Integration of National Health Insurance claims data and animal models reveals fexofenadine as a promising repurposed drug for Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a common and costly progressive neurodegenerative disease of unclear etiology. A disease-modifying approach that can directly stop or slow its progression remains a major unmet need in the treatment of PD. A clinical pharmacology-based drug repositioning strategy is a useful approach for identifying new drugs for PD. METHODS: We analyzed claims data obtained from the National Health Insurance Service (NHIS), which covers a significant portion of the South Korean population, to investigate the association between antihistamines, a class of drugs commonly used to treat allergic symptoms by blocking H1 receptor, and PD in a real-world setting. Additionally, we validated this model using various animal models of PD such as the 6-hydroxydopmaine (6-OHDA), α-synuclein preformed fibrils (PFF) injection, and Caenorhabditis elegans (C. elegans) models. Finally, whole transcriptome data and Ingenuity Pathway Analysis (IPA) were used to elucidate drug mechanism pathways. RESULTS: We identified fexofenadine as the most promising candidate using National Health Insurance claims data in the real world. In several animal models, including the 6-OHDA, PFF injection, and C. elegans models, fexofenadine ameliorated PD-related pathologies. RNA-seq analysis and the subsequent experiments suggested that fexofenadine is effective in PD via inhibition of peripheral immune cell infiltration into the brain. CONCLUSION: Fexofenadine shows promise for the treatment of PD, identified through clinical data and validated in diverse animal models. This combined clinical and preclinical approach offers valuable insights for developing novel PD therapeutics.

Light-stimulated insulin secretion from pancreatic islet-like organoids derived from human pluripotent stem cells.

Optogenetic techniques permit non-invasive, spatiotemporal, and reversible modulation of cellular activities. Here, we report a novel optogenetic regulatory system for insulin secretion in human pluripotent stem cell (hPSC)-derived pancreatic islet-like organoids using monSTIM1 (monster-opto-Stromal interaction molecule 1), an ultra-light-sensitive OptoSTIM1 variant. The monSTIM1 transgene was incorporated at the AAVS1 locus in human embryonic stem cells (hESCs) by CRISPR-Cas9-mediated genome editing. Not only were we able to elicit light-induced intracellular Ca2+ concentration ([Ca2+]i) transients from the resulting homozygous monSTIM1+/+-hESCs, but we also successfully differentiated them into pancreatic islet-like organoids (PIOs). Upon light stimulation, the ß-cells in these monSTIM1+/+-PIOs displayed reversible and reproducible [Ca2+]i transient dynamics. Furthermore, in response to photoexcitation, they secreted human insulin. Light-responsive insulin secretion was similarly observed in monSTIM1+/+-PIOs produced from neonatal diabetes (ND) patient-derived induced pluripotent stem cells (iPSCs). Under LED illumination, monSTIM1+/+-PIO-transplanted diabetic mice produced human c-peptide. Collectively, we developed a cellular model for the optogenetic control of insulin secretion using hPSCs, with the potential to be applied to the amelioration of hyperglycemic disorders.

Retinoic Acid Treatment Mitigates PM2.5-Induced Type 2 Inflammation: Insights into Modulation of Innate Immune Responses.

Some studies have demonstrated the effects of particulate matter (PM) on chronic rhinosinusitis with nasal polyps (CRSwNP) development, as well as the therapeutic role of retinoic acid (RA) in nasal polypogenesis. However, the immunologic effect of PM in innate lymphoid cells (ILCs) and the exact mechanism of the therapeutic effect of RA remain unclear. Therefore, the present study investigated the effects of fine-dust-induced inflammation in CRSwNP and the mechanisms of the therapeutic effect of RA. PM2.5 exposure exacerbated pathological damage in the nasal mucosa of mice with nasal polyps (NP) via upregulation of type 2 inflammation. Additionally, PM2.5 exposure increased the expression of type 2 cytokines and epithelial-cell-derived cytokines (IL-33 and IL-25) significantly, as well as the ILC populations in human-NP-derived epithelial cells (HNECs). Moreover, RA supplementation significantly increased the expression of ILCreg in Lin-CD45+CD127+ cells, which in turn increased the levels of the anti-inflammatory cytokine IL-10. The findings suggest that PM2.5 exposures could aggravate the CRSwNP type 2 inflammation, and RA treatment may ameliorate fine-dust-induced inflammation by modulating the innate immune response.

