Comparison of endoscopic healing and durability between infliximab originator and CT-P13 in pediatric patients with inflammatory bowel disease.

Background and aims: Favourable clinical data were published on the efficacy of CT-P13, the first biosimilar of infliximab (IFX), in pediatric inflammatory bowel disease (IBD); however, few studies have compared the effect on endoscopic healing (EH) and drug retention rate between the IFX originator and CT-P13. Therefore, we aimed to compare EH and the drug retention rate between the IFX originator and CT-P13. Methods: Children with Crohn's disease (CD) and ulcerative colitis (UC)/IBD-unclassified (IBD-U) at 22 medical centers were enrolled, with a retrospective review conducted at 1-year and last follow-up. Clinical remission, EH and drug retention rate were evaluated. Results: We studied 416 pediatric patients with IBD: 77.4% had CD and 22.6% had UC/IBD-U. Among them, 255 (61.3%) received the IFX originator and 161 (38.7%) received CT-P13. No statistically significant differences were found between the IFX originator and CT-P13 in terms of corticosteroid-free remission and adverse events. At 1-year follow-up, EH rates were comparable between them (CD: P=0.902, UC: P=0.860). The estimated cumulative cessation rates were not significantly different between the two groups. In patients with CD, the drug retention rates were 66.1% in the IFX originator and 71.6% in the CT-P13 group at the maximum follow-up period (P >0.05). In patients with UC, the drug retention rates were 49.8% in the IFX originator and 56.3% in the CT-P13 group at the maximum follow-up period (P >0.05). Conclusions: The IFX originator and CT-P13 demonstrated comparable therapeutic response including EH, clinical remission, drug retention rate and safety in pediatric IBD.

Unenhanced Breast MRI With Diffusion-Weighted Imaging for Breast Cancer Detection: Effects of Training on Performance and Agreement of Subspecialty Radiologists.

OBJECTIVE: To investigate whether reader training improves the performance and agreement of radiologists in interpreting unenhanced breast magnetic resonance imaging (MRI) scans using diffusion-weighted imaging (DWI). MATERIALS AND METHODS: A study of 96 breasts (35 cancers, 24 benign, and 37 negative) in 48 asymptomatic women was performed between June 2019 and October 2020. High-resolution DWI with b-values of 0, 800, and 1200 sec/mm² was performed using a 3.0-T system. Sixteen breast radiologists independently reviewed the DWI, apparent diffusion coefficient maps, and T1-weighted MRI scans and recorded the Breast Imaging Reporting and Data System (BI-RADS) category for each breast. After a 2-h training session and a 5-month washout period, they re-evaluated the BI-RADS categories. A BI-RADS category of 4 (lesions with at least two suspicious criteria) or 5 (more than two suspicious criteria) was considered positive. The per-breast diagnostic performance of each reader was compared between the first and second reviews. Inter-reader agreement was evaluated using a multi-rater κ analysis and intraclass correlation coefficient (ICC). RESULTS: Before training, the mean sensitivity, specificity, and accuracy of the 16 readers were 70.7% (95% confidence interval [CI]: 59.4-79.9), 90.8% (95% CI: 85.6-94.2), and 83.5% (95% CI: 78.6-87.4), respectively. After training, significant improvements in specificity (95.2%; 95% CI: 90.8-97.5; P = 0.001) and accuracy (85.9%; 95% CI: 80.9-89.8; P = 0.01) were observed, but no difference in sensitivity (69.8%; 95% CI: 58.1-79.4; P = 0.58) was observed. Regarding inter-reader agreement, the κ values were 0.57 (95% CI: 0.52-0.63) before training and 0.68 (95% CI: 0.62-0.74) after training, with a difference of 0.11 (95% CI: 0.02-0.18; P = 0.01). The ICC was 0.73 (95% CI: 0.69-0.74) before training and 0.79 (95% CI: 0.76-0.80) after training (P = 0.002). CONCLUSION: Brief reader training improved the performance and agreement of interpretations by breast radiologists using unenhanced MRI with DWI.

