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OBJECTIVE: The ethnic and sex differences in the distributions of body mass index (BMI) and waist circumference (WC) among adults are largely unknown. Therefore, we aimed to investigate the percentiles of BMI and WC in groups divided according to age, sex, and ethnicity. PATIENTS AND METHODS: We conducted a population-based binational study of adults aged =20 years based on data from two sources: US National Health and Nutrition Examination Survey (2015 to 2020) and Korea National Health and Nutrition Examination Survey (2016 to 2019). RESULTS: Weight, height, and WC were measured in 13,144 American adults and 30,191 Korean adults. Overall, BMI increased at younger ages and decreased at older ages, which indicates a reversed U-shaped relationship, and differed in terms of age, sex, and ethnicity. Women in the other Hispanic, non-Hispanic white, non-Hispanic black, and "other ethnic groups" showed a common BMI peak at ages 50-54 years. The patterns of WC distribution were similar to those of BMI distribution. CONCLUSIONS: In this binational representative study, we found varied distributions of ethnic and sex differences in BMI and WC. Considering the differences in these distributions may help improve individual and personalized treatment strategies. [ABSTRACT FROM AUTHOR]

OBJECTIVE: There is a lack of pediatric studies that have analyzed trends in mean body mass index (BMI) and the prevalence of obesity and overweight over a period that includes the mid-stage of the COVID-19 pandemic. Thus, we aimed to investigate trends in BMI, overweight, and obesity among Korean adolescents from 2005 to 2021, including the COVID-19 pandemic. SUBJECTS AND METHODS: We used data from the Korea Youth Risk Behavior Web-based Survey (KYRBS), which is nationally representative of South Korea. The study included middleand high-school students between the ages of 12 and 18. We examined trends in mean BMI and prevalence of obesity and/or overweight during the COVID-19 pandemic and compared these to those of pre-pandemic trends in each subgroup by gender, grade, and residential region. RESULTS: Data from 1,111,300 adolescents (mean age: 15.04 years) were analyzed. The estimated weighted mean BMI was 20.48 kg/m2 (95% CI, 20.46-20.51) between 2005 and 2007, and this was 21.61 kg/m2 (95% CI, 21.54-21.68) in 2021. The prevalence of overweight and obesity was 13.1% (95% CI, 12.9-13.3%) between 2005 and 2007 and 23.4% (95% CI, 22.8-24.0%) in 2021. The mean BMI and prevalence of obesity and overweight have gradually increased over the past 17 years; however, the extent of change in mean BMI and in the prevalence of obesity and overweight during the pandemic was distinctly less than before. The 17-year trends in the mean BMI, obesity, and overweight exhibited a considerable rise from 2005 to 2021; however, the slope during the COVID-19 pandemic (2020-2021) was significantly less prominent than in the pre-pandemic (2005-2019). CONCLUSIONS: These findings enable us to comprehend long-term trends in the mean BMI of Korean adolescents and further emphasize the need for practical prevention measures against youth obesity and overweight. [ABSTRACT FROM AUTHOR]

A power law topology has interesting topological properties such as low diameter and robustness and so it has been adopted in various network applications. In this paper, we propose algorithms to construct and manage the power law topology in a self-organizing manner, and introduce a use-case of the power law topology as a name resolution system for information-centric networking. Owing to the self-organizing approach, one critical problem in the power law topology, 'fragile for an intentional attack', can be solved in a native manner. We also demonstrate that the global properties of the power law topology such as degree distribution, network distance and clustering coefficient can be manipulated by these proposed algorithms. Moreover, we develop an analytical model and carry out various simulation studies to understand the properties of the constructed power law topologies. [ABSTRACT FROM AUTHOR]

Abstract Introduction Pulmonary ossification has been rarely observed in pulmonary fibrosis and in some chronic respiratory diseases such as chronic obstructive pulmonary disease. We report here a metaplastic ossification in the bronchial cartilage of a patient with multi-drug resistant tuberculosis. Case presentation We report the case of a 41-year-old Asian man from Korea with chronic multi-drug resistant tuberculosis with a rare focus of bone formation from the cartilage of a bronchus subtending an active cavity. The patient had a large multi-lobed, thick-walled cavitary tuberculosis lesion in his left upper lobe. Severe infiltration of his lymphocytes and epithelioid cells, along with some giant cells and neutrophils, was observed in the patient's bronchial wall. Desquamated bronchial epithelium and acid-fast bacilli were found inside his bronchus. A small focus of bony metaplasia was found in the cartilage of his bronchial wall. Histopathological examination confirmed calcification and showed hematopoietic cells forming in his marrow cavity. Conclusions Chronic inflammation in the lungs of our patient, caused by underlying tuberculosis, probably played a role in the development of osseous metaplasia from the associated cartilage of the bronchial wall.

