Search

We performed a double-blinded, genotype-based stratification study to explore the pharmacokinetics and pharmacodynamics of amitriptyline according to CYP2C19 and CYP2D6 genotype in Korean subjects. Twenty-four healthy adults were grouped by genotype of CYP2C19 and CYP2D6. After a single dose of 25 mg of amitriptyline, blood samples were collected and anticholinergic effects were measured. The extent of N-demethylation of amitriptyline significantly decreased in subjects carrying two nonfunctional alleles of CYP2C19. The extent of hydroxylation of amitriptyline or nortriptyline was significantly reduced in subjects carrying two CYP2D6 decreased functional alleles compared with those with no or one decreased functional allele. The overall metabolic pathway of amitriptyline was more likely to be dominated by CYP2C19 than CYP2D6. The gene variations of CYP2C19 and CYP2D6 did not change the pharmacodynamic effect. The findings of this study will provide useful information on individualized drug treatment with amitriptyline considering both CYP2D6 and CYP2C19 gene variations. [ABSTRACT FROM AUTHOR]

Objectives HIV-associated neurocognitive disorder ( HAND) is an independent predictor of early mortality and is associated with many difficulties in activities of daily living. We sought to determine the prevalence of and risk factors for HAND in HIV-infected Koreans. In addition, we investigated the performance of screening tools and components of neuropsychological ( NP) tests for diagnosing HAND. Methods HIV-infected patients were enrolled consecutively from two different urban teaching hospitals in Seoul, South Korea between March 2012 and September 2012. Participants completed a detailed NP assessment of six cognitive domains commonly affected by HIV. The Frascati criteria were used for diagnosing HAND. Four key questions, the International HIV Dementia Scale ( IHDS) and Montreal Cognitive Assessment ( MoCA)- K were also assessed as potential tools for screening for HAND. Results Among the 194 participants, the prevalence of HAND was 26.3%. Asymptomatic neurocognitive impairment and minor neurocognitive disorder accounted for 52.9 and 47.1% of the patients with HAND, respectively. In multivariate analysis, haemoglobin ( Hb) level ≤ 13 g/dL ( P = 0.046) and current use of a protease inhibitor-based regimen ( P = 0.031) were independent risk factors for HAND. The sensitivity and specificity of the IHDS were 72.6 and 60.8%, and those of MoCA-K were 52.9 and 73.4%, respectively. The IHDS ( P < 0.001) and MoCA-K ( P < 0.001) were both useful for screening for HAND. Among NP tests, the sensitivity and specificity of the Grooved Pegboard Test were 90.2 and 72.0%, and those of the Wisconsin Card Sorting Test were 61.2 and 84.4%, respectively. Conclusions HAND is a prevalent comorbidity in HIV-infected Koreans. Active screening and diagnosis with effective tools, such as the IHDS, MoCA-K and Grooved Pegboard Test, could be used to identify this important complication. [ABSTRACT FROM AUTHOR]

Oral Diseases (2011) 17, 785-793 Objective: Gingival wound healing is important to periodontal disease and surgery. This in vitro study was conducted to assess the manner in which heparin-binding epidermal growth factor-like growth factor (HB-EGF) and epiregulin cooperatively participate in the wound-healing process in the gingival epithelial and fibroblast cells of the oral mucosa. Material and Methods: Gingival epithelium and fibroblast were separated from gingival tissue biopsies and prepared to primary cultures. The changes in the mRNA expression were evaluated via real-time PCR. The effects on cell proliferation, migration, and repopulation were evaluated in vitro. Results: The different regulation of expressions of HB-EGF, epiregulin, and epidermal growth factor receptors was observed over time and with different gingival cell types. HB-EGF exerted a cell migration-inducing effect on both epithelial and fibroblast cells, whereas epiregulin did not. Both growth factors functioned as mitogens for epithelial cell proliferation, but not for fibroblast proliferation. HB-EGF strongly promoted epithelial cell repopulation and mildly promoted fibroblast repopulation, whereas epiregulin promoted only fibroblast repopulation. Conclusion: These results indicated that both growth factors might function importantly in the wound-healing process of human gingival tissue via the different regulation of the expression, cell migration, proliferation, and repopulation. [ABSTRACT FROM AUTHOR]

In the course of screening for acetylcholinesterase and butyrylcholinesterase inhibitors from natural products by an in vitro Ellman method, the extract of the roots of Vitis amurensis Rupr. (Vitaceae) showed significant cholinesterase inhibitory activity. Employing a bioassay-linked HPLC method, followed by a semi-preparative HPLC method, two compounds of interest were isolated and characterized as vitisin A and heyneanol A. They inhibited effectively both acetylcholinesterase and butyrylcholinesterase in a dose-dependent manner and exhibited higher activity against butyrylcholinesterase compared with that of galantamine, a positive control. Furthermore, the aggregation of beta-amyloid was evaluated in vitro based on a thioflavine T fluorescence assay to expand their activity profile, with the result that both compounds showed the ability to block beta-amyloid aggregation. [ABSTRACT FROM AUTHOR]

Purpose To determine the retinal vascular caliber and arteriovenous ratio (AVR) in type 2 diabetic patients without retinopathy. Methods We retrospectively reviewed the medical records of 70 patients diagnosed as type 2 diabetes without retinopathy. Digital fundus photographs of the right eye were selected for measurement. The caliber of all retinal vessels passing through an area 0.5 to 1 disc diameter around the optic disc was measured using automated computer software (Zeiss AV ratio). Seventy seven age‐ and sex‐matched healthy subjects were included in the study as a control. Results The mean AVR was 0.801 ± 0.068 in the diabetic patients compared to 0.762 ± 0.054 in the control group (P < 0.001). Higher AVR was significantly associated with increasing blood HbA1c levels (r2 = 0.106, P = 0.006). However, there was no significant correlation between AVR and body mass index (P = 0.478). Conclusion The rise in AVR seems to be an early feature of retinal vascular caliber in type 2 diabetes and correlates with an elevated blood HbA1c level. [ABSTRACT FROM AUTHOR]