Highly-enhanced active beam-wander-correction for free-space quantum communications.

In practical applications to free-space quantum communications, the utilization of active beam coupling and stabilization techniques offers notable advantages, particularly when dealing with limited detecting areas or coupling into single-mode fibers(SMFs) to mitigate background noise. In this work, we introduce highly-enhanced active beam-wander-correction technique, specifically tailored to efficiently couple and stabilize beams into SMFs, particularly in scenarios where initial optical alignment with the SMF is misaligned. To achieve this objective, we implement a SMF auto-coupling algorithm and a decoupled stabilization method, effectively and reliably correcting beam wander caused by atmospheric turbulence effects. The performance of the proposed technique is thoroughly validated through quantitative measurements of the temporal variation in coupling efficiency(coincidence counts) of a laser beam(entangled photons). The results show significant improvements in both mean values and standard deviations of the coupling efficiency, even in the presence of 2.6 km atmospheric turbulence effects. When utilizing a laser source, the coupling efficiency demonstrates a remarkable mean value increase of over 50 %, accompanied by a substantial 4.4-fold improvement in the standard deviation. For the entangled photon source, a fine mean value increase of 14 % and an approximate 2-fold improvement in the standard deviation are observed. Furthermore,the proposed technique successfully restores the fidelity of the polarization-entangled state, which has been compromised by atmospheric effects in the free-space channel, to a level close to the fidelity measured directly from the source. Our work will be helpful in designing spatial light-fiber coupling system not only for free-space quantum communications but also for high-speed laser communications.

RepID represses megakaryocytic differentiation by recruiting CRL4A-JARID1A at DAB2 promoter.

BACKGROUND: Megakaryocytes (MKs) are platelet precursors, which arise from hematopoietic stem cells (HSCs). While MK lineage commitment and differentiation are accompanied by changes in gene expression, many factors that modulate megakaryopoiesis remain to be uncovered. Replication initiation determinant protein (RepID) which has multiple histone-code reader including bromodomain, cryptic Tudor domain and WD40 domains and Cullin 4-RING E3 ubiquitin ligase complex (CRL4) recruited to chromatin mediated by RepID have potential roles in gene expression changes via epigenetic regulations. We aimed to investigate whether RepID-CRL4 participates in transcriptional changes required for MK differentiation. METHODS: The PCR array was performed using cDNAs derived from RepID-proficient or RepID-deficient K562 erythroleukemia cell lines. Correlation between RepID and DAB2 expression was examined in the Cancer Cell Line Encyclopedia (CCLE) through the CellMinerCDB portal. The acceleration of MK differentiation in RepID-deficient K562 cells was determined by estimating cell sizes as well as counting multinucleated cells known as MK phenotypes, and by qRT-PCR analysis to validate transcripts of MK markers using phorbol 12-myristate 13-acetate (PMA)-mediated MK differentiation condition. Interaction between CRL4 and histone methylation modifying enzymes were investigated using BioGRID database, immunoprecipitation and proximity ligation assay. Alterations of expression and chromatin binding affinities of RepID, CRL4 and histone methylation modifying enzymes were investigated using subcellular fractionation followed by immunoblotting. RepID-CRL4-JARID1A-based epigenetic changes on DAB2 promoter were analyzed by chromatin-immunoprecipitation and qPCR analysis. RESULTS: RepID-deficient K562 cells highly expressing MK markers showed accelerated MKs differentiation exhibiting increases in cell size, lobulated nuclei together with reaching maximum levels of MK marker expression earlier than RepID-proficient K562 cells. Recovery of WD40 domain-containing RepID constructs in RepID-deficient background repressed DAB2 expression. CRL4A formed complex with histone H3K4 demethylase JARID1A in soluble nucleus and loaded to the DAB2 promoter in a RepID-dependent manner during proliferation condition. RepID, CRL4A, and JARID1A were dissociated from the chromatin during MK differentiation, leading to euchromatinization of the DAB2 promoter. CONCLUSION: This study uncovered a role for the RepID-CRL4A-JARID1A pathway in the regulation of gene expression for MK differentiation, which can form the basis for the new therapeutic approaches to induce platelet production. Video Abstract.