BACKGROUND: Flecainide acetate is a class Ic antiarrythmic agent that is metabolized by the cytochrome P450 (CYP) 2D6 isozyme. A previous open-label, 2-period, single-sequence crossover study in healthy Korean male volunteers found differences in the pharmacokinetics of flecainide between subjects with the CYP2D6 wild-type allele and those with the CYP2D6*10 allele, as well as differences in the pharmacokinetic interaction between flecainide and the CYP2D6 inhibitor paroxetine between genotype groups. OBJECTIVE: This study evaluated QTc-interval changes after administration of a single oral dose of flecainide, with and without paroxetine, in relation to CYP2D6 genetic polymorphism. METHODS: This was a follow-on to the previous pharmacokinetic study and used data from the same group of healthy Korean male volunteers. Subjects were grouped by CYP2D6 genotype as follows: CYP2D6*1/*1 or CYP2D6*1/*2 (group 1, extensive metabolizers); CYP2D6*1/*10 (group 2, intermediate metabolizers); and CYP2D6*10/*010 or CYP2D6*10/*36 (group 3, poor metabolizers). Flecainide 200 mg was administered on day 1 (period 1); after a 7-day washout period, subjects received paroxetine 20 mg once daily from day 8 to day 14, and flecainide 200 mg on day 15 (period 2). On days 1 and 15, serial 12-lead ECGs were obtained before flecainide dosing and at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours after dosing. Baseline ECGs were obtained at the same time points on days -1 and 14. Machine-read changes in the QT interval corrected using the Fridericia formula (QTcF) and manually read changes in the QT interval individually corrected using mixed-effects modeling (QTcI) from time-matched baseline were analyzed by genotype and by period (baseline and paroxetine-inhibited state). The QRS duration and JTc interval (QTcF - QRS) were also determined. RESULTS: Twenty-one healthy volunteers (mean [SD] age, 24.5 [3.0] years; mean height, 173.5 [4.6] cm; mean weight, 69.1 [4.5] kg), 7 in each group, were enrolled in and completed the study. In period 1, all genotype groups had significant increases from time-matched baseline in both the QTcF interval (group 1:17.4 milliseconds [90% CI, 9.9-24.9], P < 0.001; group 2: 11.1 milliseconds [90% CI, 7.9-14.3], P = 0.013; and group 3: 20.5 milliseconds [90% CI, 12.8-28.2], P < 0.001) and the QTcI interval (group 1:15.4 milliseconds [90% CI, 8.0-22.9], P = 0.001; group 2: 9.1 milliseconds [90% CI, 6.5-11.8], P = 0.030; and group 3:16.4 milliseconds [90% CI, 9.3-23.5], P = 0.001); the extent of increase did not differ significantly between groups. In groups 1 and 2, the least squares mean difference between period 1 and period 2 was statistically significant for the change in QTcF interval (6.5 milliseconds [90 CI, 3.2-9.8], P = 0.002; and 6.7 milliseconds [90% CI, 3.6-9.7], P = 0.001, respectively) and QTcI interval (6.9 milliseconds [90% CI, 4.1-9.8], P < 0.001; and 5.8 milliseconds [90% CI, 3.4-8.3], P < 0.001). In group 3, the least squares mean difference between period 1 and period 2 was statistically significant for the change in QTcI interval (3.9 milliseconds [90% CI, 1.3-6.5], P = 0.015) but not for the change in QT cF interval. The changes in QRS duration did not differ significantly by genotype or period. Consistent with the findings for the QTc interval, the least squares mean difference between period 1 and period 2 was statistically significant for the change in JTc interval in groups 1 and 2 (6.9 milliseconds [90% CI, 3.7-10.2], P = 0.001; and 5.4 milliseconds [90% CI, 2.7-8.2], P = 0.001, respectively) but not in group 3. CONCLUSION: The extent of drug interaction between flecainide and paroxetine, as reflected in the change in QTc interval (used as a pharmacodynamic biomarker), was influenced by the CYP2D6*10 allele in these healthy Korean male volunteers. [ABSTRACT FROM AUTHOR]