Background and Aims: Molecular processes driving immune-active chronic hepatitis B (CHB) with and without hepatitis B e antigen (HBeAg) remain incompletely understood. This study aimed to investigate expression profiles of serum and intrahepatic HBV markers and replicative activity of HBV in CHB patients with or without HBeAg., Methods: This study recruited 111 untreated immune-active CHB (60 HBeAg-positive and 51 HBeAg-negative) patients and quantified intrahepatic covalently closed circular DNA (cccDNA), pre-genomic RNA (pgRNA), total HBV DNA (tDNA), and replicative intermediates as well as serum HBV markers (HBV DNA, hepatitis B surface antigen, hepatitis B core-related antigen). Correlations between HBV markers and clinico-virological factors influencing expression levels of HBV markers were analysed., Results: Levels of all serum markers and intrahepatic cccDNA/tDNA as well as cccDNA transcriptional activity and virion productivity were significantly reduced in HBeAg-negative patients compared to those in HBeAg-positive patients. Additionally, correlations between intrahepatic cccDNA/pgRNA and serum markers were impaired in HBeAg-negative individuals. Aminotransferase levels were positively correlated with cccDNA transcriptional activity in HBeAg-positive patients, but not in HBeAg-negative patients. Notably, among HBeAg-positive patients, there was a progressive decline in pgRNA level, transcriptional activity, and serum HBV markers as liver fibrosis advanced, which was not observed in HBeAg-negative patients., Conclusions: HBeAg loss is correlated with diminished intrahepatic HBV reservoirs and cccDNA transcription, leading to decreased serum HBV marker levels. Circulating HBV markers are not reliable indicators of intrahepatic HBV replicative activity for HBeAg-negative patients. Our findings reveal distinct disease phenotypes between immune-active CHB with and without HBeAg, highlighting the need to establish optimal surrogate biomarkers that can accurately mirror intrahepatic viral activity to aid in decision-making for antiviral therapy for immune-active CHB., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

As people age, the risk and progression of colorectal cancer (CRC), along with cholesterol levels, tend to increase. Nevertheless, epidemiological studies on serum lipids and CRC have produced conflicting results. We previously demonstrated that the reduction of squalene epoxidase (SQLE) due to accumulated cholesterol within cells accelerates CRC progression through the activation of the β-catenin pathway. This study aimed to investigate the mechanism by which age-related cholesterol accumulation within tissue accelerates CRC progression and to assess the clinical significance of SQLE in older individuals with elevated CRC risk. Using machine learning-based digital image analysis with fluorescence-immunohistochemistry, we assessed SQLE, GSK3β pS9 (GSK3β activity inhibition through serine 9 phosphorylation at GSK3β), p53 wild-type (p53 WT ), and p53 mutant (p53 MT ) levels in CRC tissues. Our analysis revealed a significant reduction in SQLE, p53 WT , and p53 MT and increase in GSK3β pS9 levels, all associated with the substantial accumulation of intra-tissue cholesterol in aged CRCs. Cox analysis underscored the significant influence of SQLE on overall survival and progression-free survival in grade 2-3 CRC patients aged over 50. SQLE and GSK3β pS9 consistently exhibited outstanding prognostic and diagnostic performance, particularly in older individuals. Furthermore, combining SQLE with p53 WT , p53 MT , and GSK3β pS9 demonstrated a robust diagnostic ability in the older population. In conclusion, we have identified that individuals aged over 50 face an increased risk of CRC progression due to aging-linked cholesterol accumulation within tissue and the subsequent reduction in SQLE levels. This study also provides valuable biomarkers, including SQLE and GSK3β pS9 , for older patients at elevated risk of CRC., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Over 50% of patients with systemic LCH are not cured with front-line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAF V600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long-term efficacy, late toxicities, relative cost and patient-reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Prolyl-tRNA synthetase 1 (PARS1) has attracted much interest in controlling pathologic accumulation of collagen containing high amounts of proline in fibrotic diseases. However, there are concerns about its catalytic inhibition for potential adverse effects on global protein synthesis. We developed a novel compound, DWN12088, whose safety was validated by clinical phase 1 studies, and therapeutic efficacy was shown in idiopathic pulmonary fibrosis model. Structural and kinetic analyses revealed that DWN12088 binds to catalytic site of each protomer of PARS1 dimer in an asymmetric mode with different affinity, resulting in decreased responsiveness at higher doses, thereby expanding safety window. The mutations disrupting PARS1 homodimerization restored the sensitivity to DWN12088, validating negative communication between PARS1 promoters for the DWN12088 binding. Thus, this work suggests that DWN12088, an asymmetric catalytic inhibitor of PARS1 as a novel therapeutic agent against fibrosis with enhanced safety., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Aim: To investigate group metacognitive training and cognitive-behavioural therapy (MCT/CBT) prospectively in a young population with various psychiatric disorders, including psychotic and mood disorders., Methods: This was a prospective study to investigate the effectiveness of group MCT/CBT on quality of life, psychotic symptoms, depression, self-esteem, perceived stress, social function and social cognition. The objective measures included the Positive and Negative Syndrome Scale (PANSS), clinical global impression (CGI), personal and social performance scale for social functioning, a computerized continuous performance test for sustained attention and a computerized emotional recognition test for social cognition. Self-report measures administered included the Subjective Well-being under Neuroleptics for quality of life, Ambiguous Intentions Hostility Questionnaire for suspiciousness, Drug Attitude Inventory, Beck Depression Inventory, Perceived Stress Scale, Brief Resilience Scale, Rosenberg Self-esteem Scale and visual analogue scale for the EQ-5D., Results: Among 110 young patients with early psychosis and mood disorders who participated, 82 (74.5%) completed the study. Social functioning, quality of life, self-esteem, resilience, depression, suspiciousness, social cognition, sustained attention and scores on the PANSS and CGI improved significantly after completing group MCT/CBT. Perceived stress, resilience and suspiciousness improved significantly only in participants with a non-psychotic disorder. Improvements in subjective well-being of the participants were associated with increases in self-esteem and resilience and decreases in depression and perceived stress., Conclusions: Our study showed that group transdiagnostic MCT/CBT for young patients with mental illness improved subjective wellbeing, self-esteem, resilience, social cognition and social functioning and significantly diminished suspiciousness, perceived stress and depression., (© 2022 John Wiley & Sons Australia, Ltd.)