The influence of dietary patterns on skin bacterial diversity, composition, and co-occurrence relationships at forearm and neck sites of healthy Korean adults.

AIMS: Diet and nutrition are important aspects of skin physiology and health. However, the influence of diet on the bacterial flora of different skin sites is not well understood. Therefore, we investigated the relationship between dietary patterns (DPs) and skin bacterial flora on the forearm (a dry site) and the neck (a sebaceous site) of healthy Korean adults. METHODS AND RESULTS: In metagenomics analysis, Shannon and Simpson indices were higher on the forearm than on the neck and were negatively correlated with the two dominant species, Cutibacterium acnes and Staphylococcus epidermidis, on two skin sites. In addition, the Simpson index of the forearm was positively associated with DP1 (characterized by a high intake of vegetables, mushrooms, meat, fish and shellfish, seaweed, and fat and oil), while that on the neck was negatively associated with DP2 (characterized by a high intake of fast food). A high intake of DP1 was associated with a lower abundance of dominant species, including C. acnes, and higher degrees of the co-occurrence network, whereas a high intake of DP2 was associated with the opposite pattern. CONCLUSIONS: Specific diets may impact both skin bacterial diversity and composition, as well as the co-occurrence of bacteria, which may vary across different skin sites.

Mental health and governmental response policy evaluation on COVID-19 based on vaccination status in Republic of Korea.

BACKGROUND: The coronavirus disease (COVID-19) pandemic has continued since the outbreak in December 2019. People experience depression and anxiety due to government policies and restrictions on physical activity due to the COVID-19 pandemic. This study aimed to compare and analyze people's experiences of COVID-19 blues, sports policy awareness, and participation intention according to their vaccination status. METHODS: This quantitative study used an online survey to collect demographic information, vaccination status, and variables. Data validity and reliability were verified through confirmatory factor analysis, and Cronbach's alpha coefficients were calculated using SPSS/AMOS 23.0. Finally, this comparative study was conducted using multivariate analysis of variance to investigate the differences in the dependent variables between the groups. RESULTS: The vaccinated group had higher scores for all factors related to COVID-19 blues (F = 19.147; p < .05; partial η2 = .046) and government policy (market responsiveness: F = 5.669, p < .05, partial η2 = .014; policy performance: F = 6.997, p < .05, partial η2 = .017; policy satisfaction: F = 7.647, p < .05, partial η2 = .019), apart from the intention to participate in sports (F = .014, p > .05, partial η2 = .000); these results demonstrate that people with COVID-19 blues and relatively high confidence in government quarantine policies were more likely to be vaccinated. In addition, all participants gave sports-participation intention the highest rating, regardless of their vaccination status; this reflects the current situation, in which individual activities are limited. CONCLUSIONS: This study analyzed the mental health of vaccinated and unvaccinated groups in Korean adult men, their perceptions of government policies, and their willingness to engage in physical activity. The findings are meaningful and highlight useful directions for future research. This study provides evidence which can help alleviate the mental damage caused by government quarantine policies and enable a better understanding of the COVID-19 pandemic. The results of this study provide important data for understanding the COVID-19 pandemic.

Toxicity and Biodistribution of Fragmented Polypropylene Microplastics in ICR Mice.

Currently, polypropylene (PP) is used in various products, thus leading to high daily exposure in humans. Thus, it is necessary to evaluate the toxicological effects, biodistribution, and accumulation of PP microplastics in the human body. In this study, administration of two particle sizes of PP microplastics (approximately 5 and 10-50 µm) did not lead to any significant changes in several toxicological evaluation parameters, including body weight and pathological examination, compared with the control group in ICR mice. Therefore, the approximate lethal dose and no-observed-adverse-effect level of PP microplastics in ICR mice were established as ≥2000 mg/kg. Furthermore, we manufactured cyanine 5.5 carboxylic acid (Cy5.5-COOH)-labeled fragmented PP microplastics to monitor real-time in vivo biodistribution. After oral administration of the Cy5.5-COOH-labeled microplastics to the mice, most of the PP microplastics were detected in the gastrointestinal tract and observed to be out of the body after 24 h in IVIS Spectrum CT. Therefore, this study provides a new insight into the short-term toxicity, distribution, and accumulation of PP microplastics in mammals.