Methadone is a mu (μ) opioid receptor agonist used clinically in adults and children to manage opioid use disorder, neonatal abstinence syndrome, and acute and chronic pain. It is typically marketed as a racemic mixture of R- and S-enantiomers. R-methadone has 30-to 50-fold higher analgesic potency than S-methadone, and S-methadone has a greater adverse effect (prolongation) on the cardiac QTc interval. Methadone undergoes stereoselective metabolism. CYP2B6 is the primary enzyme responsible for catalyzing the metabolism of both enantiomers to the inactive metabolites, S- and R-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (S- and R-EDDP). Genetic variation in the CYP2B6 gene has been investigated in the context of implications for methadone pharmacokinetics, dose, and clinical outcomes. Most CYP2B6 variants result in diminished or loss of CYP2B6 enzyme activity, which can lead to higher plasma methadone concentrations (affecting S- more than R-methadone). However, the data do not consistently indicate that CYP2B6-based metabolic variability has a clinically significant effect on methadone dose, efficacy, or QTc prolongation. Expert analysis of the published literature does not support a change from standard methadone prescribing based on CYP2B6 genotype (updates at www.cpicpgx.org)., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Gram-negative bacterial endotoxins can cause pathophysiological effects such as high fever when introduced into the bloodstream. Therefore, endotoxin testing is necessary when producing injectable pharmaceuticals. The pharmaceutical industry has widely used Limulus amebocyte lysate (LAL) to certify product quality. However, ethical concerns have been raised and the increasing scarcity of Limulus polyphemus necessitates the development of novel testing techniques. Recombinant factor C (rFC) was developed using genetic engineering techniques. The aim of this study was to investigate the validity of rFC testing and compare it with the LAL method. The specificity, linearity, accuracy, precision, and robustness of the rFC assay were evaluated. After validation, the rFC assay was found to be suitable for endotoxin detection. We compared the accuracy of the rFC and LAL assays using reference standard endotoxin. The rFC assay was as accurate as the LAL assay. We also compared the two assays using biopharmaceuticals. Greater interference occurred in some samples when the rFC assay was used than when the LAL assay was used. However, the rFC assay overcame the interference when the samples were diluted. Overall, we suggest that rFC can be applied to test biopharmaceuticals.

Background: Although previous studies have provided data on early pandemic periods of alcohol and substance use in adolescents, more adequate studies are needed to predict the trends of alcohol and substance use during recent periods, including the mid-pandemic period. This study investigated the changes in alcohol and substance use, except tobacco use, throughout the pre-, early-, and mid-pandemic periods in adolescents using a nationwide serial cross-sectional survey from South Korea., Methods: Data on 1,109,776 Korean adolescents aged 13-18 years from 2005 to 2021 were obtained in a survey operated by the Korea Disease Control and Prevention Agency. We evaluated adolescents' alcohol and substance consumption prevalence and compared the slope of alcohol and substance prevalence before and during the COVID-19 pandemic to see the trend changes. We define the pre-COVID-19 period as consisting of four groups of consecutive years (2005-2008, 2009-2012, 2013-2015, and 2016-2019). The COVID-19 pandemic period is composed of 2020 (early-pandemic era) and 2021 (mid-pandemic era)., Results: More than a million adolescents successfully met the inclusion criteria. The weighted prevalence of current alcohol use was 26.8% [95% confidence interval (CI) 26.4-27.1] from 2005 to 2008 and 10.5% (95% CI 10.1-11.0) in 2020 and 2021. The weighted prevalence of substance use was 1.1% (95% CI 1.1-1.2) from 2005 to 2008 and 0.7% (95% CI 0.6-0.7) between 2020 and 2021. From 2005 to 2021, the overall trend of use of both alcohol and drugs was found to decrease, but the decline has slowed since COVID-19 epidemic (current alcohol use: β diff 0.167; 95% CI 0.150-0.184; substance use: β diff 0.152; 95% CI 0.110-0.194). The changes in the slope of current alcohol and substance use showed a consistent slowdown with regard to sex, grade, residence area, and smoking status from 2005 to 2021., Conclusion: The overall prevalence of alcohol consumption and substance use among over one million Korean adolescents from the early and mid-stage (2020-2021) of the COVID-19 pandemic showed a slower decline than expected given the increase during the prepandemic period (2005-2019)., (© 2023. Children's Hospital, Zhejiang University School of Medicine.)

As Mobile Communication and Internet Systems (MCIS) have rapidly developed, security issues related to MCIS have become increasingly important. Therefore, the development and research of security technologies for mobile communication and internet systems are actively being conducted. Hash-Based Signature (HBS) uses a hash function to construct a digital signature scheme, where its security is guaranteed by the collision resistance of the hash function used. To provide sufficient security in the post-quantum environment, the length of hash should be satisfied for the security requirement. Modern HBS can be classified into stateful and stateless schemes. Two representative stateful and stateless HBS are eXtended Merkle Signature Scheme(XMSS) and SPHINCS+, respectively. In this paper, we propose two HBS schemes: K-XMSS and K-SPHINCS+, which replace internal hash functions of XMSS and SPHINCS+ with Korean cryptography algorithms. K-XMSS is a stateful signature, while K-SPHINCS+ is its stateless counterpart. We showcase the reference implementation of K-XMSS and K-SPHINCS+ employing Lightweight Secure Hash (LSH) and two hash functions based on block ciphers (i.e., CHAM and LEA) as the internal hash function. In addition, K-XMSS and K-SPHINCS+ using Advanced Vector Extensions 2 (AVX2) have been provided, demonstrating that they can be optimized for better performance using advanced implementation techniques than previous approaches.