Fluorescence-Based Lateral Flow Immunoassay for Quantification of Infliximab: Analytical and Clinical Performance Evaluation.

BACKGROUND: Therapeutic drug monitoring of infliximab (IFX) can improve treatment outcomes; however, the temporal gap between drug concentration monitoring and subsequent availability restricts its practical application. To address this issue, an automated monitoring method, AFIAS IFX, was developed to rapidly and accurately analyze IFX concentration in blood. The analytical and clinical performances of this method were assessed to establish its clinical utility. METHODS: The analytical performance of AFIAS IFX was evaluated according to Clinical and Laboratory Standard Institute guidelines. For clinical validation, AFIAS IFX was compared with 3 established enzyme-linked immunosorbent assay kits (LISA TRACKER, RIDASCREEN, and ImmunoGuide) using 100 consecutive samples from 28 patients treated with IFX. Passing-Bablok regression and Bland-Altman analyses were performed to compare the methods. RESULTS: The detection and quantification limits of AFIAS IFX were 0.12 and 0.20 mcg/mL, respectively. Furthermore, AFIAS IFX analyzed samples within 10 minutes for concentrations up to 50 mcg/mL, exhibiting reproducibility (coefficient of variation [CV] ≤7.8%) and accuracy (recovery 98%-101%) with serum, plasma, and whole blood samples. Clinically, it exhibited a good correlation with the 3 established enzyme-linked immunosorbent assay kits. For patients treated with Remicade (IFX), the Passing-Bablok regression slope was 1.001-1.259, with a mean difference of -1.48 to 0.28 mcg/mL. For patients treated with CT-P13, the Passing-Bablok regression slope was 0.974-1.254, with a mean difference of -2.44 to 0.15 mcg/mL. CONCLUSIONS: AFIAS IFX, a novel fluorescence-based lateral flow assay, exhibited excellent performance in analyzing IFX trough levels and is a potentially powerful tool for therapeutic drug monitoring in clinical settings, with opportunities for further development.

O- and N-Methyltransferases in benzylisoquinoline alkaloid producing plants.

BACKGROUND: Secondary metabolites such as benzylisoquinoline alkaloids (BIA) have attracted considerable attention because of their pharmacological properties and potential therapeutic applications. Methyltransferases (MTs) can add methyl groups to alkaloid molecules, altering their physicochemical properties and bioactivity, stability, solubility, and recognition by other cellular components. Five types of O-methyltransferases and two types of N-methyltransferases are involved in BIA biosynthesis. OBJECTIVE: Since MTs may be the source for the discovery and development of novel biomedical, agricultural, and industrial compounds, we performed extensive molecular and phylogenetic analyses of O- and N-methyltransferases in BIA-producing plants. METHODS: MTs involved in BIA biosynthesis were isolated from transcriptomes of Berberis koreana and Caulophyllum robustum. We also mined the methyltransferases of Coptis japonica, Papaver somniferum, and Nelumbo nucifera from the National Center for Biotechnology Information protein database. Then, we analyzed the functional motifs and phylogenetic analysis. RESULT: We mined 42 O-methyltransferases and 8 N-methyltransferases from the five BIA-producing plants. Functional motifs for S-adenosyl-L-methionine-dependent methyltransferases were retained in most methyltransferases, except for the three O-methyltransferases from N. nucifera. Phylogenetic analysis revealed that the methyltransferases were grouped into four clades, I, II, III and IV. The clustering patterns in the phylogenetic analysis suggested a monophyletic origin of methyltransferases and gene duplication within species. The coexistence of different O-methyltransferases in the deep branch subclade might support some cases of substrate promiscuity. CONCLUSIONS: Methyltransferases may be a source for the discovery and development of novel biomedical, agricultural, and industrial compounds. Our results contribute to further understanding of their structure and reaction mechanisms, which will require future functional studies.

