic regression models and Kaplan-Meier analyses were conducted for mortality and non-routine discharges (i.e., not discharged home). An ordinary least-squares regression model was fitted for length of stay (LOS)., Results: We identified 9833 people with COVID-19 including 334 with epilepsy. On univariate analysis, people with epilepsy had significantly higher ventilator use (37.70% vs 14.30%, p < .001), intensive care unit (ICU) admissions (39.20% vs 17.70%, p < .001) mortality rate (29.60% vs 19.90%, p < .001), and longer LOS (12 days vs 7 days, p < .001). and fewer were discharged home (29.64% vs 57.37%, p < .001). On multivariate analysis, only non-routine discharge (adjusted odds ratio [aOR] 2.70, 95% confidence interval [CI] 2.00-3.70; p < .001) and LOS (32.50% longer, 95% CI 22.20%-43.60%; p < .001) were significantly different. Factors associated with higher odds of mortality in epilepsy were older age (aOR 1.05, 95% CI 1.03-1.08; p < .001), ventilator support (aOR 7.18, 95% CI 3.12-16.48; p < .001), and higher Charlson comorbidity index (CCI) (aOR 1.18, 95% CI 1.04-1.34; p = .010). In epilepsy, admissions between August and December 2020 or January and May 2021 were associated with a lower odds of non-routine discharge and decreased LOS compared to admissions between March and July 2020, but this difference was not statistically significant., Significance: People with COVID-19 who had epilepsy had a higher odds of non-routine discharge and longer LOS but not higher mortality. Older age (≥65), ventilator use, and higher CCI were associated with COVID-19 mortality in epilepsy. This suggests that older adults with epilepsy and multimorbidity are more vulnerable than those without and should be monitored closely in the setting of COVID-19., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The growing use of plastic materials has resulted in a constant increase in the risk associated with microplastics (MPs). Ultra-violet (UV) light and wind break down modify MPs in the environment into smaller particles known as weathered MPs (WMPs) and these processes increase the risk of MP toxicity. The neurotoxicity of weathered polystyrene-MPs remains unclear. Therefore, it is important to understand the risks posed by WMPs. We evaluated the chemical changes of WMPs generated under laboratory-synchronized environmentally mimetic conditions and compared them with virgin MPs (VMPs). We found that WMP had a rough surface, slight yellow color, reduced molecular weight, and structural alteration compared with those of VMP. Next, 2 μg of ∼100 μm in size of WMP and VMP were orally administered once a day for one week to C57BL/6 male mice. Proteomic analysis revealed that the WMP group had significantly increased activation of immune and neurodegeneration-related pathways compared with that of the VMP group. Consistently, in in vitro experiments, the human brain-derived microglial cell line (HMC-3) also exhibited a more severe inflammatory response to WMP than to VMP. These results show that WMP is a more profound inflammatory factor than VMP. In summary, our findings demonstrate the toxicity of WMPs and provide theoretical insights into their potential risks to biological systems and even humans in the ecosystem., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Class I small heat shock proteins (CI sHSPs), OsHsp16.9A and OsHsp18.0, share 74% identity in amino acid sequences and accumulate in response to heat shock treatments. Individual rice transformants overexpressing OsHsp16.9A and OsHsp18.0 exhibit distinct thermoprotection/thermotolerance modes. Under high temperature stress, OsHsp16.9A-overexpressing lines showed higher seed germination rate, seedling survival, and pollen germination than wild-type controls, while OsHsp18.0 overexpression provided higher thermoprotection/thermotolerance for seedling survival. To elucidate the functional roles of OsHsp16.9A, mass spectrometry was used to identify OsHsp16.9A-interacting proteins. OsHsp101 was consistently identified in the OsHsp16.9A protein complex in several mass spectrometry analyses of seed proteins from OsHsp16.9A-overexpressing lines. Both OsHsp16.9A and OsHsp101 proteins accumulated during similar developmental stages of rice seeds and formed a heat-stable complex under high temperature treatments in in vitro assays. Co-localization of OsHsp16.9A and OsHsp101 was observed via ratiometric bimolecular fluorescence complementation analyses. Amino acid mutation studies revealed that OsHsp16.9A glutamate residue 74 and amino acid residues 23-36 were essential for OsHsp16.9A-OsHsp101 interaction. Moreover, overexpressing OsHsp16.9A in OsHsp101 knockdown mutants did not increase the seed germination rate under heat stress, which further confirmed the functional roles of OsHsp16.9A-OsHsp101 interaction in conferring thermotolerance to rice plants., 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.)

Ca 2+ overload-induced mitochondrial dysfunction is considered as a major contributing factor in the pathogenesis of alcohol-associated liver disease (ALD). However, the initiating factors that drive mitochondrial Ca 2+ accumulation in ALD remain elusive. Here, we demonstrate that an aberrant increase in hepatic GRP75-mediated mitochondria-associated ER membrane (MAM) Ca 2+ -channeling (MCC) complex formation promotes mitochondrial dysfunction in vitro and in male mouse model of ALD. Unbiased transcriptomic analysis reveals PDK4 as a prominently inducible MAM kinase in ALD. Analysis of human ALD cohorts further corroborate these findings. Additional mass spectrometry analysis unveils GRP75 as a downstream phosphorylation target of PDK4. Conversely, non-phosphorylatable GRP75 mutation or genetic ablation of PDK4 prevents alcohol-induced MCC complex formation and subsequent mitochondrial Ca 2+ accumulation and dysfunction. Finally, ectopic induction of MAM formation reverses the protective effect of PDK4 deficiency in alcohol-induced liver injury. Together, our study defines a mediatory role of PDK4 in promoting mitochondrial dysfunction in ALD., (© 2023. The Author(s).)

Prostate cancer is the fifth leading cause of cancer-related mortality in men, primarily because of treatment resistance, recurrence, and metastasis. In the present study, we investigated the role of paracrine interleukin-8 (IL-8) in the antagonistic expression of IL-8 and androgen receptor (AR), and the contribution of IL-8 to prostate cancer aggressiveness. In hormone-responsive LNCaP cells that do not express IL-8, recombinant IL-8 treatment significantly increased expressions of IL-8, CXC chemokine receptor 2 (CXCR2), matrix metalloproteinase (MMP)-2/9, Snail, and vimentin. IL-8 treatment significantly decreased AR and E-cadherin expression. IL-8-induced gene expression changes were suppressed by navarixin, a CXCR1/2 inhibitor, and gallein, a Gβγ inhibitor. In PC-3 androgen-refractory prostate cancer cells, IL-8 knockdown reduced expressions of CXCR2, MMP-2/9, Snail, and vimentin, and increased AR and E-cadherin expressions at the mRNA and protein levels. Co-culture with MEG-01 human megakaryocytic cells secreting high levels of IL-8 induced gene expression changes in both LNCaP and PC-3 cells, similar to those induced by IL-8 treatment. The altered gene expressions were accompanied by significant activation of transcription factor Snail in LNCaP and PC-3 cells. Treatment with the CXCR blocker navarixin inhibited the invasion of PC-3 cells but not LNCaP cells. However, invasion induced by MEG-01 was inhibited by navarixin in both LNCaP and PC-3 cells. The collective findings demonstrate that IL-8 enhances CXCR2 expression, which antagonistically regulates AR expression. More importantly, through changes in IL-8/CXCR2-regulated gene expression, IL-8 induces antiandrogen therapy resistance and epithelial-mesenchymal transition in prostate cancer.