Objectives: The burden of neurological disorders is increasing worldwide, including Asia. The purpose of this study was to determine the burden of neurological disorders between 1990 and 2019 in Asia using the Global Burden of Disease (GBD) Sociodemographic Index., Design, Setting, Outcome and Participants: The GBD Study is updated every year and the most recent version provides the burden of diseases according to age, gender and region from 1990 to 2019. The burden of neurological disorders was evaluated as incidence, prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost and years lived with disability., Results: In 2019, DALYs of neurological diseases were 64.4 million in South-East Asia (95% uncertainty interval (UI) 45.2 to 94.2) and 85.0 million in Western Pacific regions (95% UI 63.0 to 118.5). Stroke, migraine, Alzheimer's disease and other dementias had the highest DALYs in the WHO South-East Asia and WHO Western Pacific regions in 2019. DALYs of stroke, Alzheimer's disease and other dementias, Parkinson's disease, brain and central nervous system cancer, multiple sclerosis, migraine and tension-type headache increased in both regions in 2019 compared with 1990. Infectious diseases such as tetanus, meningitis and encephalitis decreased in both regions. DALYs of idiopathic epilepsy and motor neuron disease increased in the WHO South-East Asia region and decreased in the WHO Western Pacific region., Conclusions: This study demonstrated the burden of neurological diseases in Asia. To reduce the burden of neurological diseases, strategies suitable for each country's real healthcare needs and challenges are needed; this study can serve as the cornerstone of these strategies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cognitive dysfunction is a core feature of psychosis-spectrum illnesses, and the characterization of related genetic mechanisms may provide insights regarding the disease pathophysiology. Substantial efforts have been made to determine the genetic component of cognitive symptoms, without clear success. Illness-related moderators and environmental factors such as medications hinder the detection of genomic association with cognition. Polypharmacy is common in psychotic disorders, and the cumulative effects of medication regimens can confound gene-cognition associations. A review of the relative contributions of important pharmacological and genetic relationships identifies that the effects of medications on cognition in psychotic disorders may be at least, if not more, impactful than individual genes, thus underscoring the importance of accounting for medication exposure in gene-cognition association studies.

Objective: Osteoprotegerin (OPG) is a component of the tumor necrosis factor receptor superfamily. Several studies have shown a relationship between OPG and cardiovascular disease. We investigated the association between plasma OPG levels and hemorrhagic transformation in stroke patients who received endovascular thrombectomy (EVT)., Methods: We prospectively enrolled 360 patients diagnosed with acute ischemic stroke and performed EVT from April 2014 to December 2020. Blood sampling for plasma OPG was performed after fasting for 12 h after EVT. Hemorrhagic transformation was defined using the definition and classification of the European Cooperative Acute Stroke Study-3 trial., Results: Of all the included patients, 130 (36.1%) experienced hemorrhagic transformation. The mean ± standard deviation of the plasma OPG concentrations was 200.2 ± 74.4 pg/mL. In multivariable analysis, after adjusting for age, sex, body mass index (BMI), and variables with p < 0.1 in univariable analysis (diabetes mellitus, atrial fibrillation, coronary artery disease, alcohol intake, current smoking, NIHSS, ASPECT score, mass effect, hemoglobin, vitamin D 25(OH)D), increased plasma OPG concentration was independently related to any hemorrhagic transformation (highest tertile vs. lowest tertile of OPG; odds ratio [OR] 2.31, 95% confidence interval [CI] (1.29-4.14), p = 0.005) and severity of hemorrhagic transformation (OR 2.92, 95% CI (1.66-5.12), p = 0.001)., Conclusions: Our results demonstrate that increased plasma OPG level is related to the occurrence and severity of hemorrhagic transformation in patients with cerebral infarction who receive EVT., (Copyright © 2022. Published by Elsevier B.V.)