Fecal Calprotectin at Postinduction Is Capable of Predicting Persistent Remission and Endoscopic Healing after 1 Year of Treatment with Infliximab in Pediatric Patients with Crohn's Disease.

Background/Aims: : The recent update on Selecting Therapeutic Targets in Inflammatory Bowel Disease initiative has added a decrease in fecal calprotectin (FC) to an acceptable range as an intermediate target for Crohn's disease (CD). We aimed to investigate whether postinduction FC could predict future persistent remission (PR) and endoscopic healing (EH) after 1 year of treatment with infliximab (IFX) in pediatric patients with CD. Methods: : This multicenter retrospective observational study included pediatric patients with CD who were followed up for at least 1 year after starting IFX. The association of postinduction FC with PR and EH was investigated. Results: : A total of 132 patients were included in this study. PR and EH were observed in 71.2% (94/132) and 73.9% (82/111) of the patients, respectively. In multivariate logistic regression analysis, only the postinduction FC level was associated with PR (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.08 to 0.66; p=0.009). The FC levels at initiation of IFX and postinduction were significantly associated with EH (OR, 0.73; 95% CI, 0.53 to 0.99; p=0.044 and OR, 0.20; 95% CI, 0.06 to 0.49; p=0.002, respectively). According to the receiver operating characteristic curve analysis, the optimal cutoff level for postinduction FC associated with PR was 122 mg/kg, and that associated with EH was 377 mg/kg. Conclusions: : Postinduction FC was associated with PR and EH after 1 year of treatment with IFX in pediatric patients with CD. Our findings emphasize the importance of FC as an intermediate target in the treat-to-target era.

Dual Biological Therapy for Ulcerative Colitis with Intractable Pyoderma Gangrenosum.

Pyoderma gangrenosum is one of the dermatological extra-intestinal manifestations of ulcerative colitis (UC). We report a case of a 26-year-old male patient suffering from relapsed UC with a newly developed pyoderma gangrenosum. His skin and intestinal symptoms were intractable to treatment with steroids, immunosuppressants, or a single biological agent such as infliximab, golimumab, or vedolizumab. For the first time in Korea, we report a successful treatment experience of pyoderma gangrenosum in UC using dual biological agents, vedolizumab and infliximab. We strategically targeted each of the intestinal and skin symptoms, with a specific biological agent based on the drug's mechanism of action.

Clinical impact of metformin exposure during Staphylococcus aureus bacteremia in patients with diabetes mellitus.

PURPOSE: Increasing evidence has suggested that metformin may play positive roles in a wide range of infectious diseases. This study aimed to investigate the clinical impact of metformin exposure during Staphylococcus aureus bacteremia (SAB) in patients with diabetes. METHODS: A 3-year observational cohort study of 452 patients (aged ≥ 16 years) with SAB was performed at a tertiary care hospital. Metformin exposure was defined as receiving metformin during SAB, regardless of metformin use before the onset of bacteremia. RESULTS: Of 452 patients, 51 (11.3%) were classified in Group A (diabetes with metformin exposure), 115 (25.4%) in Group B (diabetes without metformin exposure), and 286 (63.3%) in Group C (no diabetes). The 30-day mortality rate in Group A was significantly lower than that in Group B (3.9% [2/51] versus 14.8% [17/115]; p = 0.04) and lower than that in Group C (3.9% [2/51] versus 17.1% [49/286]; p = 0.02). The mortality rates did not differ between Group B and Group C (14.8% [17/115] versus 17.1% [49/286]; p = 0.57). The rates of persistent and recurrent bacteremia were comparable among the three groups. Multivariate analysis indicated that metformin exposure was significantly associated with reduced mortality (adjusted odds ratio, 0.20; 95% confidence interval, 0.04-0.88; p = 0.03). CONCLUSIONS: Metformin exposure during SAB appears to be an independent predictor of survival in patients with diabetes.

Systemic antibiotics cause deterioration of emphysema associated with exaggerated inflammation and autophagy.