Diabetes mellitus is a chronic disease with high economic and social burdens. This study aimed to determine the risk factors of microalbuminuria among patients with type 2 diabetes mellitus. Microalbuminuria is predictive of early-stage renal complications and subsequent progression to renal dysfunction. We collected data on type 2 diabetes patients who participated in the 2019-2020 Korea National Health and Nutrition Examination Survey. The risk factors for microalbuminuria among patients with type 2 diabetes were analyzed using logistic regression. As a result, the odds ratios were 1.036 (95% confidence interval (CI) = 1.019-1.053, p < 0.001) for systolic blood pressure, 0.966 (95% CI = 0.941-0.989, p = 0.007) for high-density lipoprotein cholesterol level, 1.008 (95% CI = 1.002-1.014, p = 0.015) for fasting blood sugar level, and 0.855 (95% CI = 0.729-0.998, p = 0.043) for hemoglobin level. A significant strength of this study is the identification of low hemoglobin level (i.e., anemia) as a risk factor for microalbuminuria in patients with type 2 diabetes. This finding implies that the early detection and management of microalbuminuria can prevent the development of diabetic nephropathy.

Background: The timeliness of raising vaccine acceptance and uptake among the public is essential to overcoming COVID-19; however, the decision-making process among patients with underlying medical conditions is complex, leading individuals to vaccine hesitancy because of their health status. Although vaccine implementation is more effective when deployed as soon as possible, vaccine hesitancy is a significant threat to the success of vaccination programs., Objective: This study aims to evaluate the effectiveness of a communication tool for patients with underlying medical conditions who should decide whether to receive a COVID-19 vaccine., Methods: This 3-arm prospective randomized controlled trial will test the effect of the developed communication intervention, which is fully automated, patient decision aid (SMART-DA), and user-centered information (SMART-DA-α). The web-based intervention was developed to help decision-making regarding COVID-19 vaccination among patients with underlying medical conditions. Over 450 patients will be enrolled on the web from a closed panel access website and randomly assigned to 1 of 3 equal groups stratified by their underlying disease, sex, age, and willingness to receive a COVID-19 vaccine. SMART-DA-α provides additional information targeted at helping patients' decision-making regarding COVID-19 vaccination. Implementation outcomes are COVID-19 vaccination intention, vaccine knowledge, decisional conflict, stress related to decision-making, and attitudes toward vaccination, and was self-assessed through questionnaires., Results: This study was funded in 2020 and approved by the Clinical Research Information Service, Republic of Korea. Data were collected from December 2021 to January 2022. This paper was initially submitted before data analysis. The results are expected to be published in the winter of 2023., Conclusions: We believe that the outcomes of this study will provide valuable new insights into the potential of decision aids for supporting informed decision-making regarding COVID-19 vaccination and discovering the barriers to making informed decisions regarding COVID-19 vaccination, especially among patients with underlying medical conditions. This study will provide knowledge about the common needs, fears, and perceptions concerning vaccines among patients, which can help tailor information for individuals and develop policies to support them., Trial Registration: Korea Clinical Information Service KCT0006945; https://cris.nih.go.kr/cris/search/detailSearch.do/20965., International Registered Report Identifier (irrid): DERR1-10.2196/42837., (©Minjung Lee, Bumjo Oh, Nan-He Yoon, Shinkyeong Kim, Young-Il Jung. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 19.01.2023.)

Background: Healthy aging for all in the community is a shared public health agenda for countries with aging populations, but there is a lack of empirical evidence on community-wide preventive models that promote the health of older people residing in socially-disadvantaged communities. The Health and Wellness Program for Seniors (HWePS) is a technology-enhanced, multi-level, integrated health equity intervention model. This study evaluates the effect of the HWePS on the health and well-being of older adults residing in urban, low-income communities.  METHODS/DESIGN: HWePS is a prospective, non-randomized comparison trial conducted in an intervention and a control neighborhood (dong) in Seoul, South Korea, over 12 months. Older people who reside in the small areas and meet the inclusion/exclusion criteria are eligible to participate. The multi-level, multi-faceted HWePS intervention is a preventive community care model for older residents guided by the expanded chronic care model, the comprehensive health literacy intervention model, and the Systems for Person-centered Elder Care model along with health equity frameworks. HWePS consists of four components: a health literacy intervention based on individual and community needs assessments, personalized (self-)care management featuring nurse coaching and peer support, a healthy-living and healthy-aging community initiative, and information and communication technology (ICT) systems. The primary outcomes are self-reported health and health-related quality of life. Outcome assessors and data analysts are blinded to group assignment. Process evaluation will be also conducted., Discussion: As a multi-level health equity project, HWePS has adopted a novel study design that simultaneously targets individual- and community-level factors known to contribute to health inequality in later life in the community. The study will provide insights into the effectiveness and implementation process of an integrated, multi-level, preventive community care model, which in turn can help improve the health outcomes of older residents and reduce disparities in underserved urban communities., Trial Registration: ISRCTN29103760. Registered 2 September 2021, https://www.isrctn.com/ISRCTN29103760., (© 2023. The Author(s).)

Excessive stress plays a critical role in the pathogenesis of mood disorders such as depression. Fermented natural products have recently attracted attention because of their health benefits. We evaluated the antidepressant-like efficacy of fermented Perilla frutescens (FPF), and its underlying mechanisms, in sleep deprivation (SD)-induced stress mice. SD-stressed mice revealed a remarkable increase in the immobility time in both forced swimming test and tail suspension test; this increase was ameliorated by treatment with FPF at doses of 100 and 150 mg/kg. FPF treatment also reduced the level of stress hormones such as corticosterone and adrenocorticotropic hormone. Additionally, FPF increased the levels of serotonin and dopamine which were significantly decreased in the brain tissues of SD-stressed mice. The increased expression of proinflammatory cytokines, such as TNF-α and IL1β, and the decreased expression of brain-derived neurotrophic factor (BDNF) in the stressed mice were significantly reversed by FPF treatment. Furthermore, FPF also increased phosphorylation of tropomyosin receptor kinase B (TrkB), extracellular regulated protein kinase (ERK), and cAMP response element binding protein (CREB). Among the six components isolated from FPF, protocatechuic acid and luteolin-7- O -glucuronide exhibited significant antidepressant-like effects, suggesting that they are major active components. These findings suggest that FPF has therapeutic potential for SD-induced stress, by correcting dysfunction of hypothalamic-pituitary-adrenal axis and modulating the BDNF/TrkB/ERK/CREB signaling pathway.