Background Unlike patients with stroke caused by other mechanisms, the effect of elevated plasma total homocysteine (tHcy) on the prognosis of patients with both ischemic stroke and atrial fibrillation (AF) is unknown. This study aimed to evaluate the association between tHcy level and the functional outcome of patients with AF-related stroke. Methods and Results We included consecutive patients with AF-related stroke between 2013 and 2015 from the registry of a real-world prospective cohort from 11 large centers in South Korea. A 3-month modified Rankin Scale score ≥3 was considered an unfavorable outcome. Since tHcy is strongly affected by renal function, we performed a subgroup analysis according to the presence of renal dysfunction. A total of 910 patients with AF-related stroke were evaluated (mean age, 73 years; male sex, 56.0%). The mean tHcy level was 11.98±8.81 μmol/L. In multivariable analysis, the tHcy level (adjusted odds ratio, 1.04; 95% CI, 1.01-1.07, per 1 μmol/L) remained significantly associated with unfavorable outcomes. In the subgroup analysis based on renal function, tHcy values above the cutoff point (≥14.60 μmol/L) showed a close association with the unfavorable outcome only in the normal renal function group (adjusted odds ratio, 3.10; 95% CI, 1.60-6.01). In patients with renal dysfunction, tHcy was not significantly associated with the prognosis of AF-related stroke. Conclusions A higher plasma tHcy level was associated with unfavorable outcomes in patients with AF-related stroke. This positive association may vary according to renal function but needs to be verified in further studies.

Background: The administration of L-glutamine (Gln) suppresses allergic airway inflammation via the rapid upregulation of MAPK phosphatase (MKP)-1, which functions as a negative regulator of inflammation by deactivating p38 and JNK mitogen-activated protein kinases (MAPKs). However, the role of endogenous Gln remains to be elucidated. Therefore, we investigated the mechanism by which endogenous Gln regulates MKP-1 induction and allergic airway inflammation in an ovalbumin-based murine asthma model., Methods: We depleted endogenous Gln levels using L-γ-glutamyl-p-nitroanilide (GPNA), an inhibitor of the Gln transporter ASCT2 and glutamine synthetase small interfering siRNA. Lentivirus expressing MKP-1 was injected to achieve overexpression of MKP-1. Asthmatic phenotypes were assessed using our previously developed ovalbumin-based murine model, which is suitable for examining sequential asthmatic events, including neutrophil infiltration. Gln levels were analyzed using a Gln assay kit., Results: GPNA or glutamine synthetase siRNA successfully depleted endogenous Gln levels. Importantly, homeostatic MKP-1 induction did not occur at all, which resulted in prolonged p38 MAPK and cytosolic phospholipase A 2 (cPLA 2 ) phosphorylation in Gln-deficient mice. Gln deficiency augmented all examined asthmatic reactions, but it exhibited a strong bias toward increasing the neutrophil count, which was not observed in MKP-1-overexpressing lungs. This neutrophilia was inhibited by a cPLA 2 inhibitor and a leukotriene B4 inhibitor but not by dexamethasone., Conclusion: Gln deficiency leads to the impairment of MKP-1 induction and activation of p38 MAPK and cPLA 2 , resulting in the augmentation of neutrophilic, more so than eosinophilic, airway inflammation., (© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Aim: Non-suicidal self-injury (NSSI) is common among adolescents, and several different factors can affect its prevalence. The present study examined the associated characteristics predicting NSSI among adolescents in South Korea., Methods: In total, 1674 high school students were recruited for a cross-sectional survey. They completed self-reported assessments, including the Deliberate Self-Harm Inventory (DSHI), the Center for Epidemiological Studies Depression Scale (CESD), the State-Trait Anxiety Inventory for Children (STAIC), and the Prodromal Questionnaire-16 (PQ-16), as well as their bullying experience. The NSSI group was defined as the sample group with at least one NSSI behaviour on the DSHI scale. A logistic regression analysis was performed using the NSSI group as the dependent variable., Results: The prevalence of NSSI was 28.3% (boys, 30.4%; girls, 24.4%) among adolescents. The most common type of NSSI behaviour among adolescents was interference with wound healing and sex differences in the method were examined. The CES-D, STAIC-trait, and PQ-16 scores were significantly higher and the RSES score was significantly lower in the NSSI group than those in the non-NSSI group. Participants' experience with bullying, such as being victims, bullies, bully-victims, and witness to bullying, were more likely to be in the NSSI group. In a logistic regression analysis, NSSI was significantly associated with male sex, low academic achievement, higher depression, psychotic-like experiences, being bullied, and witnessing bullying., Conclusion: The results of this study suggest the need to identify and manage related psychologic factors in adolescents with NSSI, including psychotic-like symptoms., (© 2021 John Wiley & Sons Australia, Ltd.)