On the architecture of collaboration in inter-organizational natural resource management networks.

This paper reviews the architecture of collaboration that exists within inter-organizational natural resource management (NRM) networks. It presents an integrative conceptual framework designed to help operationalize the multi-level interactions that occur between different dimensions of trust, risk perception, and control as key concepts in inter-organizational collaboration. The objective is to identify and justify a series of propositions considered suitable for assessing inter-organizational NRM network collaboration through empirical work. Such an integrative conceptualization goes beyond the existing trust scholarship related to collaborative NRM, and, we argue, offers a useful starting point for further exploring some of the 'inner' social dynamics affecting collaborative performance using complex systems thinking. To help establish the relevance of the conceptual framework to transboundary resource governance, a survey operationalizing different dimensions of trust, perceived risk, and control is piloted in the Salish Sea, an ecosystem that spans the Canada-US border between British Columbia and Washington State. Key challenges associated with operationalizing the framework and future research needs are identified.

Differential dynamics of cullin deneddylation via COP9 signalosome subunit 5 interaction.

Cullin-RING E3 ubiquitin ligases (CRLs) spatiotemporally regulate the proteasomal degradation of numerous cellular proteins involved in cell cycle control, DNA replication, and maintenance of genome stability. Activation of CRLs is controlled via neddylation by NEDD8-activating, -conjugating, and -attaching enzymes to the C-terminus of scaffold cullins (CULs), whereas the COP9 signalosome (CSN) inactivates CRLs via deneddylation. Here, we show that the deneddylation rate of each CUL is differentially modulated. Dose- or time-dependent treatment with pevonedistat, a small molecule inhibitor of NEDD8-activating enzyme (NAE), rapidly inhibits neddylation in most CULs, including CUL1, CUL3, CUL4A/B, and CUL5, whereas the deneddylation of CUL2 is slowly increased. We revealed that the different deneddylation speeds of each CUL depend on its binding strength with CSN5, the catalytic core of the CSN complex. Immunoprecipitation analysis revealed that CUL2 has a lower binding affinity for CSN5 than other CULs. Consistently, released cells treated with CSN5 inhibitor showed that CUL2 was slowly converted to the deneddylated form compared to the rapid deneddylation of other CULs. These findings provide mechanistic insights into the different dynamics of CULs in neddylation-deneddylation conversion.

The differentially expressed gene signatures of the Cullin 3-RING ubiquitin ligases in neuroendocrine cancer.

Cullin-RING ubiquitin E3 ligase (CRLs) composed of four components including cullin scaffolds, adaptors, substrate receptors, and RING proteins mediates the ubiquitination of approximately 20% of cellular proteins that are involved in numerous biological processes. While CRLs deregulation contributes to the pathogenesis of many diseases, including cancer, how CRLs deregulation occurs is yet to be fully investigated. Here, we demonstrate that components of CRL3 and its transcriptional regulators are possible prognosis marker of neuroendocrine (NE) cancer. Analysis of Cancer Cell Line Encyclopedia (CCLE) through the CellMinerCDB portal revealed that expression of CRL3 scaffold Cullin 3 (CUL3) highly correlates with NE signature, and CUL3 silencing inhibited NE cancer proliferation. Moreover, subset of 151 BTB (Bric-a-brac, Tramtrack, Broad complex) domain-containing proteins that have dual roles as substrate receptors and adaptor subunits in CRL3, as well as the expression of transcription factors (TFs) that control the transcription of BTB genes were upregulated in NE cancer. Analysis using published ChIP-sequencing data in small cell lung cancer (SCLC), including NE or non-NE SCLC verified that gene promoter of candidates which show high correlation with NE signature enriched H3K27Ac. These observations suggest that CRL3 is a master regulator of NE cancer and knowledge of specifically regulated CRL3 genes in NE cancer may accelerate new therapeutic approaches.

Effect of Airborne Particulate Matter on the Immunologic Characteristics of Chronic Rhinosinusitis with Nasal Polyps.