Background: Muscle atrophy, leading to muscular dysfunction and weakness, is an adverse outcome of sustained period of glucocorticoids usage. However, the molecular mechanism underlying this detrimental condition is currently unclear. Pyruvate dehydrogenase kinase 4 (PDK4), a central regulator of cellular energy metabolism, is highly expressed in skeletal muscle and has been implicated in the pathogenesis of several diseases. The current study was designed to investigated and delineate the role of PDK4 in the context of muscle atrophy, which could be identified as a potential therapeutic avenue to protect against dexamethasone-induced muscle wasting., Methods: The dexamethasone-induced muscle atrophy in C2C12 myotubes was evaluated at the molecular level by expression of key genes and proteins involved in myogenesis, using immunoblotting and qPCR analyses. Muscle dysfunction was studied in vivo in wild-type and PDK4 knockout mice treated with dexamethasone (25 mg/kg body weight, i.p., 10 days). Body weight, grip strength, muscle weight and muscle histology were assessed. The expression of myogenesis markers were analysed using qPCR, immunoblotting and immunoprecipitation. The study was extended to in vitro human skeletal muscle atrophy analysis., Results: Knockdown of PDK4 was found to prevent glucocorticoid-induced muscle atrophy and dysfunction in C2C12 myotubes, which was indicated by induction of myogenin (0.3271 ± 0.102 vs 2.163 ± 0.192, ****P < 0.0001) and myosin heavy chain (0.3901 ± 0.047 vs. 0.7222 ± 0.082, **P < 0.01) protein levels and reduction of muscle atrophy F-box (10.77 ± 2.674 vs. 1.518 ± 0.172, **P < 0.01) expression. In dexamethasone-induced muscle atrophy model, mice with genetic ablation of PDK4 revealed increased muscle strength (162.1 ± 22.75 vs. 200.1 ± 37.09 g, ***P < 0.001) and muscle fibres (54.20 ± 11.85% vs. 84.07 ± 28.41%, ****P < 0.0001). To explore the mechanism, we performed coimmunoprecipitation and liquid chromatography-mass spectrometry analysis and found that myogenin is novel substrate of PDK4. PDK4 phosphorylates myogenin at S43/T57 amino acid residues, which facilitates the recruitment of muscle atrophy F-box to myogenin and leads to its subsequent ubiquitination and degradation. Finally, overexpression of non-phosphorylatable myogenin mutant using intramuscular injection prevented dexamethasone-induced muscle atrophy and preserved muscle fibres., Conclusions: We have demonstrated that PDK4 mediates dexamethasone-induced skeletal muscle atrophy. Mechanistically, PDK4 phosphorylates and degrades myogenin via recruitment of E3 ubiquitin ligase, muscle atrophy F-box. Rescue of muscle regeneration by genetic ablation of PDK4 or overexpression of non-phosphorylatable myogenin mutant indicates PDK4 as an amenable therapeutic target in muscle atrophy., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Drug repositioning, which involves the identification of new therapeutic indications for approved drugs, considerably reduces the time and cost of developing new drugs. Recent computational drug repositioning methods use heterogeneous networks to identify drug-disease associations. This review reveals existing network-based approaches for predicting drug-disease associations in three major categories: graph mining, matrix factorization or completion, and deep learning. We selected eleven methods from the three categories to compare their predictive performances. The experiment was conducted using two uniform datasets on the drug and disease sides, separately. We constructed heterogeneous networks using drug-drug similarities based on chemical structures and ATC codes, ontology-based disease-disease similarities, and drug-disease associations. An improved evaluation metric was used to reflect data imbalance as positive associations are typically sparse. The prediction results demonstrated that methods in the graph mining and matrix factorization or completion categories performed well in the overall assessment. Furthermore, prediction on the drug side had higher accuracy than on the disease side. Selecting and integrating informative drug features in drug-drug similarity measurement are crucial for improving disease-side prediction.

Dynamic regulation of mitochondrial morphology provides cells with the flexibility required to adapt and respond to electron transport chain (ETC) toxins and mitochondrial DNA-linked disease mutations, yet the mechanisms underpinning the regulation of mitochondrial dynamics machinery by these stimuli is poorly understood. Here, we show that pyruvate dehydrogenase kinase 4 (PDK4) is genetically required for cells to undergo rapid mitochondrial fragmentation when challenged with ETC toxins. Moreover, PDK4 overexpression was sufficient to promote mitochondrial fission even in the absence of mitochondrial stress. Importantly, we observed that the PDK4-mediated regulation of mitochondrial fission was independent of its canonical function, i.e., inhibitory phosphorylation of the pyruvate dehydrogenase complex (PDC). Phosphoproteomic screen for PDK4 substrates, followed by nonphosphorylatable and phosphomimetic mutations of the PDK4 site revealed cytoplasmic GTPase, Septin 2 (SEPT2), as the key effector molecule that acts as a receptor for DRP1 in the outer mitochondrial membrane to promote mitochondrial fission. Conversely, inhibition of the PDK4-SEPT2 axis could restore the balance in mitochondrial dynamics and reinvigorates cellular respiration in mitochondrial fusion factor, mitofusin 2-deficient cells. Furthermore, PDK4-mediated mitochondrial reshaping limits mitochondrial bioenergetics and supports cancer cell growth. Our results identify the PDK4-SEPT2-DRP1 axis as a regulator of mitochondrial function at the interface between cellular bioenergetics and mitochondrial dynamics.

Stress exposure is a major risk factor for mental disorders such as depression. Because of the limitations of classical antidepressants such as side effects, low efficacy, and difficulty in long-term use, new natural medicines and bioactive molecules from plants with greater safety and efficacy have recently attracted attention. Luteolin-7- O -glucuronide (L7Gn), a bioactive molecule present in Perilla frutescens , is known to alleviate severe inflammatory responses and oxidative stress in macrophages. However, its antistress and antidepressant effects have not been elucidated. The present study aims to explore the antidepressant the effect of L7Gn on stress-induced behaviors and the underlying mechanism in a mouse sleep deprivation (SD) model. L7Gn treatment improved depression-like and stress coping behaviors induced by SD stress, as confirmed by the tail suspension test and forced swimming test. Furthermore, L7Gn treatment reduced the blood corticosterone and hippocampal proinflammatory cytokine levels which were increased by SD stress, and L7Gn also increased the mRNA and protein levels of hippocampal brain-derived neurotrophic factor (BDNF) which were reduced by SD stress. Additionally, treatment with L7Gn resulted in increases in the phosphorylation of tropomyosin-related kinase B (TrkB), extracellular signal-regulated kinase (ERK), and cAMP response element-binding protein (CREB), which are downstream molecules of BDNF signaling. These findings suggest that L7Gn have therapeutic potential for SD-induced stress, via activating the BDNF signaling., Competing Interests: The authors declare no conflict of interest.

Background Aims: The acute respiratory distress syndrome (ARDS) resulting from coronavirus disease 2019 (COVID-19) is associated with a massive release of inflammatory cytokines and high mortality. Mesenchymal stromal cells (MSCs) have anti-inflammatory properties and have shown activity in treating acute lung injury. Here the authors report a case series of 11 patients with COVID-19-associated ARDS (CARDS) requiring mechanical ventilation who were treated with remestemcel-L, an allogeneic MSC product, under individual patient emergency investigational new drug applications., Methods: Patients were eligible if they were mechanically ventilated for less than 72 h prior to the first infusion. Patients with pre-existing lung disease requiring supplemental oxygen or severe liver or kidney injury were excluded. Each patient received two infusions of remestemcel-L at a dose of 2 million cells/kg per infusion given 48-120 h apart., Results: Remestemcel-L infusions were well tolerated in all 11 patients. At the end of the 28-day follow-up period, 10 (91%, 95% confidence interval [CI], 59-100%) patients were extubated, nine (82%, 95% CI, 48-97%) patients remained liberated from mechanical ventilation and were discharged from the intensive care unit and two (18%, 95 CI%, 2-52%) patients died. The median time to extubation was 10 days. Eight (73%, 95% CI, 34-100%) patients were discharged from the hospital. C-reactive protein levels significantly declined within 5 days of MSC infusion., Conclusions: The authors demonstrate in this case series that remestemcel-L infusions to treat moderate to severe CARDS were safe and well tolerated and resulted in improved clinical outcomes., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: An elevated adenosine deaminase (ADA) level in the cerebrospinal fluid (CSF) is considered a reliable marker of tuberculous meningitis (TBM). However, CSF-ADA levels can also be elevated in other diseases. We aimed to find the most common diagnosis of patients with elevated CSF-ADA levels for the last 10 years., Methods: We retrospectively investigated the diagnoses of all patients with elevated CSF-ADA (ADA ≥ 10 IU/L) levels between 2010 and 2019 at the Samsung Medical Center. Definite TBM was defined based on microbiological evidence. Clinical TBM was defined based on the brain imaging and response to the standard TB treatment. We compared the laboratory characteristics of the three most common diagnoses., Results: CSF-ADA levels were elevated in 137 (5.6%) of 2,600 patients. The most common diagnoses included hematologic malignancy (HM; n = 36, 26.2%), TBM (n = 26, 19.0%), and viral meningitis (VM; n = 25, 18.2%). CSF-ADA levels did not differ significantly between TBM [median (interquartile range (IQR)), 20.2 IU/L (13.8-29.3)] and HM [16.5 (12.8-24.0)]. However, CSF-ADA levels were lower in VM [14.0 (11.0-16.1)] than in TBM (p = 0.027). Lymphocyte-dominant pleocytosis was more common in VM [77.0% (70.8-81.5)] than in TBM [16.0 (3.0-51.0), p = 0.015] or HM [36.0 (10.0-72.0); p = 0.032]. Interestingly, the CSF characteristics of clinical TBM were similar to those of VM but not definite TBM., Conclusion: The most common diagnoses with elevated CSF-ADA levels were HM, followed by TBM and VM. Clinicians should carefully consider the differential diagnoses in patients with elevated CSF-ADA levels, especially those in the early stage of meningitis without microbiological evidence for TBM., 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 © 2022 Song, Kim, Jung, Choe, Kang and Min.)