Background & Aims: Liver Imaging Reporting and Data System (LI-RADS) and European Association for the Study (EASL) criteria for hepatocellular carcinoma (HCC) diagnosis have been updated in 2018. We aimed to compare the HCC diagnostic performance of LI-RADS and EASL criteria with extracellular contrast agents-MRI (ECA-MRI) and hepatobiliary agents-MRI (HBA-MRI)., Methods: We prospectively evaluated 179 participants with cirrhosis (n = 105) or non-cirrhotic chronic hepatitis B (CHB) (n = 74) who underwent both ECA-MRI and HBA-MRI before surgery for de novo nodule(s) measuring 10-30 mm. We compared the HCC diagnostic performance of EASL and LR-5 in both MRIs., Results: In an analysis of 215 observations (175 HCCs, 17 non-HCC malignancies and 23 benign lesions) identified from cirrhotic or non-cirrhotic CHB participants, LR-5 with ECA-MRI provided the highest sensitivity (80.7%), followed by EASL with ECA-MRI (76.2%), LR-5 with HBA-MRI (67.3%) and EASL with HBA-MRI (63.0%, all P < .05). The specificities were comparable (89.4%-91.5%). When the analysis is limited to participants with pathological cirrhosis (123 observations), the sensitivity of LR-5 with ECA-MRI was similar to that of EASL with ECA-MRI (82.7% vs 80.2%, P = .156), but higher than LR-5 with HBA-MRI (65.1%) or EASL with HBA-MRI (62.8%, both P < .001), with comparable specificities (87.5%-91.7%)., Conclusions: The LR-5 with ECA-MRI yielded the highest sensitivity with a similar specificity for HCC diagnosis in cirrhosis and non-cirrhotic CHB participants, while the sensitivities of LR-5 and EASL with ECA-MRI are similar for cirrhosis participants. This indicates non-invasive diagnosis criteria can differ by contrast agents and presence of cirrhosis., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: To determine longitudinal changes of the ganglion cell-inner plexiform layer (GC-IPL) thickness in patients with non-exudative age-related macular degeneration (AMD) without other ophthalmic disease., Methods: Thirty-three eyes of 33 patients with early and intermediate non-exudative AMD (non-exudative AMD group) and 33 normal control eyes were followed for 2 years, and GC-IPL thickness was measured by spectral domain optical coherence tomography at 1-year intervals. The mean rate of GC-IPL reduction was estimated using a linear mixed model and compared between two groups., Results: The mean age of patients in the non-exudative AMD group and control groups were 68.82 ± 6.81 years and 67.73 ± 5.87 years, respectively (p = 0.488). The mean GC-IPL thickness at the first visit was 76.61 ± 16.33 μm in the non-exudative AMD and 81.76 ± 3.69 μm in control group (p = 0.387), and these values significantly decreased over time, with an average reduction rate of average GC-IPL -0.86 μm/year in the non-exudative AMD group and -0.32 μm/year in the control group. The difference between two groups was statistically significant (p < 0.001), and there was also a significant interaction between group and duration in linear mixed models in mean GC-IPL thickness (p = 0.001)., Conclusions: The reduction rate of the GC-IPL thickness was greater in non-exudative AMD eyes, even at relatively early stages of the disease. Physicians should maintain awareness of the presence of non-exudative AMD in various cases of ophthalmic diseases where GC-IPL thickness evaluation is necessary., (© 2021 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Aim: In many Asian countries, youth mental health services are not well-developed and access to treatment is generally delayed. Here, we present a community-based service model based on our experience with Mindlink, the first early-intervention centre of its kind in Korea., Methods: We describe the history of this mental health early-intervention service and the characteristics of users, as well as its intervention programmes and research directions. We also propose ways to further develop youth mental health services., Results: A community-based early-intervention service for youth was first introduced in 2012, when a special team was formed in a community mental health centre of Korea. As the numbers of young clients increased, a youth-friendly, early-intervention centre called Mindlink was opened in 2016. Mindlink targets those aged 15-30 years with mental illness less than 5 years in duration. Its goal is to detect mental illness in young people early and provide comprehensive multidisciplinary interventions. It provides intensive case management and group programmes including cognitive-behavioural therapy, family intervention, psychoeducation, behavioural activation and physical health promotion. The Korean government has officially announced that the Mindlink model is effective and is currently in the process of scaling it up on a national level., Conclusion: An accessible, youth-friendly, stigma-free, community mental health centre such as Mindlink allows early detection and appropriate management of mental illness in young patients., (© 2020 The Authors. Early Intervention in Psychiatry Published by John Wiley & Sons Australia, Ltd.)

Aim: The duration of untreated psychosis (DUP) is an important prognostic indicator of schizophrenia. We explored the effects of patient personality and family relationships on delayed schizophrenia treatment., Methods: We prospectively included data from 169 patients diagnosed with first-episode schizophrenia. Personality traits were investigated using the Big Five Inventory (BFI-10) and family relationship was assessed employing the Family Adaptability and Cohesion Evaluation Scale-III (FACES-III). We explored patient clinical characteristics using the Positive and Negative Syndrome Scale (PANSS) and the Social and Occupational Functioning Scale (SOFAS). The DUP was defined as the time between the first appearance of psychotic symptoms and commencement of adequate antipsychotic treatment. Subjects were divided into two groups by the 3-month median DUP cutoff., Results: The average and median DUPs were 12 and 3 months, respectively. A longer DUP was associated with older age, a higher PANSS score, and a lower SOFAS score. The frequency of suicide attempts tended to be higher in the delayed treatment group (P = .055). The delayed treatment group scored significantly higher in conscientiousness factor of the BFI-10 and scored significantly lower family cohesion and adaptability factors of the FACES-III. Logistic regression showed that a longer DUP was significantly associated with higher-level conscientiousness on the BFI-10 and poorer family cohesion on the FACES-III., Conclusion: Treatment delay was associated with reduced family cohesion and higher patient conscientiousness, suggesting that the family plays a crucial role in terms of patient access to mental health services when early psychotic symptoms appear., (© 2020 John Wiley & Sons Australia, Ltd.)

Intrauterine inflammation is shown to be associated with preterm birth, fetal inflammatory response syndrome, and other pregnancy-related comorbidities such as central nervous system diseases including cerebral palsy and periventricular leukomalacia, pulmonary diseases such as bronchopulmonary dysplasia and respiratory distress syndrome, and necrotizing enterocolitis, to name a few. Many animal studies on intrauterine inflammation demonstrate that ascending infection of reproductive organs or the production of proinflammatory cytokines by some stimuli in utero results in such manifestations. Melatonin, known for its primary function in maintaining circadian rhythm, is now recognized as one of the most potent antioxidant and anti-inflammatory drugs. In some studies, melatonin injection in pregnant animals with intrauterine inflammation significantly reduced the number of preterm births, the severity of structural disintegration of the fetal lungs observed in bronchopulmonary dysplasia, and perinatal brain injuries with improvement in neuromotor function. These implicated benefits of melatonin in pregnant women with intrauterine inflammation seem promising in many research studies, strongly supporting the hypothesis that melatonin has antioxidative and anti-inflammatory properties that can potentially be taken by pregnant women who are at risk of having intrauterine inflammation. In this review, the potential of melatonin for improving outcomes of the pregnancies with intrauterine inflammation will be discussed., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: This study aimed to evaluate the association between soluble TGF-β (sTGF-β) and soluble PD-L1 (sPDL1), the dynamics of sTGF-β during treatment and its prognostic role in biliary tract cancer (BTC)., Methods: The study population consisted of 90 BTC patients with first-line chemotherapy (cohort 1) and 35 BTC patients with second- or third-line chemotherapy (cohort 2). Plasma sTGF-β and sPDL1 levels were measured using an enzyme-linked immunosorbent assay., Results: In both groups, sTGF-β was positive correlated with sPDL1 for baseline and change values after treatment. sTGF-β was elevated at disease progression compared to baseline in cohort 1 (P < .001). Increased sTGF-β after treatment revealed worse DFS and OS (P = .024, P = .028, respectively) in cohort 1 and significantly shorter OS (P = .020) in cohort 2. In multivariable analysis, this prognostic value of increased sTGF-β for OS retained its significance in both cohorts (Hazard ratio (HR) = 1.8, 95% CI, 1.1-3.0, P = .028, in cohort 1; HR = 4.7, 95% CI, 1.5-14.6, P = .007, in cohort 2)., Conclusions: In BTC, sTGF-β was positively correlated with sPDL1 for baseline and changes after chemotherapy, and increased as tumour burden. sTGF-β could be associated with survival; particularly, an elevated value after treatment suggests worse prognosis., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Aims: Isolation of Helicobacter pylori is considered difficult because of the requirement of the additional biopsy tissue and the effort involved in the isolation of the bacterium. We investigated whether H pylori can be cultured from tissue samples used for the rapid urease test (RUT)., Methods: Totally, 174 specimens from 87 patients referred for endoscopy were prospectively included. During endoscopy, two biopsy specimens were obtained, one each from the gastric antrum and the corpus, and were placed into a commercially available RUT kit. After detection of urease activity, H pylori was cultured using tissue leftover in the RUT, regardless of the result., Results: H pylori was successfully isolated using leftover tissue in 72.4% (63/87) of the patients. In 32 patients, H pylori was isolated from both specimens, while in 31 patients, it was isolated from either antrum or corpus. Eighty-one H pylori strains were isolated from 141 specimens with positive RUT results (57.4%), whereas 14 strains were isolated from 33 specimens with negative RUT results (42.4%). The median interval between tissue acquisition and inoculation onto the isolation media was 3.6 hours (range: 0.5-27.5 hours) in cases with successful cultures, compared to 23.5 hours (range: 0.5-76.0 hours) in cases with failed cultures. Among the positive RUT tissues, 80.4% (45/56) were cultured successfully when the tissue was inoculated within 4 hours of the biopsy., Conclusions: RUT kits can be used as transport media for H pylori, and this media is most efficient when used within 4 hours of the test., (© 2020 John Wiley & Sons Ltd.)