The interaction between the microbial environment and the host is important for immune homeostasis. Recent research suggests that microbiota dysbiosis can be involved in respiratory diseases. Emphysema is a chronic inflammatory disease, but it is unclear whether dysbiosis caused by antibiotics can affect disease progression. Here, we tried to elucidate the effect of systemic antibiotics on smoking-exposed emphysema models. In this study, the antibiotic mixture caused more alveolar destruction and airspace expansion in the smoking group than in the smoking only or control groups. This emphysema aggravation as a result of antibiotic exposure was associated with increased levels of inflammatory cells, IL-6, IFNγ and protein concentrations in bronchoalveolar lavage fluid. Proteomics analysis indicated that autophagy could be involved in antibiotic-associated emphysema aggravation, and increased protein levels of LC3B, atg3, and atg7 were identified by Western blotting. In microbiome and metabolome analyses, the composition of the gut microbiota was different with smoking and antibiotic exposure, and the levels of short-chain fatty acids (SCFAs), including acetate and propionate, were reduced by antibiotic exposure. SCFA administration restored emphysema development with reduced inflammatory cells, IL-6, and IFNγ and decreased LC3B, atg3, and atg7 levels. In conclusion, antibiotics can aggravate emphysema, and inflammation and autophagy may be associated with this aggravation. This study provides important insight into the systemic impact of microbial dysbiosis and the therapeutic potential of utilizing the gut microbiota in emphysema.

Efficacy of Combined Initial Treatment of Methotrexate with Infliximab in Pediatric Crohn's Disease: A Pilot Study.

BACKGROUND: The combination of antitumor necrosis factor-alpha (TNF-α) agents with immunomodulators (IMMs) is a common treatment for pediatric Crohn's disease (CD). Although methotrexate (MTX) can be a first-line medication as an IMM, most clinicians in real-life practice, especially in South Korea, are more familiar with thiopurines. This study aimed to compare the efficacy and immunogenicity of MTX and azathioprine (AZA) as concurrent therapies for pediatric CD. METHODS: In this pilot study, 29 newly diagnosed pediatric patients with moderate-to-severe CD were randomized to receive either MTX (n = 15) (15 mg/body surface area (BSA) per week) or oral AZA (n = 14) (0.5 mg/kg per day) in combination with Infliximab (IFX). The primary outcomes were the proportion of patients in endoscopic, biochemical, and transmural remission after 14 and 54 weeks of IFX therapy. The trough levels (TLs) of IFX and anti-drug antibody (ADA) levels were also compared. RESULTS: Among the 29 patients, there were no significant differences in the biochemical (p = 1.0 at week 14, p = 0.45 at week 54), endoscopic (p = 0.968 at week 14, p = 0.05 at week 54), or transmural (p = 0.103 at week 54) remission rates between the two medications during the concurrent therapy. Additionally, the trends in the IFX trough and ADA levels over time during the treatments were similar for both medications, with no significant differences (p = 0.686, p = 0.389, respectively). CONCLUSION: The MTX showed comparable efficacy to the AZA in pediatric CD patients with moderate-to-severe disease. This effectively maintained adequate IFX levels and reduced ADA production. Therefore, although additional large-scale clinical trials are needed, this study demonstrated that either MTX or AZA can be selected as IMMs in the concurrent treatment of pediatric CD, depending on individual medical institutions' circumstances.

Impact of the histologic grade of acute gastrointestinal graft-versus-host disease on outcomes in pediatric patients treated with allogeneic hematopoietic stem cell transplantation.