Background: Cognitive impairment is a core deficit across psychotic disorders, the causes and therapeutics of which remain unclear. Epidemiological observations have suggested associations between cognitive dysfunction in psychotic disorders and cardiovascular risk factors, but an underlying etiology has not been established., Methods: Neuropsychological performance using the Brief Assessment of Cognition in Schizophrenia (BACS) was assessed in 616 individuals of European ancestry (403 psychosis, 213 controls). Polygenic risk scores for coronary artery disease (PRS CAD ) were quantified for each participant across 13 p-value thresholds (P T 0.5-5e -8 ). Cardiovascular and psychotropic medications were categorized for association analyses. Each PRS CAD was examined in relation to the BACS and the optimized P T was confirmed with five-fold cross-validation and independent validation. Functional enrichment analyses were used to identify biological mechanisms linked to PRS CAD -cognition associations. Multiple regression analyses examined PRS CAD under the optimal P T and medication burden in relation to the BACS composite and subtest scores., Results: Higher PRS CAD was associated with lower BACS composite scores (p = 0.001) in the psychosis group, primarily driven by the Verbal Memory subtest (p < 0.001). Genes linked to multiple nervous system related processes and pathways were significantly enriched in PRS CAD . After controlling for PRS CAD , a greater number of cardiovascular medications was also correlated with worse BACS performance in patients with psychotic disorders (p = 0.029)., Conclusions: Higher PRS CAD and taking more cardiovascular medications were both significantly associated with cognitive impairment in psychosis. These findings indicate that cardiovascular factors may increase the risk for cognitive dysfunction and related functional outcomes among individuals with psychotic disorders., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Bupropion is metabolized to its active metabolite, hydroxybupropion (HB), by the genetically polymorphic cytochrome P450 2B6 (CYP2B6) enzyme. Despite its significant role in bupropion metabolism, the magnitude of the impact of CYP2B6 genotype on the exposure of bupropion has not been quantified., Objectives: A systematic review and meta-analysis was conducted to quantify the association of bupropion and HB exposure with CYP2B6 variant alleles and genotype-defined metabolizer phenotypes., Methods: MEDLINE, EMBASE, Web of Science, Scifinder, PsycINFO, and CENTRAL were screened to identify studies that met the following inclusion criteria (search updated on February 2021): (1) area under the plasma drug concentration-time curve (AUC) of bupropion and/or HB in relation to CYP2B6 genotypes was studied, and (2) study participants were genotyped for common CYP2B6 variant alleles including at least CYP2B6*6. The Newcastle Ottawa Scale was used to assess risk of bias in each included study. The ratio of means (RoM) between CYP2B6 genotype or genotype-defined phenotype groups for bupropion exposure was calculated for each study and combined in a meta-analysis., Results: Eleven studies met the inclusion criteria for this systematic review, and 10 (including N = 413 participants) were included in the meta-analysis. All 10 studies involved healthy adult volunteers, where other medications were not allowed. The AUCs of HB and the active moiety (bupropion + HB) were significantly reduced in CYP2B6*6 carriers compared with the non-carriers (HB: RoM 0.77, 95% CI 0.71-0.83; active moiety: RoM 0.81, 95% CI 0.75-0.88). Both CYP2B6 poor and intermediate metabolizers had significantly decreased exposures to HB and the active moiety than normal metabolizers., Conclusion: The CYP2B6*6 allele and genotype-determined CYP2B6 poor and intermediate metabolizer phenotypes are associated with significantly lower exposures to HB and the total active moiety. The findings of this study suggest opportunities to further study precision dosing strategies for bupropion therapy based on CYP2B6 genotype., (© 2021 Pharmacotherapy Publications, Inc.)