Objectives: This study was conducted to investigate the dose-response characteristics of radioiodine on salivary glands and to investigate the mechanism responsible for radioiodine-induced salivary glands toxicity., Methods: Twenty-four mice were divided into six groups: 0, 0.05, 0.10, 0.20, 0.40, and 0.80 mCi/20 g mouse, administered orally. Mortalities were noted 12 months after radioiodine administration. Body weights, gland weights, salivary lag times, flow rates, and changes in 99m Tc pertechnetate were recorded. Histopathological changes and mRNA expressions were also evaluated, and immunohistochemical analysis and apoptotic assays were performed., Results: Survival rates, body weights, gland weights, and flow rates decreased, and lag times increased on increasing radioiodine dose. Animals administered radioiodine showed acinar atrophy, striated duct dilations, and lymphocytic infiltration in glands and irregular destruction of epithelial surfaces of tongue. The uptake and excretion of 99m Tc pertechnetate were impaired by radioiodine. Immunohistochemical analysis showed that numbers of salivary epithelial, myoepithelial, and endothelial cells decreased and that numbers of ductal cells increased with radioiodine dose. Oxidative stress biomarker levels increased; reactive oxygen species scavenger levels decreased; and numbers of apoptotic cells increased in animals exposed to higher radioiodine doses., Conclusion: These dose-related, long-term effects on salivary gland should be taken into account when determining radioiodine doses., Level of Evidence: NA Laryngoscope, 130:2173-2178, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: The role of sex hormones for voice changes in men and women is presently unknown. To determine the effect of sex hormone on the vocal fold, changes of the extracellular matrix (ECM) in vocal fold lamina propria were assessed in orchiectomized (ORX) and ovariectomized (OVX) rats., Methods: Male and female Sprague-Dawley rats were divided into sham-operated control male (CON-ORX), ORX, sham-operated female (CON-OVX), and OVX rats. Histological changes and expression of ECM-related genes in lamina propria of the vocal fold were evaluated at 4 and 12 weeks after surgery., Results: Testosterone and estradiol levels decreased in the ORX and OVX groups, respectively. ORX groups did not have significant changes compared with CON-ORX groups. However, the expression of hyaluronic acid (HA) was decreased in the OVX group compared with the CON-OVX group. The expression of collagen I in OVX was lower than in the CON-OVX group. Collagen III levels were elevated at 4 weeks in the OVX group, but collagen III levels were diminished at 12 weeks in the OVX group. Expression of elastin in the ECM was less dense in the OVX group compared with controls. The expression MMP-1 and MMP-9 showed significantly increase in the OVX group compared to the CON-OVX group., Conclusion: No changes of the ECM-related genes in the vocal fold lamina propria were observed in ORX groups with reduced testosterone. However, changes of several ECM-related genes were observed in OVX groups with decreased estrogen. These results indicate that the vocal fold is an estrogen-sensitive target organ and that decreased estrogen, not testosterone, can affect the expression of several ECM-related molecules of vocal fold., Level of Evidence: NA Laryngoscope, 130:732-740, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Aim: This study investigated the clinical characteristics and psychosocial factors associated with depression in patients with early psychosis according to stage of illness., Methods: The present study includes patients who fulfil the DSM-5 criteria for schizophrenia spectrum and other psychotic disorders. Patients were divided into two groups according to illness stage (the acute stage of first-episode psychosis and stabilization phase of recent-onset psychosis). Clinically meaningful depression was defined as moderate or severe on the depression dimension of the Clinician-Rated Dimensions of Psychosis Symptom Severity scale in the DSM-5., Results: In total, 340 (207 first-episode and 133 recent-onset) patients were recruited in this study. Patients with comorbid depression were characterized by frequent suicidal ideation, a past suicide attempt, and lower scores on the Subjective Well-being Under Neuroleptics and Brief Resilience Scale in both groups. Long duration of untreated psychosis and higher scores on the Early Trauma Inventory Self Report were associated with depression in the acute stage of first-episode psychosis. In the stabilization phase of recent-onset psychosis group, a monthly income and scores for sexual desire and on the Family Adaptability and Cohesion Evaluation Scale-III were significantly lower in patients with depression than in those without depression., Conclusion: Comorbid depression was associated with high suicidality, lower quality of life and poor resilience in patients with first-episode and recent-onset psychosis. Depression was associated with factors that had been present before the initiation of treatment in patients with first-episode psychosis and with environmental factors in those in the stabilization phase., (© 2019 John Wiley & Sons Australia, Ltd.)