The inflammatory mechanisms of environmental pollutants in chronic rhinosinusitis (CRS) have recently been proposed. However, the mechanisms underlying the inflammatory effects of particulate matter (PM) on nasal polyp (NP) tissues remain unknown. Here we investigated the mechanism underlying the inflammatory effects of PM10 on human nasal polyp-derived fibroblasts (NPDFs). We isolated NPDFs from human NP tissues obtained from patients with CRS with NPs (CRSwNP). The NPDFs were exposed to PM10 in vitro. Immunologic characteristics were assessed using real-time polymerase chain reaction, enzyme-linked immunosorbent assay, Western blot, and flow cytometry. Additionally, we investigated the effect of NPDF-conditioned media (CM) on the expression of CD4+ T cell inflammatory mediators. PM10-treated NPDFs significantly upregulated interleukin (IL)-6, IL-4, and IL-33 expression and CXCL1 protein levels than PM10-treated normal tissues. MAP kinase, AP-1, and NF-kB were the primary cell signaling proteins. Immune cells in NPDF-CM had elevated IL-13, IL-17A, and IL-10 expression, but no significant difference in IFN-γ, TNF-α, and IL-4 expression. Moreover, under a Th2 inducing condition, NPDF-CM-treated CD4+ T cells had increased expression of IL-13, IL-10, and IL-17, which was reversed on ST2 inhibitor addition. Our study suggests that PM10 exposure could significantly increase the Th2 inflammatory pathway in NP tissues, specifically the IL-33/ST2 pathway-mediated immune response.

Multi-scale causality analysis between COVID-19 cases and mobility level using ensemble empirical mode decomposition and causal decomposition.

The global spread of the coronavirus disease 2019 (COVID-19) pandemic has affected the world in many ways. Due to the communicable nature of the disease, it is difficult to investigate the causal reason for the epidemic's spread sufficiently. This study comprehensively investigates the causal relationship between the spread of COVID-19 and mobility level on a multi time-scale and its influencing factors, by using ensemble empirical mode decomposition (EEMD) and the causal decomposition approach. Linear regression analysis investigates the significance and importance of the influential factors on the intrastate and interstate causal strength. The results of an EEMD analysis indicate that the mid-term and long-term domain portrays the macroscopic component of the states' mobility level and COVID-19 cases, which represents overall intrinsic characteristics. In particular, the mobility level is highly associated with the long-term variations of COVID-19 cases rather than short-term variations. Intrastate causality analysis identifies the significant effects of median age and political orientation on the causal strength at a specific time-scale, and some of them cannot be identified from the existing method. Interstate causality results show a negative association with the interstate distance and the positive one with the airline traffic in the long-term domain. Clustering analysis confirms that the states with the higher the gross domestic product and the more politically democratic tend to more adhere to social distancing. The findings of this study can provide practical implications to the policymakers that whether the social distancing policies are effectively working or not should be monitored by long-term trends of COVID-19 cases rather than short-term.

Comparison of the Characteristics of Recycled Carbon Fibers/Polymer Composites by Different Recycling Techniques.

In this study, three recycling methods, namely, mechanical grinding, steam pyrolysis, and the supercritical solvent process, which are used to acquire recycled carbon fibers (RCFs), were compared for their application in synthesizing polymer-matrix composites. RCF-reinforced polyethylene (PE) composites were prepared to compare the mechanical properties of the composites generated using the three recycling methods. The PE/RCF composites exhibited 1.5 times higher mechanical strength than the RCF-reinforced PE composites, probably because of the surface oxidation effects during the recycling processes that consequently enhanced interfacial forces between the RCF and the matrix. Further, the steam pyrolysis process showed the highest energy efficiency and can thus be applied on a large production scale in domestic recycled CF markets.

Molecular double clips within RepID WD40 domain control chromatin binding and CRL4-substrate assembly.

The cell cycle is modulated by ubiquitin ligases, including CRL4, which facilitate degradation of the chromatin-bound substrates involved in DNA replication and chromosome segregation. One of the members of the CRL4 complex, RepID (DCAF14/PHIP), recognizes kinetochore-localizing BUB3, known as the CRL4 substrate, and recruits CRL4 to the chromatin/chromosome using the WD40 domain. Here, we show that the RepID WD40 domain provides different platforms to CRL4 and BUB3. Deletion of the H-box or exon 8 located in the RepID WD40 domain compromises the interaction between RepID and CRL4, whereas BUB3 interacts with the exon 1-2 region. Moreover, deletion mutants of other exons in the WD40 domain lost chromatin binding affinity. Structure prediction revealed that the RepID WD40 domain has two beta-propeller folds, linked by loops, which are possibly crucial for chromatin binding. These findings provide mechanistic insights into the space occupancy of the RepID WD40 domain to form a complex with CRL4, BUB3, or chromatin.