Identifying genetic contributors to cognitive impairments in psychosis-spectrum disorders can advance understanding of disease pathophysiology. Although CNS medications are known to affect cognitive performance, they are often not accounted for in genetic association studies. In this study, we performed a genome-wide association study (GWAS) of global cognitive performance, measured as composite z-scores from the Brief Assessment of Cognition in Schizophrenia (BACS), in persons with psychotic disorders and controls (N = 817; 682 cases and 135 controls) from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Analyses accounting for anticholinergic exposures from both psychiatric and non-psychiatric medications revealed five significantly associated variants located at the chromosome 3p21.1 locus, with the top SNP rs1076425 in the inter-alpha-trypsin inhibitor heavy chain 1 (ITIH1) gene (P = 3.25×E-9). The inclusion of anticholinergic burden improved association models (P < 0.001) and the number of significant SNPs identified. The effect sizes and direction of effect of the top variants remained consistent when investigating findings within individuals receiving specific antipsychotic drugs and after accounting for antipsychotic dose. These associations were replicated in a separate study sample of untreated first-episode psychosis. The chromosome 3p21.1 locus was previously reported to have association with the risk for psychotic disorders and cognitive performance in healthy individuals. Our findings suggest that this region may be a psychosis risk locus that is associated with cognitive mechanisms. Our data highlight the general point that the inclusion of medication exposure information may improve the detection of gene-cognition associations in psychiatric genetic research., (© 2021. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Elevations in peripheral inflammatory markers have been reported in patients with psychosis. Whether this represents an inflammatory process defined by individual or subgroups of markers is unclear. Further, relationships between peripheral inflammatory marker elevations and brain structure, cognition, and clinical features of psychosis remain unclear. We hypothesized that a pattern of plasma inflammatory markers, and an inflammatory subtype established from this pattern, would be elevated across the psychosis spectrum and associated with cognition and brain structural alterations. Clinically stable psychosis probands (Schizophrenia spectrum, n = 79; Psychotic Bipolar disorder, n = 61) and matched healthy controls (HC, n = 60) were assessed for 15 peripheral inflammatory markers, cortical thickness, subcortical volume, cognition, and symptoms. A combination of unsupervised exploratory factor analysis and hierarchical clustering was used to identify inflammation subtypes. Levels of IL6, TNFα, VEGF, and CRP were significantly higher in psychosis probands compared to HCs, and there were marker-specific differences when comparing diagnostic groups. Individual and/or inflammatory marker patterns were associated with neuroimaging, cognition, and symptom measures. A higher inflammation subgroup was defined by elevations in a group of 7 markers in 36% of Probands and 20% of HCs. Probands in the elevated inflammatory marker group performed significantly worse on cognitive measures of visuo-spatial working memory and response inhibition, displayed elevated hippocampal, amygdala, putamen and thalamus volumes, and evidence of gray matter thickening compared to the proband group with low inflammatory marker levels. These findings specify the nature of peripheral inflammatory marker alterations in psychotic disorders and establish clinical, neurocognitive and neuroanatomic associations with increased inflammatory activation in psychosis. The identification of a specific subgroup of patients with inflammatory alteration provides a potential means for targeting treatment with anti-inflammatory medications., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Nontuberculous mycobacteria (NTM) are widely present in environments, such as soil and water, and have recently been recognized as important pathogenic bacteria. The incidence of NTM-related infections is steadily increasing. As the diagnosis and treatment of NTM infection should be distinguished from tuberculosis, and the treatment should be specific to the species of NTM acquired, accurate species identification is required., Methods: In this study, two-step multiplex PCR (mPCR) and multigene sequence-based analysis were used to accurately identify NTM species in 320 clinical isolates from Gyeongsang National University Hospital (GNUH). In particular, major mycobacterial strains with a high isolation frequency as well as coinfections with multiple species were diagnosed through two-step mPCR. Multigene sequencing was performed to accurately identify other NTM species not detected by mPCR. Variable regions of the genes 16S rRNA, rpoB , hsp65 , and 16S-23S rRNA internal transcribed spacer were included in the analysis., Results: Two-step mPCR identified 234 (73.1%) cases of M . intracellulare , 26 (8.1%) cases of M . avium subsp. avium , and 13 (4.1%) cases of M . avium subsp. hominissuis infection. Additionally, 9 (2.8%) M . fortuitum , 9 (2.8%) M . massiliense , 2 (0.6%) M . abscessus , and 4 (1.2%) M . kansasii isolates were identified. Coinfection was identified in 7 (2.2%) samples. The sixteen samples not classified by two-step mPCR included 6 (1.9%) cases of M . chimaera , 4 (1.3%) M . gordonae , 1 (0.3%) M . colombiense , 1 (0.3%) M . mageritense , and 1 (0.3%) M . persicum identified by sequence analysis., Conclusions: The results of this study suggest a strategy for rapid detection and accurate identification of species using two-step mPCR and multigene sequence-based analysis. To the best of our knowledge, this study is the first to report the identification of NTM species isolated from patients in Gyeongnam/Korea., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Min-Jeong Kim et al.)

Predicting risk for major adverse cardiovascular events (MACE) is an evidence-based practice that incorporates lifestyle, history, and other risk factors. Statins reduce risk for MACE by decreasing lipids, but it is difficult to stratify risk following initiation of a statin. Genetic risk determinants for on-statin MACE are low-effect size and impossible to generalize. Our objective was to determine high-level epistatic risk factors for on-statin MACE with GWAS-scale data. Controlled-access data for 5890 subjects taking a statin collected from Vanderbilt University Medical Center's BioVU were obtained from dbGaP. We used Random Forest Iterative Feature Reduction and Selection (RF-IFRS) to select highly informative genetic and environmental features from a GWAS-scale dataset of patients taking statin medications. Variant-pairs were distilled into overlapping networks and assembled into individual decision trees to provide an interpretable set of variants and associated risk. 1718 cases who suffered MACE and 4172 controls were obtained from dbGaP. Pathway analysis showed that variants in genes related to vasculogenesis (FDR = 0.024), angiogenesis (FDR = 0.019), and carotid artery disease (FDR = 0.034) were related to risk for on-statin MACE. We identified six gene-variant networks that predicted odds of on-statin MACE. The most elevated risk was found in a small subset of patients carrying variants in COL4A2 , TMEM178B , SZT2 , and TBXAS1 (OR = 4.53, p < 0.001). The RF-IFRS method is a viable method for interpreting complex "black-box" findings from machine-learning. In this study, it identified epistatic networks that could be applied to risk estimation for on-statin MACE. Further study will seek to replicate these findings in other populations.