Introduction: Acute gastrointestinal graft-versus-host disease (GVHD) is a common life-threatening complication after hematopoietic stem cell transplantation (HCT). We aimed to investigate outcomes according to the clinical, endoscopic, and histologic severity of gastrointestinal GVHD in pediatric patients treated with allogeneic HCT. Methods: This retrospective cohort study included pediatric patients who underwent sufficient endoscopic and histopathologic evaluation for clinically suspected acute gastrointestinal GVHD between 2010 and 2020. Results: Fifty-one patients were included (male proportion, 68.6% [35/51]; median age at HCT, 6.4 years). When the patients were classified according to the histologic severity of gastrointestinal GVHD, the severe group had an earlier onset of GVHD symptoms and a higher proportion of patients with severe clinical gastrointestinal GVHD than the mild-to-moderate and "absent" groups. In Cox proportional hazards regression analysis, the groups with more severe clinical and histologic gastrointestinal GVHD showed a higher risk of non-relapse mortality (NRM). The 5-year overall survival (OS) rates were 58.3 and 36.4% in the mild-to-moderate and histologic gastrointestinal GVHD groups, respectively (p = 0.0384). Patients with higher clinical and histologic grades of gastrointestinal GVHD showed higher cumulative incidence of NRM. Discussion: Our results demonstrated that histologic severity of gastrointestinal GVHD is a relevant factor affecting OS and NRM, and patients with mild-to-moderate or severe histologic gastrointestinal GVHD have worse outcomes than patients without histologic GVHD. These findings support the importance of assessing the histologic grade in the diagnostic evaluation of patients with clinical gastrointestinal GVHD.

MRI Features of Multiple Cranial Neuropathies in Guillain-Barré Syndrome Occurring after COVID-19 Vaccination: A Case Report.

Guillain-Barré syndrome (GBS) is an immune-mediated demyelinating polyneuropathy characterized by progressive, ascending, and symmetrical paralysis. It is known to be triggered by an antecedent infection or vaccination. Recently, GBS development following coronavirus disease 2019 (COVID-19) vaccination has been reported. Cranial neuropathies in typical GBS patients usually involve the facial and the lower cranial nerves (from IX to XII). We report a rare case of multiple cranial neuropathies involving trigeminal, abducens, and facial nerves in a patient who developed GBS following COVID-19 vaccination on the basis of obvious MRI features.

Infliximab vs adalimumab: Points to consider when selecting anti-tumor necrosis factor agents in pediatric patients with Crohn's disease.

Biologic agents with various mechanisms against Crohn's disease (CD) have been released and are widely used in clinical practice. However, two anti-tumor necrosis factor (TNF) agents, infliximab (IFX) and adalimumab (ADL), are the only biologic agents approved by the Food and Drug Administration for pediatric CD currently. Therefore, in pediatric CD, the choice of biologic agents should be made more carefully to achieve the therapeutic goal. There are currently no head-to-head trials of biologic agents in pediatric or adult CD. There is a lack of accumulated data for pediatric CD, which requires the extrapolation of adult data for the positioning of biologics in pediatric CD. From a pharmacokinetic point of view, IFX is more advantageous than ADL when the inflammatory burden is high, and ADL is expected to be advantageous over IFX in sustaining remission in the maintenance phase. Additionally, we reviewed the safety profile, immunogenicity, preference, and compliance between IFX and ADL and provide practical insights into the choice of anti-TNF therapy in pediatric CD. Careful evaluation of clinical indications and disease behavior is essential when prescribing anti-TNF agents. In addition, factors such as the efficacy of induction and maintenance of remission, safety profile, immunogenicity, patient preference, and compliance play an important role in evaluating and selecting treatment options.

Free antibodies-to-infliximab are biomarker for predicting the effect of dose intensification in pediatric Crohn's disease patients with secondary loss of response.