Surviving entanglement in optic-microwave conversion by an electro-optomechanical system.

In recent development of quantum technologies, a frequency conversion of quantum signals has been studied widely. We investigate the optic-microwave entanglement that is generated by applying an electro-optomechanical frequency conversion scheme to one mode in an optical two-mode squeezed vacuum state. We quantify entanglement of the converted two-mode Gaussian state, where surviving entanglement of the state is analyzed with respect to the parameters of the electro-optomechanical system. Furthermore, we show that there exists an upper bound for the entanglement that survives after the conversion of highly entangled optical states. Our study provides a theoretical platform for a practical quantum illumination system.

Radiomics analysis of contrast-enhanced CT for classification of hepatic focal lesions in colorectal cancer patients: its limitations compared to radiologists.

OBJECTIVE: To evaluate diagnostic performance of a radiomics model for classifying hepatic cyst, hemangioma, and metastasis in patients with colorectal cancer (CRC) from portal-phase abdominopelvic CT images. METHODS: This retrospective study included 502 CRC patients who underwent contrast-enhanced CT and contrast-enhanced liver MRI between January 2005 and December 2010. Portal-phase CT images of training (n = 386) and validation (n = 116) cohorts were used to develop a radiomics model for differentiating three classes of liver lesions. Among multiple handcrafted features, the feature selection was performed using ReliefF method, and random forest classifiers were used to train the selected features. Diagnostic performance of the developed model was compared with that of four radiologists. A subgroup analysis was conducted based on lesion size. RESULTS: The radiomics model demonstrated significantly lower overall and hemangioma- and metastasis-specific polytomous discrimination index (PDI) (overall, 0.8037; hemangioma-specific, 0.6653; metastasis-specific, 0.8027) than the radiologists (overall, 0.9622-0.9680; hemangioma-specific, 0.9452-0.9630; metastasis-specific, 0.9511-0.9869). For subgroup analysis, the PDI of the radiomics model was different according to the lesion size (< 10 mm, 0.6486; ≥ 10 mm, 0.8264) while that of the radiologists was relatively maintained. For classifying metastasis from benign lesions, the radiomics model showed excellent diagnostic performance, with an accuracy of 84.36% and an AUC of 0.9426. CONCLUSION: Albeit inferior to the radiologists, the radiomics model achieved substantial diagnostic performance when differentiating hepatic lesions from portal-phase CT images of CRC patients. This model was limited particularly to classifying hemangiomas and subcentimeter lesions. KEY POINTS: • Albeit inferior to the radiologists, the radiomics model could differentiate cyst, hemangioma, and metastasis with substantial diagnostic performance using portal-phase CT images of colorectal cancer patients. • The radiomics model demonstrated limitations especially in classifying hemangiomas and subcentimeter liver lesions.

The Association of Laboratory Test Abnormalities With Mortality Risk in Pediatric Intensive Care.

OBJECTIVES: To determine the bivariable associations between abnormalities of 28 common laboratory tests and hospital mortality and determine how mortality risks changes when the ranges are evaluated in the context of commonly used laboratory test panels. DESIGN: A 2009-2016 cohort from the Health Facts (Cerner Corporation, Kansas City, MO) database. SETTING: Hospitals caring for children in ICUs. PATIENTS: Children cared for in ICUs with laboratory data. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 2,987,515 laboratory measurements in 71,563 children. The distribution of laboratory test values in 10 groups defined by population percentiles demonstrated the midrange of tests was within the normal range except for those measured predominantly when significant abnormalities are suspected. Logistic regression analysis at the patient level combined the population-based groups into ranges with nonoverlapping mortality odds ratios. The most deviant test ranges associated with increased mortality risk (mortality odds ratios > 5.0) included variables associated with acidosis, coagulation abnormalities and blood loss, immune function, liver function, nutritional status, and the basic metabolic profile. The test ranges most associated with survival included normal values for chloride, pH, and bicarbonate/total Co2. When the significant test ranges from bivariable analyses were combined in commonly used test panels, they generally remained significant but were reduced as risk was distributed among the tests. CONCLUSIONS: The relative importance of laboratory test ranges vary widely, with some ranges strongly associated with mortality and others strongly associated with survival. When evaluated in the context of test panels rather than isolated tests, the mortality odds ratios for the test ranges decreased but generally remained significant as risk was distributed among the components of the test panels. These data are useful to develop critical values for children in ICUs, to identify risk factors previously underappreciated, for education and training, and for future risk score development.