Background There is insufficient evidence on the effect of statins, particularly high-intensity statins, in patients with acute ischemic stroke and atrial fibrillation. We investigated the impact of statins on the outcomes in these patients, including those who might be vulnerable to statin therapy and those without clinical atherosclerotic cardiovascular diseases. Methods and Results A total of 2153 patients with acute ischemic stroke and atrial fibrillation were enrolled in the present nationwide, multicenter, cohort study. The primary composite end point was the occurrence of net adverse clinical and cerebral events (NACCE; death from any cause, stroke, acute coronary syndrome, or major bleeding) over a 3-year period based on statin intensity. NACCE rates were lower in patients receiving low- to moderate-intensity (adjusted hazard ratio 0.64; 95% CI: 0.52-0.78) and high-intensity statins (hazard ratio 0.51; 95% CI 0.40-0.66) than in those not receiving statin therapy. High-intensity statins were associated with a lower risk for NACCE than low- to moderate-intensity statins (hazard ratio 0.76; 95% CI 0.59-0.96). Subgroup analyses showed that the differences in hazard ratio for 3-year NACCE favored statin use across all subgroups, including older patients, those with low cholesterol levels, patients receiving anticoagulants, and patients without clinical atherosclerotic cardiovascular diseases. Magnified benefits of high-intensity statins compared with low- to moderate-intensity statins were observed in patients who underwent revascularization therapy and those under 75 years of age. Conclusions Statins, particularly high-intensity statins, could reduce the risk for NACCE in patients with acute ischemic stroke and atrial fibrillation; this needs to be further explored in randomized controlled trials.

Explicitly fitting effects for major genes or QTL that account for a large percentage of variation in a whole genomic prediction model may increase prediction accuracy. This study compared approaches to account for a major effect of an F94L variant in the MSTN gene within the genomic prediction using bovine whole-genomic SNP markers. Among the beef cattle breeds, Limousin have been known to have an F94L variant that is not present in Angus. The reference population in this study consisted of 3060 beef cattle including pure-bred Limousin (PL), cross-bred Limousin with Angus (LF) and pure-bred Angus, genotyped using a BovineSNP50 BeadChip and directly for the MSTN-F94L variant. We compared prediction accuracies in PL animals using the three datasets from only the PL population, admixed PL and LF (AL) or multibreed analysis using all of the PL, LF and Angus (MB) population according to four-fold cross-validation after K-means clustering. The MSTN-F94L variant was the most strongly associated with five traits (birth weight, calving ease direct, milk, weaning weight and yield grade) among the 13 measured traits in PL and AL populations. Fitting the MSTN-F94L variant as a random effect, the genomic prediction accuracies for birth weight increased by 2.7% in PL, by 2.2% in AL and by 3.2% in MB. Prediction accuracies for five traits increased in the MB analysis. Fitting MSTN-F94L as a fixed effect in PL, AL and MB analyses resulted in increased prediction accuracy in PL for eight traits. Prediction accuracies can be improved by including a causal variant in genomic evaluation compared with simply using whole-genome SNP markers. Fitting the causal variant as a fixed effect along with markers fitted as random effects resulted in greater prediction accuracies for most traits. Causal variants should be genotyped along with SNP markers., (© 2019 Stichting International Foundation for Animal Genetics.)

Age-related hearing loss (ARHL) is a major neurodegenerative disorder and the leading cause of communication deficit in the elderly population, which remains largely untreated. The development of ARHL is a multifactorial event that includes both intrinsic and extrinsic factors. Recent studies suggest that NAD + /NADH ratio may play a critical role in cellular senescence by regulating sirtuins, PARP-1, and PGC-1α. Nonetheless, the beneficial effect of direct modulation of cellular NAD + levels on aging and age-related diseases has not been studied, and the underlying mechanisms remain obscure. Herein, we investigated the effect of β-lapachone (β-lap), a known plant-derived metabolite that modulates cellular NAD + by conversion of NADH to NAD + via the enzymatic action of NADH: quinone oxidoreductase 1 (NQO1) on ARHL in C57BL/6 mice. We elucidated that the reduction of cellular NAD + during the aging process was an important contributor for ARHL; it facilitated oxidative stress and pro-inflammatory responses in the cochlear tissue through regulating sirtuins that alter various signaling pathways, such as NF-κB, p53, and IDH2. However, augmentation of NAD + by β-lap effectively prevented ARHL and accompanying deleterious effects through reducing inflammation and oxidative stress, sustaining mitochondrial function, and promoting mitochondrial biogenesis in rodents. These results suggest that direct regulation of cellular NAD + levels by pharmacological agents may be a tangible therapeutic option for treating various age-related diseases, including ARHL., (© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Introduction: The eradication rates for Helicobacter pylori have decreased in Korea although the prevalence of this bacterium has also decreased. Antibiotic resistance is likely to be a crucial factor in H. pylori eradication success, and we therefore mapped these resistance patterns nationwide in Korea., Materials and Methods: Five hundred and ninety adult subjects were prospectively enrolled from 2017 to 2018 from 15 centers across six geographic areas of Korea. A total of 580 biopsy tissues had been sampled from these patients during an upper endoscopy and were frozen at -80°C and delivered to a central laboratory. The agar dilution method was used to determine the minimum inhibitory concentration of amoxicillin, clarithromycin, metronidazole, tetracycline, ciprofloxacin, and levofloxacin for each H. pylori isolate., Results: The culture success rate was 60.2% (349/580). Resistance rates against clarithromycin, metronidazole, amoxicillin, tetracycline, levofloxacin, and ciprofloxacin were 17.8%, 29.5%, 9.5%, 0%, 37.0%, and 37.0%, respectively. The geographic distribution of metronidazole and quinolone resistance was highly variable. Some subjects had multiple H. pylori strains in the antrum and body of the stomach and showed a heterogeneous resistance profile between these anatomic areas. The H. pylori multidrug resistance (MDR) rate was 25.2% (88/349) among amoxicillin, clarithromycin, metronidazole, tetracycline, and quinolone and 11.2% (39/349) among four of these major antibiotics except for quinolone. The Seoul and Chungcheong areas showed a relatively lower MDR rate., Conclusion: The antibiotic resistance of H. pylori differs by drug and geographic area in Korea. Detailed nationwide antibiotic resistance mapping is needed to develop an effective H. pylori eradication strategy., (© 2019 John Wiley & Sons Ltd.)