Background: Risperidone is a second-generation antipsychotic drug metabolized to an active metabolite, 9-hydroxyrisperidone, primarily by cytochrome P450 (CYP) 2D6 and to a lesser extent by CYP3A4. The extent to which drug metabolism genetics impacts risperidone and 9-hydroxyrisperidone exposure has not been clarified., Objective: A systematic review and meta-analysis evaluated the impact of genetically defined CYP2D6 function on risperidone pharmacokinetics applying a standardized genotype-phenotype translation system., Methods: A comprehensive electronic database search identified studies reporting relationships between genetically determined CYP2D6 metabolism and risperidone pharmacokinetic properties. The exposure of risperidone or active moiety (risperidone + 9-hydroxyrisperidone) was measured by dose-adjusted steady-state serum or plasma concentration or area under the concentration-time curve as primary outcomes. Subjects were assigned to CYP2D6 poor metabolizer, intermediate metabolizer, normal metabolizer, or ultrarapid metabolizer groups using a standardized genotype-phenotype translation method. Effect sizes between groups were pooled and stratified by single or multiple dosing regimens., Results: A total of 15 studies involving 2125 adult subjects were included in the meta-analysis. Following multiple-dose oral administration, compared with CYP2D6 normal metabolizers, the risperidone dose-adjusted steady-state serum/plasma concentration was 2.35-fold higher in intermediate metabolizers (95% confidence interval [CI] 1.77-3.13, p<0.0001) and 6.20-fold higher in poor metabolizers (95% CI 5.05-7.62, p<0.0001); the active moiety dose-adjusted steady-state concentration was 1.18-fold higher in intermediate metabolizers (95% CI 1.11-1.25, p<0.0001) and 1.44-fold higher in poor metabolizers (95% CI 1.23-1.69, p<0.0001). Higher area under the concentration-time curve of risperidone and active moiety was also found in single-dose studies., Conclusion: Genetically defined impaired CYP2D6 activity is associated with increased exposure of both risperidone and risperidone + 9-hydroxyrisperidone in adults receiving oral formulations. Additional studies are needed to quantify the clinical impact of these relationships., (© 2020 Pharmacotherapy Publications, Inc.)

Introduction: The use of pharmacogenomic (PGx) testing to guide decisions and improve patient outcomes has increased in recent years. PGx testing represents a decision support tool that may inform dosing, increase the likelihood of treatment response, and identify patients at risk for medication side effects., Methods: This is a narrative review of utilization of PGx testing in psychiatry from stakeholders including, pharmacists, genetic counselors, implementation scientists, industry, and clinicians., Results: While many limitations exist to streamline use of PGx testing in psychiatry, various stakeholders are crucial to clinical implementation., Discussion: PGx testing can assist in medication selection and improve patient outcomes; however, more data are needed to understand when and how to incorporate PGx testing into psychiatric practice., Competing Interests: Dr. Lisa Brown is an employee and stockholder of Myriad Genetics, producer of a pharmacogenetic test. Dr. Seenae Eum has no related conflicts to declare. Dr. Susanne Haga has received research support from the National Institutes of Health (NIGMS). Dr. Jeffrey Strawn has received research support from the National Institutes of Health (NIMH, NIEHS, NICHD) as well as Allergan, Otsuka, Neuronetics and The Yung Family Foundation. He has received material support from and provided consultation to Myriad Genetics. Dr. Strawn also receives royalties from the publication of two texts (Springer) and serves as an author for UpToDate and an Associate Editor for Current Psychiatry. Dr. Heather Zeirhut receives research support from the National Society of Genetic Counselors. She is a Senior Advisor and Chair of the Advisory Board for GeneMatters, LLC, a tele- genetic counseling company., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Annona squamosa L. is a branched shrub, which is believed to be originated from the America and West Indies. Fruits of this plant are commonly known as custard apple, sugar apple, or sweetsops. A number of studies have proven a range of biological activities associated with various parts of A. squamosa., Aims: The main aim of the present investigation was to evaluate potential inhibitory effects of A. squamosa leaf extract (ALE) on melanogenesis and its underlying mechanisms in B16F10 murine melanoma cells., Methods: Inhibitory effects of A. squamosa leaf extract (ALE) on melanogenesis were primarily assessed by determining melanin contents. Effects of ALE on tyrosinase activity and the expression of proteins associated with melanogenesis were then determined. GC-MS analysis was carried out to identify the phytochemical profile of A. squamosa leaf extract., Results: Antimelanogenic effects of ALE were found to exert through the inhibition of melanocyte inducing transcription factor (MITF) and activation of p38. GC-MS analysis identified ent-kaur-16-en-19-ol, 18-oxokauran-17-yl acetate, and β-sitosterol as major phytochemicals., Conclusion: To our knowledge, this is the first study on the antimelanogenic effects of A. squamosa leaves, rationalizing the use A. squamosa leaf extract as a natural depigmentation agent for the treatment of skin diseases and the development of cosmetic products with enhanced skin-lightening capabilities., (© 2019 Wiley Periodicals, Inc.)