We used a rigorous PRoBE (prospective-specimen collection, retrospective-blinded-evaluation) study design to compare the ability of biomarkers of systemic inflammation and biomarkers of gastrointestinal (GI) tissue damage to predict response to corticosteroid treatment, the incidence of clinically severe disease, 6-month nonrelapse mortality (NRM), and overall survival in patients with acute graft-versus-host disease (GVHD). We prospectively collected serum samples of newly diagnosed GVHD patients (n = 730) from 19 centers, divided them into training (n = 352) and validation (n = 378) cohorts, and measured TNFR1, TIM3, IL6, ST2, and REG3α via enzyme-linked immunosorbent assay. Performances of the 4 strongest algorithms from the training cohort (TNFR1 + TIM3, TNFR1 + ST2, TNFR1 + REG3α, and ST2 + REG3α) were evaluated in the validation cohort. The algorithm that included only biomarkers of systemic inflammation (TNFR1 + TIM3) had a significantly smaller area under the curve (AUC; 0.57) than the AUCs of algorithms that contained ≥1 GI damage biomarker (TNFR1 + ST2, 0.70; TNFR1 + REG3α, 0.73; ST2 + REG3α, 0.79; all P < .001). All 4 algorithms were able to predict short-term outcomes such as response to systemic corticosteroids and severe GVHD, but the inclusion of a GI damage biomarker was needed to predict long-term outcomes such as 6-month NRM and survival. The algorithm that included 2 GI damage biomarkers was the most accurate of the 4 algorithms for all endpoints., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Prior work has shown that combining bootstrap imputation with tree-based machine learning variable selection methods can provide good performances achievable on fully observed data when covariate and outcome data are missing at random (MAR). This approach however is computationally expensive, especially on large-scale datasets., Methods: We propose an inference-based method, called RR-BART, which leverages the likelihood-based Bayesian machine learning technique, Bayesian additive regression trees, and uses Rubin's rule to combine the estimates and variances of the variable importance measures on multiply imputed datasets for variable selection in the presence of MAR data. We conduct a representative simulation study to investigate the practical operating characteristics of RR-BART, and compare it with the bootstrap imputation based methods. We further demonstrate the methods via a case study of risk factors for 3-year incidence of metabolic syndrome among middle-aged women using data from the Study of Women's Health Across the Nation (SWAN)., Results: The simulation study suggests that even in complex conditions of nonlinearity and nonadditivity with a large percentage of missingness, RR-BART can reasonably recover both prediction and variable selection performances, achievable on the fully observed data. RR-BART provides the best performance that the bootstrap imputation based methods can achieve with the optimal selection threshold value. In addition, RR-BART demonstrates a substantially stronger ability of detecting discrete predictors. Furthermore, RR-BART offers substantial computational savings. When implemented on the SWAN data, RR-BART adds to the literature by selecting a set of predictors that had been less commonly identified as risk factors but had substantial biological justifications., Conclusion: The proposed variable selection method for MAR data, RR-BART, offers both computational efficiency and good operating characteristics and is utilitarian in large-scale healthcare database studies., (© 2022. The Author(s).)

Background/aims: Drugs with anticholinergic properties (DAPs) are associated with adverse health outcomes in older patients. The objective of this study was to evaluate the factors that determine the prescribing of more DAPs in long-term care hospitals (LTCHs) in Korea. In addition, the current patterns of DAP prescription were explored using a novel platform, which can collect data from LTCHs., Methods: This was a Health-RESPECT (integrated caRE Systems for elderly PatiEnts using iCT) sub-study, which is a pragmatic, cluster-randomized, controlled trial. The Health-RESPECT platform was used to collect prescribed medication data of 466 patients (aged ≥ 65 years) from seven LTCHs. DAPs were identified using the Korean Anticholinergic Burden Scale (KABS). Physical frailty, cognitive function, functional status, and quality of life were evaluated., Results: Among 466 LTCH patients, 88.8% (n = 414) were prescribed DAPs, and the prevalence of high KABS (≥ 3) was 70.4% (n = 328). The drugs that contributed most to the total KABS were quetiapine (20.7%), chlorpheniramine (19.5%), tramadol (9.8%), cimetidine (5.8%), and furosemide (3.6%). Polypharmacy, higher body mass index, less dependence, better communication and cognitive functions, and poorer quality of life were associated with high KABS., Conclusion: Although the patients with a high burden of DAPs were less dependent and had better cognitive and communication functions, they had poorer quality of life. DAP use in LTCH patients should be monitored carefully, and the risk/ benefit relationship for their use should be considered.