Criticality: A New Concept of Severity of Illness for Hospitalized Children.

OBJECTIVES: To validate the conceptual framework of "criticality," a new pediatric inpatient severity measure based on physiology, therapy, and therapeutic intensity calibrated to care intensity, operationalized as ICU care. DESIGN: Deep neural network analysis of a pediatric cohort from the Health Facts (Cerner Corporation, Kansas City, MO) national database. SETTING: Hospitals with pediatric routine inpatient and ICU care. PATIENTS: Children cared for in the ICU (n = 20,014) and in routine care units without an ICU admission (n = 20,130) from 2009 to 2016. All patients had laboratory, vital sign, and medication data. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A calibrated, deep neural network used physiology (laboratory tests and vital signs), therapy (medications), and therapeutic intensity (number of physiology tests and medications) to model care intensity, operationalized as ICU (versus routine) care every 6 hours of a patient's hospital course. The probability of ICU care is termed the Criticality Index. First, the model demonstrated excellent separation of criticality distributions from a severity hierarchy of five patient groups: routine care, routine care for those who also received ICU care, transition from routine to ICU care, ICU care, and high-intensity ICU care. Second, model performance assessed with statistical metrics was excellent with an area under the curve for the receiver operating characteristic of 0.95 for 327,189 6-hour time periods, excellent calibration, sensitivity of 0.817, specificity of 0.892, accuracy of 0.866, and precision of 0.799. Third, the performance in individual patients with greater than one care designation indicated as 88.03% (95% CI, 87.72-88.34) of the Criticality Indices in the more intensive locations was higher than the less intense locations. CONCLUSIONS: The Criticality Index is a quantification of severity of illness for hospitalized children using physiology, therapy, and care intensity. This new conceptual model is applicable to clinical investigations and predicting future care needs.

Correlation of site of obstruction between two dynamic evaluation modalities in obstructive sleep apnea patients: drug-induced sleep endoscopy and sleep videofluoroscopy.

PURPOSE: Drug-induced sleep endoscopy (DISE) and sleep videofluoroscopy (SVF) are two dynamic modalities for evaluating the upper airway in patients with obstructive sleep apnea (OSA). We evaluated the correlation of obstructive sites determined by DISE and SVF in OSA patients and elucidate findings that can improve the accuracy of upper airway assessment. METHODS: A consecutive series of 63 patients with OSA who underwent DISE and SVF were the subjects of this study. The DISE and SVF findings were divided according to the anatomical structure responsible for the collapse, including the soft palate (SP), oropharyngeal lateral walls (LW), tongue base (TB), and larynx (LX). The obstruction was graded on the three-point scale: 0, no obstruction; 1, partial obstruction; or 2, complete obstruction. Additionally, grade 1.5 TB obstruction was designated when the posterior displacement of the anterior tongue was detected during simultaneous retropalatal obstruction. The agreement rate and Cohen's kappa test between the two modalities were also assessed. RESULTS: The agreement rate between the two modalities was highest in LX (88.9%) followed by SP (85.7%), TB (76.1%), and LW (74.6%) (Cohen's kappa value = 0.757 in LX, 0.642 in SP, 0.637 in TB, 0.612 in LW, respectively). When grade 1.5 and 2 TB obstructions were combined, the agreement rate increased to 88.9% (Cohen's kappa value = 0.757). CONCLUSIONS: We found a good overall agreement between the two dynamic airway evaluation modalities during drug-induced sleep, and this correlation may be improved if the posterior displacement of the anterior tongue during DISE is used as a sign of TB obstruction.