Glial cells are the resident immune cells of the central nervous system. Reactive glial cells release inflammatory mediators that induce neurotoxicity or aggravate neurodegeneration. Regulation of glial activation is crucial for the initiation and progression of neuropathological conditions. Constituents of the peach tree (Prunus persica L. Batsch), which has a global distribution, have been found to exert therapeutic effects in pathological conditions, such as rashes, eczema and allergies. However, the therapeutic potential of its aerial parts (leaves, fruits and twigs) remains to be elucidated. The present study aimed to evaluate the anti‑inflammatory role of P. persica methanol extract (PPB) on lipopolysaccharide (LPS)‑stimulated glial cells. High‑performance liquid chromatography coupled with tandem mass spectrometry analysis showed that PPB contained chlorogenic acid and catechin, which have antioxidant properties. Western blot and reverse transcription polymerase chain reaction results indicated that PPB reduced the transcription of various proinflammatory enzymes (nitric oxide synthase and cyclooxygenase‑2) and cytokines [tumor necrosis factor‑α, interleukin (IL)‑1β and IL‑6] in LPS‑stimulated BV2 cells. In addition, PPB inhibited the activation of NF‑κB and various mitogen‑activated protein kinases required for proinflammatory mediator transcription. Finally, nitrite measurement and immunocytochemistry results indicated that PPB also suppressed nitrite production and NF‑κB translocation in LPS‑stimulated primary astrocytes. Thus, PPB may be used as a potential therapeutic agent for neurodegenerative diseases and neurotoxicity via the suppression of glial cell activation.

Abnormal neuroanatomic brain networks have been reported in schizophrenia, but their characterization across patients with psychotic disorders, and their potential alterations in nonpsychotic relatives, remain to be clarified. Participants recruited by the Bipolar and Schizophrenia Network for Intermediate Phenotypes consortium included 326 probands with psychotic disorders (107 with schizophrenia (SZ), 87 with schizoaffective disorder (SAD), 132 with psychotic bipolar disorder (BD)), 315 of their nonpsychotic first-degree relatives and 202 healthy controls. Single-subject gray matter graphs were extracted from structural MRI scans, and whole-brain neuroanatomic organization was compared across the participant groups. Compared with healthy controls, psychotic probands showed decreased nodal efficiency mainly in bilateral superior temporal regions. These regions had altered morphological relationships primarily with frontal lobe regions, and their network-level alterations were associated with positive symptoms of psychosis. Nonpsychotic relatives showed lower nodal centrality metrics in the prefrontal cortex and subcortical regions, and higher nodal centrality metrics in the left cingulate cortex and left thalamus. Diagnosis-specific analysis indicated that individuals with SZ had lower nodal efficiency in bilateral superior temporal regions than controls, probands with SAD only exhibited lower nodal efficiency in the left superior and middle temporal gyrus, and individuals with psychotic BD did not show significant differences from healthy controls. Our findings provide novel evidence of clinically relevant disruptions in the anatomic association of the superior temporal lobe with other regions of whole-brain networks in patients with psychotic disorders, but not in their unaffected relatives, suggesting that it is a disease-related trait. Network disorganization primarily involving frontal lobe and subcortical regions in nonpsychotic relatives may be related to familial illness risk.

We introduce Multi-Expert Region-based Convolutional Neural Network (ME R-CNN) which is equipped with multiple experts (ME) where each expert is learned to process a certain type of regions of interest (RoIs). This architecture better captures the appearance variations of the RoIs caused by different shapes, poses, and viewing angles. In order to direct each RoI to the appropriate expert, we devise a novel "learnable" network, which we call, expert assignment network (EAN). EAN automatically learns the optimal RoI-expert relationship even without any supervision of expert assignment. As the major components of ME R-CNN, ME and EAN, are mutually affecting each other while tied to a shared network, neither an alternating nor a naive end-to-end optimization is likely to fail. To address this problem, we introduce a practical training strategy which is tailored to optimize ME, EAN, and the shared network in an end-to-end fashion. We show that both of the architectures provide considerable performance increase over the baselines on PASCAL VOC 07, 12, and MS COCO datasets.