Objectives: There are limited data regarding blood pressure (BP) variability among older adults living in long-term care hospitals (LTCHs). We aimed to collect data from LTCH and analyse BP characteristics and its variability among these patients using a novel platform., Methods: The Health-RESPECT (integrated caRE Systems for elderly PatiEnts using iCT) platform was used to construct a daily BP dataset using data of 394 older patients from 6 LTCHs. BP variability was expressed as coefficient of variation (CV = standard deviation/mean of BP × 100). Physical frailty and cognitive function were evaluated using the K-FRAIL questionnaire and the Cognitive Performance Scale of the interRAI Long-Term Care Facilities tool, respectively., Results: From September 2019 to September 2020, 151,092 BP measurements, 346.5 (IQR 290.8-486.3) measurements per patient, were included. The mean BP was 123.4 ± 10.8/71.3 ± 6.5 mmHg. BP was significantly lower in frail patients (122.2 ± 11.3/70.4 ± 6.8 mmHg) than in pre-frail/robust patients (124.4 ± 10.4/72.1 ± 6.1 mmHg, P < 0.05). However, CV of systolic (10.7 ± 2.3% versus 11.3 ± 2.3%, P = 0.005) and diastolic (11.6 ± 2.3% versus 12.4 ± 2.4%, P < 0.001) BP was higher in frail patients. The mean BP was lower, but BP variability was higher in patients with cognitive impairment. The mean BP, but not BP variability, was higher in treated hypertensive patients, as the number of antihypertensive medications increased., Conclusion: Older patients with physical or cognitive frailty had lower BP but higher BP variability. Relationship among frailty, increased BP variability and adverse clinical outcomes should be investigated., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Insomnia, the most common sleep disorder, is characterized by a longer sleep latency, greater sleep fragmentation, and consequent excessive daytime fatigue. Due to the various side effects of prescribed hypnotics, demand for new drugs is still high. Recent studies have suggested the adenosine receptor (AR) as a potential therapeutic target for insomnia, however, clinically useful hypnotics targeting AR are not yet available. In the present study, we evaluated the hypnotic effect of rosmarinic acid, a phenolic compound widely found in medicinal plants, through pentobarbital-induced sleep test, electroencephalography/electromyography (EEG/EMG), and immunohistochemistry in mice. The underlying mechanisms were assessed by pharmacological approach using 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and SCH5826, antagonists for A 1 R and A 2 AR, respectively. Receptor-binding assay and functional agonism were also performed. Our study provides a new evidence that rosmarinic acid has a direct binding activity (Ki = 14.21 ± 0.3 μM) and agonistic activity for A 1 R. We also found that rosmarinic acid significantly decreased sleep fragmentation and onset latency to NREM sleep, and these effects were abolished by DPCPX. The results from c-Fos immunostaining showed that rosmarinic acid decreased the neuronal activity in wake-promoting brain regions, such as the basal forebrain and the lateral hypothalamus, while increasing the neuronal activity in the ventrolateral preoptic nucleus, a sleep-promoting region; all these effects were significantly inhibited by DPCPX. Taken together, this study suggests that rosmarinic acid possesses novel activity as an A 1 R agonist and thereby exerts a hypnotic effect, and thus it may serve as a potential therapeutic agent for insomnia through targeting A 1 R., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Computational prediction of drug-target interactions (DTIs) is of particular importance in the process of drug repositioning because of its efficiency in selecting potential candidates for DTIs. A variety of computational methods for predicting DTIs have been proposed over the past decade. Our interest is which methods or techniques are the most advantageous for increasing prediction accuracy. This article provides a comprehensive overview of network-based, machine learning, and integrated DTI prediction methods. The network-based methods handle a DTI network along with drug and target similarities in a matrix form and apply graph-theoretic algorithms to identify new DTIs. Machine learning methods use known DTIs and the features of drugs and target proteins as training data to build a predictive model. Integrated methods combine these two techniques. We assessed the prediction performance of the selected state-of-the-art methods using two different benchmark datasets. Our experimental results demonstrate that the integrated methods outperform the others in general. Some previous methods showed low accuracy on predicting interactions of unknown drugs which do not exist in the training dataset. Combining similarity matrices from multiple features by data fusion was not beneficial in increasing prediction accuracy. Finally, we analyzed future directions for further improvements in DTI predictions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The blood-brain barrier (BBB), which consists mainly of brain microvascular endothelial cells and astrocytes connected by tight junctions (TJs) and adhesion molecules (AMs), maintains the homeostatic balance between brain parenchyma and extracellular fluid. Accumulating evidence shows that BBB dysfunction is a common feature of neurodegenerative diseases, including stroke, traumatic brain injury, and Alzheimer's disease. Among the various pathological pathways of BBB dysfunction, reactive oxygen species (ROS) are known to play a key role in inducing BBB disruption mediated via TJ modification, AM induction, cytoskeletal reorganization, and matrix metalloproteinase activation. Thus, antioxidants have been suggested to exert beneficial effects on BBB dysfunction-associated brain diseases. In this review, we summarized the sources of ROS production in multiple cells that constitute or surround the BBB, such as BBB endothelial cells, astrocytes, microglia, and neutrophils. We also reviewed various pathological mechanisms by which BBB disruption is caused by ROS in these cells. Finally, we summarized the effects of various natural polyphenols on BBB dysfunction to suggest a therapeutic strategy for BBB disruption-related brain diseases.

Background: Neoadjuvant chemotherapy (NAC) is frequently used in gastrointestinal cancers (GIC), and pathological, radiological, and tumor marker responses are assessed during and after NAC., Aim: To evaluate the relationship between pathologic, radiologic, tumor marker responses and recurrence-free survival (RFS), overall survival (OS), adjuvant chemotherapy (AC) decisions, and the impact of changing to a different AC regimen after poor response to NAC., Methods and Results: Medical records of GIC patients treated with NAC at Mount Sinai between 1/2012 and 12/2018 were reviewed. One hundred fifty-six patients (58.3% male, mean age 63 years) were identified. Primary tumor sites were: 43 (27.7%) pancreas, 62 (39.7%) gastroesophageal, and 51 (32.7%) colorectal. After NAC, 31 (19.9%) patients had favorable pathologic response (FPR; defined as College of American Pathologists [CAP] score 0-1). Of 107 patients with radiological data, 59 (55.1%) had an objective response, and of 113 patients with tumor marker data, 61 (54.0%) had a ≥50% reduction post NAC. FPR, but not radiographic or serological responses, was associated with improved RFS (HR 0.28; 95% CI 0.11-0.72) and OS (HR 0.13; 95% CI 0.2-0.94). Changing to a different AC regimen from initial NAC, among all patients and specifically among those with unfavorable pathological response (UPR; defined as CAP score 2-3) after NAC, was not associated with improved RFS or OS., Conclusions: GIC patients with FPR after NAC experienced significant improvements in RFS and OS. Patients with UPR did not benefit from changing AC. Prospective studies to better understand the role of pathological response in AC decisions and outcomes in GIC patients are needed., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Variable selection in the presence of both missing covariates and outcomes is an important statistical research topic. Parametric regression are susceptible to misspecification, and as a result are sub-optimal for variable selection. Flexible machine learning methods mitigate the reliance on the parametric assumptions, but do not provide as naturally defined variable importance measure as the covariate effect native to parametric models. We investigate a general variable selection approach when both the covariates and outcomes can be missing at random and have general missing data patterns. This approach exploits the flexibility of machine learning models and bootstrap imputation, which is amenable to nonparametric methods in which the covariate effects are not directly available. We conduct expansive simulations investigating the practical operating characteristics of the proposed variable selection approach, when combined with four tree-based machine learning methods, extreme gradient boosting, random forests, Bayesian additive regression trees, and conditional random forests, and two commonly used parametric methods, lasso and backward stepwise selection. Numeric results suggest that, extreme gradient boosting and Bayesian additive regression trees have the overall best variable selection performance with respect to the F 1 score and Type I error, while the lasso and backward stepwise selection have subpar performance across various settings. There is no significant difference in the variable selection performance due to imputation methods. We further demonstrate the methods via a case study of risk factors for 3-year incidence of metabolic syndrome with data from the Study of Women's Health Across the Nation.

Anode materials providing a high specific capacity with a high cycling performance are one of the key parameters for lithium ion batteries' (LIBs) applications. Herein, a high-capacity NiFe 2 O 4 (NFO) film anode is prepared by E-beam evaporation, and the effect of the heat treatment is studied on the microstructure and electrochemical properties of LIBs. The NiFe 2 O 4 film annealed at 800 °C (NFO-800) showed a highly crystallized structure and different surface morphologies when compared to the electrode annealed at a lower temperature (NFO-600, NFO-700). In the electrochemical measurements, the high specific capacity (1804 mA g -1 ) and capacity retention ratio (95%) after 100 cycles were also achieved by the NFO-800 electrode. The main reason for the good electrochemical performance of the NFO-800 electrode is a high structure integrity, which could improve the cycle stability with a high discharge capacity. The NiFe 2 O 4 electrode with an annealing process could be further proposed as an alternative ferrite material.