Subsequent changes after injection should be considered when determining the precise volume of injected dermal filler. Several studies have used scoring systems to evaluate facial volumes; however, these scoring systems are not particularly objective. This present study aimed to evaluate the volumetric changes over time on three-dimensional (3D) images and the maintenance potential of various hyaluronic acid (HA) fillers used for mid-face volume augmentation. This split-face clinical study included nine Korean subjects who each received a mid-facial injection of the test filler (B) on one side and a random control filler (J, R, or Y) on the contralateral side. Global, photographic, and 3D scanning assessments were conducted at baseline and after 30 min, 3 days, and 2, 4, 12, and 24 weeks. In all nine cases, the 3D images revealed the largest differences in height where the test filler (B) was injected. The results of subjective scoring systems correlated with the results of 3D imaging. The volumes of monophasic fillers (B and J) were maintained for longer periods of time than those of biphasic fillers (R and Y). The B filler yielded excellent volumizing and spreading effects and good injectability. This filler would be suitable for injection into high-pressure areas, such as the lateral cheek, chin, and nasolabial fold. Moreover, the 3D imaging analysis provided objective and digitized data. The present authors hope that their data will allow physicians to better understand the durational changes in HA fillers and, thus, provide accurate predictions to their patients., (© 2019 Wiley Periodicals, Inc.)

Background: The eradication rate of Helicobacter pylori has declined, mainly due to antimicrobial resistance. To overcome resistance-associated treatment failure, the efficacy of culture-based, susceptibility-guided therapy was demonstrated as the first-line eradication therapy for H pylori infection., Aims: To evaluate the efficacy of culture-based therapy as the first-line eradication therapy in regions with high levels of antimicrobial resistance., Methods: Helicobacter pylori-positive patients without previous eradication treatment history were recommended to undergo culture to determine the minimal inhibitory concentration (MIC). If they consented, 7-day clarithromycin-containing PPI triple; 7-day esomeprazole, moxifloxacin, and amoxicillin (MEA) therapy; or 7- or 14-day esomeprazole, bismuth, metronidazole, and tetracycline (quadruple) therapy were administered based on the agar dilution-determined MIC. Eradication, treatment compliance, and adverse events were examined., Results: In total, 74 patients were enrolled, and 69 patients completed the protocols. The overall resistance rates to amoxicillin, clarithromycin, metronidazole, and moxifloxacin were 6.7%, 31.0%, 41.8%, and 39.2%, respectively. The patients were allocated to the PPI triple (n = 50), MEA (n = 8) or quadruple (n = 16) therapy. The eradication rate in the intention-to-treat analysis was 93.1% (69 of 74 patients). The eradication rates in the per-protocol analysis were 100.0% (69 of 69 patients). Epigastric pain, nausea, and vomiting were less common than those of other empirical therapies., Conclusions: Culture-based, susceptibility-guided therapy is effective first-line eradication therapy, especially in regions with high levels of antimicrobial resistance., (© 2019 John Wiley & Sons Ltd.)

This study aimed to evaluate the improvement in strength and durability of the bond between dentin and composite resins following plasma drying of the etched dentin surface using non-thermal atmospheric pressure plasma. Plasma drying was applied to the etched dentin before applying adhesive. Conventional wet-bonding and helium (He) gas-dried bonding schemes were used as control groups. The bond strength of the composite resin to dentin was measured as the microtensile bond strength at 24 h after bonding and after 10,000 cycles of thermocycling. Hybrid layer formation was observed using micro-Raman spectroscopy and scanning electron microscopy. Although the bond-strength values were not statistically different either at 24 h after bonding or after thermocycling, the bond strength of the plasma-dried bonding group was significantly higher than the conventional wet-bonding group and He gas-dried bonding group. Micro-Raman spectral analysis revealed effective penetration of the adhesive and an improved polymerization rate of the adhesive after plasma drying. Plasma drying increased the penetration of hydrophobic resin into the collagen mesh structure, which improved mechanical bonding and long-term durability between dentin and composite resin., (© 2018 Eur J Oral Sci.)

The rapid and accurate detection of the presence of microorganisms, such as viruses, has been an important issue in the fields of public health, as well as agriculture. A PCR-based detection method has been developed and applied in these fields to determine the presence of specific pathogens. Although the major advantage of real-time PCR is the monitoring of amplification and ability to quantify the template genes, the method described here should solve the problem of nonspecific product synthesis. We obtained viral RNA from infected samples by freezing and thawing; we rapidly synthesized cDNA from RNA, and then amplified the cDNA by rapid PCR in 10 Min. Finally, the PCR products were hybridized and quickly confirmed to be the target analyte on a DNA chip. Our newly proposed methods overcome the drawbacks of PCR-based detection and provide three additional advantages, namely, rapidly obtaining large amounts of RNA from samples, quickly detecting infective or pathogenic genes, and speedily confirming the detected exogenous genes. This application might be useful for detecting viral RNA and for the diagnosis of RNA virus-mediated diseases., (© 2018 International Union of Biochemistry and Molecular Biology, Inc.)

Ethiopia is an ecologically diverse country; the low altitude regions are hot and humid whereas the high altitude regions are cooler. In this study we analyzed the transcriptome response of high altitude (Addis Ababa) and low altitude (Awash) chickens to heat stress conditions that are prevalent in the low altitude regions. The chickens were free ranged for 20 h in an enclosure in Awash, and then the heart, breast muscle and spleen tissues were collected at 6:00 am, 12:00 noon and 6:00 pm to follow a daily circadian cycle. Through RNA-sequencing analysis, we identified differentially expressed genes (DEGs) that were significant (q < 0.05). These DEGs were subjected to protein-protein interaction (PPI) network and gene co-expression network (GCN) analyses to understand their role. KEGG pathway analysis and Gene Ontology analysis of all the identified DEGs and the genes identified from the PPI network and GCN analyses revealed that several immune-related pathways, such as proteasome, focal adhesion, influenza A, the ErbB signaling pathway and glycerophospholipid metabolism, were enriched in response to heat stress. These results suggest that the high altitude chickens were under heat stress and might be immunologically susceptible. Our findings will help in developing a genetic approach to mitigate production loss due to heat stress., (© 2018 Stichting International Foundation for Animal Genetics.)