In platelets, oxidative stress reportedly increases platelet adhesion to vessels, thus promoting the vascular pathology of various neurodegenerative diseases, including Alzheimer's disease (AD). Recently, it has been shown that β-amyloid (Aβ) can increase oxidative stress in platelets; however, the underlying mechanism remains elusive. In the present study, we aimed to elucidate the signaling pathway of platelet adhesion induced by Aβ 1-40 , the major form of circulating Aβ, through Western blotting, immunofluorescence confocal microscopy, and fluorescence-activated cell sorting analysis. Additionally, we examined whether rosmarinic acid (RA), a natural polyphenol antioxidant, can modulate these processes. Our results show that Aβ 1-40 -induced platelet adhesion is mediated through NADPH oxidase/ROS/PKC-δ/integrin α IIb β 3 signaling, and these signaling pathways are significantly inhibited by RA. Collectively, these results suggest that RA may have beneficial effects on platelet-associated vascular pathology in AD.

The National Lung Screening Trial (NLST) found that low-dose computed tomography (LDCT) screening provided lung cancer (LC) mortality benefit compared to chest radiography (CXR). Considerable research concerns identifying the differential treatment effects that may exist in certain subpopulations. We shed light on several important issues in existing research and highlight the need for further investigation of the heterogeneous comparative effect of LDCT versus CXR, using more flexible and rigorous statistical approaches. We used a high-performance Bayesian machine learning approach designed for censored survival data, accelerated failure time Bayesian additive regression trees model (AFT-BART), to flexibly capture the relationships between the failure time and predictors. We then used the counterfactual framework to draw Markov chain Monte Carlo samples of the individual treatment effect for each participant. Using these posterior samples, we explored the possible treatment effect heterogeneity via a stepwise binary tree approach. When re-analyzed with AFT-BART, LDCT did not have a statistically significant LC or overall mortality benefit compared to CXR. The Asian and Black (particularly those with pack-year ≥ 37 years and without emphysema) NLST population were shown to have enhanced overall mortality benefit from LDCT than the population average. Although inconclusive for LC mortality benefit, Asians, Blacks and Whites with history of chronic obstructive pulmonary disease showed a small trend towards benefit from LDCT. Causal inference with flexible machine learning modeling can provide valuable knowledge for informing treatment decision and planning targeted clinical trials emphasizing personalized medicine approaches., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: To investigate racial disparities among unresectable/metastatic pancreatic ductal adenocarcinoma (PDA) patients treated with contemporary chemotherapy regimens at an urban center., Methods: Retrospective review of all PDA patients treated at a single institution between 2012-2017. Continuous and categorical variables were tested using t -test, Mann-Whitney U, chi-squared or Fisher's exact test as appropriate. Kaplan-Meier curves were generated and Cox proportional hazards models were used to analyze survival outcomes., Results: One hundred and forty-five patients identified as: White [69], African American (AA, 34), Asian [15], and Other [27]. Fifty-five-point-seven percent of patients received gemcitabine-based therapy vs. 36.6% received fluorouracil (5-FU) based therapy, specifically 26.1% received FOLFIRINOX and 43.7% received gemcitabine/nab-paclitaxel. In a univariable model, Asians had significantly worse overall survival (OS) than Whites [hazard ratio (HR) 2.74, P=0.013], but there were no OS differences between AA vs. Whites (HR 1.51, P=0.297) nor Other vs. Whites (HR 2.05, P=0.062). On multivariable analysis, Asians had worse OS compared to Whites (HR 2.62, P=0.018), and gemcitabine-based therapy was inferior to 5-FU-based therapy (HR 2.65, P=0.005). There were no OS differences between AA vs . Whites nor Other vs . Whites (HR 1.12, P=0.769 and HR 0.8, P=0.763, respectively)., Conclusions: In this series of advanced PDA patients treated with contemporary chemotherapy, AA and White patients had comparable outcomes, but Asians had worse OS than White patients.

Functional modules can be predicted using genome-wide protein-protein interactions (PPIs) from a systematic perspective. Various graph clustering algorithms have been applied to PPI networks for this task. In particular, the detection of overlapping clusters is necessary because a protein is involved in multiple functions under different conditions. graph entropy (GE) is a novel metric to assess the quality of clusters in a large, complex network. In this study, the unweighted and weighted GE algorithm is evaluated to prove the validity of predicting function modules. To measure clustering accuracy, the clustering results are compared to protein complexes and Gene Ontology (GO) annotations as references. We demonstrate that the GE algorithm is more accurate in overlapping clusters than the other competitive methods. Moreover, we confirm the biological feasibility of the proteins that occur most frequently in the set of identified clusters. Finally, novel proteins for the additional annotation of GO terms are revealed.

Objective: Dementia and epilepsy often co-occur and are associated with poor health outcomes and increased healthcare utilization. The literature on the association between readmission and co-occurrence of dementia and epilepsy is scant. Our objective was to determine if dementia in patients with epilepsy >40 years old is associated with 30-day hospital readmission, in-hospital mortality, discharge disposition, and length-of-stay., Methods: This retrospective cohort study used the 2014 Nationwide Readmissions Database, containing data from hospital discharges across the US and readmissions. Epilepsy and dementia were identified using previously validated ICD-9-CM codes. Primary outcome was 30-day readmission, analyzed with univariable and multivariable logistic regressions. Secondary outcomes were discharge disposition, in-hospital mortality, and length-of-stay, analyzed with univariable multinomial logistic, univariable logistic, and univariable ordinary least squared regressions, respectively. The top ten causes of readmission in each group were compared as well. All analyses accounted for survey weights, cluster, and stratum., Results: Patients with epilepsy with dementia (n = 15,588) had longer hospital stays [15% (95%CI 10-20%)], and higher odds of readmission [OR 1.11 (95%CI 1.05-1.17)], transfer to another facility [OR 2.18 (95%CI 1.93-2.46)], and in-hospital mortality [OR 1.50 (95%CI 1.25-1.79)] compared to those without dementia (n = 186,289).The top two causes of readmission were septicemia (dementia: 14.81%; no dementia: 9.45%) and epilepsy/convulsions (dementia: 5.91%; no dementia: 6.25%). Other top 10 causes of readmissions in those with epilepsy and dementia which were not present in those without dementia included delirium (5.21%), urinary tract infections (4.98%), and aspiration pneumonitis (4.29%)., Significance: Dementia in epilepsy is associated with worse outcomes, including higher in-hospital mortality and higher readmissions. Potentially preventable causes of readmission in those with epilepsy and dementia were identified, including septicemia, delirium, urinary tract infection, and aspiration pneumonitis. Future studies are needed to inform interventions aimed at decreasing premature mortality and reducing potentially preventable readmissions in this vulnerable population., Competing Interests: Declaration of Competing Interest NJ receives grant funding paid to her institution for grants unrelated to this work from NINDS (NIH U24NS107201, NIH IU54NS100064) and PCORI. She receives an honorarium for her work as an Associate Editor of Epilepsia. MM is supported on the following grants: National Cancer Institute P30 CA196521, National Institute of Aging P30AG028741 & P30AG028741- 09S1 & R01AG054540 grants. Other authors report no disclosures., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Our objective was to determine proportions, causes, and predictors of 30-day readmissions among older adults with epilepsy. Understanding predictors of readmissions may inform future interventions aimed at reducing avoidable hospitalizations in this vulnerable population., Methods: Individuals 65 years or older with epilepsy were identified using previously validated ICD-9-CM codes in any diagnostic position in the 2014 Nationwide Readmissions Database. Proportions of 30-day readmissions and causes of readmissions in older adults with epilepsy were compared to both older adults without and younger adults (18-64 years old) with epilepsy. We identified predictors of readmission in older adults with epilepsy using logistic regression., Results: There were 92,030 older adults with, 3,166,852 older adults without, and 168,622 younger adults with epilepsy. Proportions of readmissions were higher in older adults with (16.2%) than older adults without (12.5%) and younger adults with epilepsy (15.1%). The main cause of readmission for older adults with and without epilepsy was septicemia, and epilepsy/seizure in younger adults with epilepsy. Predictors of 30-day readmissions in older adults with epilepsy were: non-elective admissions (OR 1.37, 95%CI 1.27-1.48), public insurance (Medicaid vs. private insurance OR 1.19, 95%CI 1.02-1.39; Medicare vs. private insurance OR 1.11, 95%CI 1.00-1.22), lower median household income for patient's zip code ($1-$39,999 vs. $66,000 + OR 1.15, 95% CI 1.08-1.22), hospital location in large metropolitan areas (OR 1.22, 95%CI 1.05-1.42), higher Charlson-Deyo comorbidity index (OR 1.11, 95%CI 1.10-1.02), and male sex (OR 1.04, 95%CI 1.00-1.09)., Significance: Our findings suggest that targeted interventions to reduce the risk of infection may potentially reduce readmission in older people with epilepsy, similarly to those without. Provision of coordinated care and appropriate discharge planning may reduce readmissions particularly in those who are males, are of lower socioeconomic status and with more comorbidities., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Obesity is now recognized as a disease. This study revealed a novel role for pyruvate dehydrogenase kinase (PDK) in diet-induced hypertrophic obesity. Mice with global or adipose tissue-specific PDK2 deficiency were protected against diet-induced obesity. The weight of adipose tissues and the size of adipocytes were reduced. Adipocyte-specific PDK2 deficiency slightly increased insulin sensitivity in HFD-fed mice. In studies with 3T3-L1 preadipocytes, PDK2 and PDK1 expression was strongly increased during adipogenesis. Evidence was found for epigenetic induction of both PDK1 and PDK2. Gain- and loss-of-function studies with 3T3-L1 cells revealed a critical role for PDK1/2 in adipocyte differentiation and lipid accumulation. PDK1/2 induction during differentiation was also accompanied by increased expression of hypoxia-inducible factor-1α (HIF1α) and enhanced lactate production, both of which were absent in the context of PDK1/2 deficiency. Exogenous lactate supplementation increased the stability of HIF1α and promoted adipogenesis. PDK1/2 overexpression-mediated adipogenesis was abolished by HIF1α inhibition, suggesting a role for the PDK-lactate-HIF1α axis during adipogenesis. In human adipose tissue, the expression of PDK1/2 was positively correlated with that of the adipogenic marker PPARγ and inversely correlated with obesity. Similarly, PDK1/2 expression in mouse adipose tissue was decreased by chronic high-fat diet feeding. We conclude that PDK1 and 2 are novel regulators of adipogenesis that play critical roles in obesity., (© 2021. The Author(s).)

Background: Previous studies have found that Black patients with multiple myeloma undergo autologous stem-cell transplantation (ASCT) less frequently than their white counterparts, although the factors leading to decreased access and utilization have not been fully elucidated., Patients and Methods: To identify whether racial differences in transplantation timing played a role in these disparities, we retrospectively analyzed 410 Black and white patients who received their first transplant at The Mount Sinai Hospital between 2011 and 2016 (260 white and 150 Black patients). We compared the time from initial diagnosis to stem-cell collection and the time from collection to transplantation between the 2 races while controlling for age, socioeconomic status, and functional status., Results: Between Blacks and whites, time from diagnosis to collection was higher in Black patients (median 238, vs. 195 days, respectively, P = .051). Functional status, socioeconomic status, and age were also significantly associated with time to collection, and after controlling for these covariates, the effect of race was not significant (P = .0625). Conversely, time from collection to transplantation was increased in white patients compared to Black., Conclusion: Increased time from diagnosis to stem-cell collection for Black patients was driven in part by socioeconomic status and baseline functional status., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: In Arabidopsis thaliana (Arabidopsis), clade IIb lateral organ boundary domain (LBD) 37, 38, and 39 proteins negatively regulate anthocyanin biosynthesis and affect nitrogen responses., Objective: To investigate the possible role of LBD genes in anthocyanin accumulations among green and purple cabbages (Brassica oleracea var. capitata), we determined sequence variations and expression levels of cabbage homologs of Arabidopsis LBD37, 38, and 39., Methods: DNA and mRNA sequences of BoLBD37, BoLBD37L (BoLBD37-like), BoLBD38, BoLBD38L (BoLBD38-like), and BoLBD39 gene in cabbage were determined. Allelic variations of BoLBD37L alleles in cabbages, resulting from insertions, were validated by genomic DNA PCR. Gene expressions were examined by semi-quantitative reverse transcription (RT-PCR) or quantitative RT-PCR., Results: Based on the expression analyses, BoLBD37L with two alleles, BoLBD37L-G and BoLBD37L-P, was selected as a candidate gene important for differential anthocyanin accumulation. BoLBD37L-P contains an 136 base pair insertion in the 2nd exon, producing two splicing variants encoding truncated proteins. Most purple cabbage lines were found to have BoLBD37L-P allele as homozygotes or heterozygotes, and only two out of sixty-four purple cabbages were identified as BoLBD37L-G homozygotes. Expression analyses of anthocyanin biosynthesis genes and their upstream regulators, including BoLBD37L, suggest that truncated proteins encoded by splicing variants of BoLBD37L-P may disrupt the BoLBD37L function as repressor., Conclusion: Difference in the C-terminal region of BoLBD37L-G and BolBD37L-P may affect the expression of downstream genes, BoMYB114L and BoTT8, resulting in differential anthocyanin accumulation.

Background: The Systems for Person-Centered Elder Care (SPEC), a complex intervention, was conducted to examine its effectiveness as a technology-enhanced, multidisciplinary, and integrated care model for frail older persons among ten nursing homes (NHs) in South Korea where formal long-term care has recently been introduced. The purpose of this study was to evaluate the implementation fidelity of the SPEC intervention and to identify moderating factors that influence the implementation fidelity., Methods: This study was a process evaluation based on an evidence-based framework for implementation fidelity using a mixed-methods design. Quantitative data from consultant logbooks, NH documentations, an information and communications technology (ICT) system, and a standardized questionnaire were collected from April 2015 to December 2016 and analyzed by calculating the descriptive statistics. Semi-structured focus group interviews were held with multidisciplinary teams from the participating NHs. Qualitative data from a semi-structured questionnaire and the focus group interviews were analyzed using content analysis., Results: The SPEC program demonstrated good implementation fidelity, and adherence to the SPEC program was strong in all aspects, such as content, coverage, frequency, and duration. Of the participating on-site coordinators, 60% reported that the SPEC model positively impacted needs assessment and the reporting system for resident care. The important facilitating factors were tailored facilitating strategies, assurance of the quality of delivery, and recruitment strategies., Conclusion: The effectiveness of the SPEC program was driven by good implementation fidelity. The key factors of good implementation fidelity were tailored delivery of evidence-based interventions over process evaluation work, facilitating strategies, and ICT support. Larger implementation studies with a more user-friendly ICT system are recommended., Trial Registration: ISRCTN registry, ISRCTN11972147 . Registered on 16 March 2015.