Background: This article describes the development of the smartphone application for cognitive-behavioural case management of young individuals with early psychosis and examines the acceptance and potential clinical benefits of this application through a pilot survey., Methods: Gwangju Bukgu-Community Mental Health Center developed and launched a smartphone application (Heal Your Mind [HYM]) for cognitive-behavioural case management and symptom monitoring. The HYM application for clients includes 6 main modules including thought record, symptom record, daily life record, official notices, communication and scales. The key module is the "thought record" for self-directed cognitive-behavioural treatment. When the client writes and sends the self-cognitive-behavioural therapy sheet to the case manager, the latter receives a notification and can provide feedback in real time. We conducted a survey to investigate the acceptance and feasibility of this approach among young clients with early psychosis., Results: A total of 24 clients with early psychosis participated in this survey. More than 80% of participants reported that it was easy to learn to use this application, and no one described this application as very complicated or reported that they needed a long time to learn how to use it. About 80% of participants were satisfied with this application, and 70% reported that they received help as a result of using this application., Conclusions: This study suggests that this smartphone application is useful for young individuals with early psychosis and that it may contribute to the development of both young customer- and case manager-friendly systems for this clinical population., (© 2017 John Wiley & Sons Australia, Ltd.)

Objectives: This study was conducted to determine whether a nitinol stent coated with doxycycline prevents tracheal inflammation and fibrosis in a rabbit., Methods: A nitinol stent coated with doxycycline was designed by us. Twelve rabbits were divided into three groups: normal, control (nondoxycycline-coated stent), and doxycycline-coated stent group. The stents were inserted into the tracheal lumen through the oral cavity. Tracheal granulation was evaluated and graded by laryngoscopy. Histological examinations evaluated the inflammatory response and fibrosis. Real-time polymerase chain reaction (PCR) and Western blot assessed the changes to the extracellular matrix (ECM)., Results: Endoscopic findings showed that the nitinol stent coated with doxycycline resulted in lesser granulation tissue in the trachea than the noncoated stent. Histologic examination further revealed that the doxycycline-coated stent was associated with decreased inflammatory cells and reduced fibrosis, compared to the noncoated stent. In PCR and Western blot, the doxycycline-coated stent showed lower expression of ECM components inducing fibrosis., Conclusion: A nitinol stent coated with doxycycline showed favorable effects in reducing tracheal inflammation and fibrosis in a rabbit model. Further research is required to study the beneficial effects of local application of doxycycline for prevention of tracheal stenosis., Level of Evidence: NA. Laryngoscope, 128:1558-1563, 2018., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Among swine reproductive traits, sow lifetime productivity (SLP) is considered a profitable trait in commercial pig farming. Notably, longevity and efficiency in SLP can be adopted as the key phenotype representing SLP. In this study, we conducted a co-association network analysis using results from a genome-wide association study for SLP-related traits. A total of 656 purebred Landrace female pigs were genotyped using a 60K SNP array. Significantly associated SNPs identified from the GWAS were annotated for the specific genes. Then, we constructed an association weight matrix to build a network based on the co-associations between the genes and 10 SLP traits. The entire network consisted of 495 nodes and 37 755 significant edges. We identified three key regulatory transcription factors: STAT2 (signal transducer and activator of transcription 2), MYF6 (myogenic factor 6) and TFCP2L1 (transcription factor CP2 like 1). The network revealed that the STAT2 and MYF6 regulatory modules cooperate with each other and specifically influence the longevity and efficiency of sows, whereas the TFCP2L1 family specifically affects the improvement of litter size., (© 2018 Stichting International Foundation for Animal Genetics.)

Aims: The relationship between directly measured body fat and all-cause mortality has been rarely studied. The aim of this study was to evaluate the predictive significance of computed tomography (CT)-measured body fat, including both visceral fat area (VFA) and subcutaneous fat area (SFA), for mortality., Methods: The study included 36 656 participants who underwent abdominal CT as part of a health check-up at a single university-affiliated healthcare center in 2007 to 2015. Of those, 32 593 participants with data regarding vital status as of May 2016 were included in the final analysis. The main factors evaluated were VFA, SFA and visceral-to-subcutaneous fat area ratio (VSR), and the primary outcome was all-cause mortality., Results: There were 253 deaths during a mean follow-up of 5.7 years. Increased SFA was associated with decreased all-cause mortality, whereas an increased VFA and VSR were related to increased all-cause mortality. Compared with the predictive power of body mass index (BMI), SFA and VSR showed a larger area under the curve than did BMI. In Kaplan-Meier survival curve analysis, increased SFA and VSR were associated with decreased and increased hazard of all-cause death, respectively. However, in multivariate Cox proportional hazard regression analysis, only VSR was independently associated with all-cause mortality. Moreover, this relationship was paralleled by the harmful impact of increased VSR on metabolic profiles., Conclusion: Increased VSR was an independent predictor of all-cause mortality. This suggests that the location of fat deposits may be more important than the actual amount of body fat., (© 2017 John Wiley & Sons Ltd.)

Background: Amoxicillin (Amx) is one of the most important antibiotics for eradication of Helicobacter pylori (H. pylori). Main determinants of genetically stable Amx resistance are mutations in the C-terminus of penicillin-binding protein 1A (pbp1A). However, contribution of individual mutation remains unclear., Methods: 77 Amx-resistant (Amx R ) and 77 Amx-susceptible (Amx S ) H. pylori strains were isolated from gastric tissues, and DNA sequencing was performed to compare C-terminus sequences of pbp1A gene between Amx R and Amx S strains. Natural transformation of these mutated genes into amoxicillin-susceptible strains was performed., Results: Among many mutations in pbp1A, D479E (OR: 37.4, 95% CI: 5.53-252.49, P < .001), and T593 mutation (OR: 32.0, 95% CI: 4.04-252.86, P < .001) independently contributed to Amx resistance in H. pylori strains. In the transformation experiment, T593 mutations were identified in their transformants showing Amx resistance. However, PCR product of D479E was not inserted into recipient (ATCC 43504) resulting in transformation failure., Conclusion: Amx resistance is associated with various substitutions in pbp1A and T593 mutation contributes to Amx resistance of H. pylori., (© 2017 John Wiley & Sons Ltd.)