Objective: To assess whether epilepsy is associated with increased odds of 30-day readmission due to psychiatric illness during the postpartum period., Methods: The 2014 Nationwide Readmissions Database and the International Classification of Disease, Ninth Revision, Clinical Modification codes were used to identify postpartum women up to 50 years old in the United States, including the subgroup with epilepsy. The primary outcome was 30-day readmission and was categorized as (1) readmission due to psychiatric illness, (2) readmission due to all other causes, or (3) no readmission. Secondary outcome was diagnosis at readmission. The association of the primary outcome and presence of epilepsy was examined using multinomial logistic regression., Results: Of 1 558 875 women with admissions for delivery identified, 6745 (.45%) had epilepsy. Thirteen of every 10 000 women had 30-day psychiatric readmissions in the epilepsy group compared to one of every 10 000 in the no-epilepsy group (p < .0001). Of every 10 000 women with epilepsy, 256 had 30-day readmissions due to other causes compared to 115 of every 10 000 women in the no-epilepsy group (p < .0001). The odds ratio for readmission due to psychiatric illness was 10.13 (95% confidence interval = 5.48-18.72) in those with epilepsy compared to those without. Top psychiatric causes for 30-day readmissions among women with epilepsy were mood disorders, schizophrenia and other psychotic disorders, and substance-related disorders., Significance: This large-scale study demonstrated that postpartum women with epilepsy have higher odds of readmission due to a psychiatric illness compared to women without epilepsy. Postpartum treatment strategies and interventions to prevent psychiatric readmissions are necessary in this vulnerable population., (© 2021 International League Against Epilepsy.)

Background: Antibiotic exposure has been associated with worse outcomes with immune checkpoint inhibitors (ICIs) in cancer patients, likely due to disruption of the gut microbiome. Other commonly prescribed medications, such as proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs), are also known to disrupt the microbiome, but data on their association with ICI outcomes are conflicting., Methods: We conducted a retrospective, multicenter, international cohort study including 314 hepatocellular carcinoma (HCC) patients treated with ICIs from 2017 to 2019 to assess the association between PPI or H2RA exposure (up to 30 days before ICI) and overall survival. Secondary outcomes included overall response rate (ORR) and development of any treatment-related adverse events (AEs)., Results: Baseline PPI/H2RA exposure was not associated with overall survival in univariable (HR 1.01, 95% CI 0.75-1.35) or multivariable analysis (HR 0.98, 95% CI 0.71-1.36). Baseline PPI/H2RA exposure was not associated with either ORR (OR 1.32, 95% CI 0.66-2.65) or AEs (OR 1.07, 95% CI 0.54-2.12) in multivariable analysis., Conclusions: Our results suggest that exposure to PPI/H2RA prior to ICIs does not adversely affect outcomes in HCC patients., Competing Interests: Conflict of interest statement: DJP received lecture fees from ViiV Healthcare and Bayer Healthcare and travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, and Astra Zeneca; received research funding (to institution) from MSD and BMS. LR reports receiving consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, Celgene, Eisai, Exelixis, Hengrui, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi; lectures fees from AbbVie, Amgen, Eisai, Gilead, Incyte, Ipsen, Lilly, Roche, Sanofi; travel fees from Ipsen; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Roche. NP reports receiving consulting fees from Amgen, Merck Serono, Servier; lectures fees from AbbVie, Gilead, Lilly; travel fees from Amgen, ArQule; and institutional research funding from Basilea, Merck Serono, Servier. TP reports receiving institutional research funding from Lilly., (© The Author(s), 2021.)

Background and Objectives: The objective of this study was to evaluate the impact of an information and communication technologies (ICT)-enhanced, multidisciplinary integrated care model, called Systems for Person-centered Elder Care (SPEC), on frail older adults at nursing homes., Research Design and Methods: SPEC was implemented at 10 nursing homes in South Korea in random order using a stepped-wedge design. Data were collected on all participating older residents in the homes before the first implementation and until 6 months after the last implementation. The 21-month SPEC intervention guided by the chronic care model (CCM) consists of 5 strategies: comprehensive geriatric assessment, care planning, optional interdisciplinary case conferences, care coordination, and a cloud-based ICT tool along with a free messaging app. The primary outcome was quality of care measured by a composite quality indicator (QI) from the interRAI assessment system. Usual care continued over the control periods. Nursing home staff were not blinded to the intervention., Results: There were a total of 482 older nursing home residents included in the analysis. Overall quality of care measured by the composite QI was significantly improved (adjusted mean difference: -0.025 [95% CI: -0.037 to -0.014, p < .0001]). The intervention effect was consistent in the subgroup analysis by cognition and activities of daily living. There were no important adverse events or side effects., Discussion and Implications: The SPEC, a CCM-guided, ICT-supported, multidisciplinary integrated care management intervention, can improve the quality of care measured by health and functional outcomes for frail older persons residing in nursing homes with limited health care provision., Clinical Trials Registration Number: ISRCTN11972147., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America.)

The aims were to develop an integrated electronic medication reconciliation (ieMR) platform, evaluate its effects on preventing potential duplicated medications, analyze the distribution of the potential duplicated medications by the Anatomical Therapeutic and Chemical (ATC) code for all inpatients, and determine the rate of 30-day medication-related hospital revisits for a geriatric unit. The study was conducted in a tertiary medical center in Taiwan and involved a retrospective quasi pre-intervention (July 1-November 30, 2015) and post-intervention (October 1-December 31, 2016) study design. A multidisciplinary team developed the ieMR platform covering the process from admission to discharge. The ieMR platform included six modules of an enhanced computer physician order entry system (eCPOE), Pharmaceutical-care, Holistic Care, Bedside Display, Personalized Best Possible Medication Discharge Plan, and Pharmaceutical Care Registration System. The ieMR platform prevented the number of potential duplicated medications from pre (25,196 medications, 2.3%) to post (23,413 medications, 3.8%) phases (OR 1.71, 95% CI, 1.68-1.74; p < .001). The most common potential duplicated medications classified by the ATC codes were cardiovascular system (28.4%), alimentary tract and metabolism (26.4%), and nervous system (14.9%), and by chemical substances were sennoside (12.5%), amlodipine (7.5%), and alprazolam (7.4%). The rate of medication-related 30-day hospital revisits for the geriatric unit was significantly decreased in post-intervention compared with that in pre-intervention (OR = 0.12; 95% CI, 0.03-0.53; p < .01). This study indicated that the ieMR platform significantly prevented the number of potential duplicated medications for inpatients and reduced the rate of 30-day medication-related hospital revisits for the patients on the geriatric unit.

Age-related macular degeneration (AMD), especially neovascular AMD with choroidal neovascularization (CNV), is the leading cause of blindness in the elderly. Although matrix metalloproteinases (MMPs) are involved in pathological ocular angiogenesis, including CNV, the cellular origin of MMPs in AMD remains unknown. The present study investigated the role of microglial MMPs in CNV. MMP activities were analyzed by gelatin zymography in aqueous humor samples from patients with CNV and laser-induced CNV mice. Active MMP-9 was increased in the aqueous humor samples from neovascular AMD patients compared with control subjects. In the retinal pigment epithelium (RPE)/choroid from CNV mice, active MMP-9 increased, beginning 1 h post-CNV induction, and remained upregulated until Day 7. In RPE/choroid from CNV mice, active MMP-9 was suppressed by minocycline, a known microglial inhibitor, at 6 h and 1-day post-CNV induction. Flow cytometry revealed that the proportion of activated microglia increased very early, beginning at 1 h post-CNV induction, and was maintained until Day 7. Similarly, immunohistochemistry revealed increased microglial activation and MMP-9 expression on CNV lesions at 6 h and 1-day post-CNV induction. SB-3CT, an MMP inhibitor, decreased vascular leakage and lesion size in laser-induced CNV mice. These findings indicated nearly immediate recruitment of activated microglia and very early MMP-9 activation in the RPE/choroid. The present study newly identified a potential role for early microglial MMP-9 expression in CNV, and furthermore that modulating microglial MMP expression is a novel putative therapeutic for CNV., Competing Interests: JL was employed by company JD Bioscience Inc. The remaining 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 © 2021 Kim, Kim, Do, Lee, Yanai, Lee, Suk and Park.)