Background: Immunogenicity to antitumor necrosis factor alpha agents, such as infliximab (IFX), may lead to therapeutic failure. Objectives: This study evaluated the relationship between free and total antibodies-to-infliximab (ATIs), trough levels (TLs) of IFX, and the response to dose intensification. Design: We performed a prospective, observational study including pediatric patients with Crohn's disease (CD) receiving IFX maintenance therapy without dose intensification. Methods: We compared clinical and laboratory outcomes according to the presence of free and total ATIs. Factors associated with response to IFX dose intensification were investigated by analyzing IFX TLs and free and total ATIs. Results: Of the 98 patients, 9 patients had detectable free ATIs and 38 patients had total ATIs. Patients with free ATIs had significantly lower TLs (0.7 versus 5.1 µg/mL, p < 0.001) than patients without free ATIs. However, there was no difference in the IFX TLs according to the presence of total ATIs (p = 0.2523). Analysis of the 38 samples with total ATIs showed that response to dose intensification was significantly lower in patients with free ATIs than those without free ATIs (22.2% versus 65.5%, p < 0.001). In addition, free ATIs were the only factor with poor response to dose intensification [odds ratio (OR): 14.15, 95% confidence interval (CI): 1.31-151.97, p = 0.0140]. According to the receiver operating characteristic analysis, the optimal cutoff level indicating non-response to IFX dose intensification was 30.0 AU/mL for free ATIs concentration (area under curve, 0.792; 95% CI: 0.590-0.942; sensitivity, 60.0%; specificity, 96.7%; p = 0.0241). Conclusion: Free ATIs, but not total ATIs, have a negative impact on the course of CD. Free ATIs are potential reliable biomarker for predicting the effect of dose intensification in patients with loss of response to IFX. Future studies based on serial and proactive therapeutic drug monitoring are required in the future.

Impact of 6-month triptorelin formulation on predicted adult height and basal gonadotropin levels in patients with central precocious puberty.

Background: Triptorelin, a long-acting gonadotropin-releasing hormone (GnRH) agonist, is available in 1-, 3-, and 6-month formulations to treat central precocious puberty (CPP). The triptorelin pamoate 22.5-mg 6-month formulation recently approved for CPP offers greater convenience to children by reducing the injection frequency. However, worldwide research on using the 6-month formulation to treat CPP is scarce. This study aimed to determine the impact of the 6-month formulation on predicted adult height (PAH), changes in gonadotropin levels, and related variables. Methods: We included 42 patients (33 girls and nine boys) with idiopathic CPP treated with a 6-month triptorelin (6-mo TP) formulation for over 12 months. Auxological parameters, including chronological age, bone age, height (cm and standard deviation score [SDS]), weight (kg and SDS), target height (TH), and Tanner stage, were evaluated at baseline, and after 6, 12, and 18 months of treatment. Hormonal parameters, including serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol for girls or testosterone for boys, were analyzed concurrently. Results: The mean age at treatment initiation was 8.6 ± 0.83 (8.3 ± 0.62 for girls, 9.6 ± 0.68 for boys). The peak LH level following intravenous GnRH stimulation at diagnosis was 15.47 ± 9.94 IU/L. No progression of the modified Tanner stage was observed during treatment. Compared to baseline, LH, FSH, estradiol, and testosterone were significantly reduced. In particular, the basal LH levels were well suppressed to less than l.0 IU/L, and the LH/FSH ratio was less than 0.66. The bone age/chronological age ratio remained stable with a decreasing trend (1.15 at the start of treatment, 1.13 at 12 months, 1.11 at 18 months). PAH SDS increased during treatment (0.77 ± 0.79 at baseline, 0.87 ± 0.84 at the start of treatment, 1.01 ± 0.93 at six months, and 0.91 ± 0.79 at 12 months). No adverse effects were observed during treatment. Conclusion: The 6-mo TP suppressed the pituitary-gonadal axis stably and improved the PAH during treatment. Considering its convenience and effectiveness, a significant shift to long-acting formulations can be expected.

Clinical and microbiological characteristics of rifampicin-resistant MRSA bacteraemia.

OBJECTIVES: The clinical significance of rifampicin resistance in Staphylococcus aureus infections has not been demonstrated. Here, we evaluated the clinical characteristics of rifampicin-resistant S. aureus infection. METHODS: Data were collected from adult patients who were hospitalized with MRSA bacteraemia between March 2007 and May 2020 at a tertiary hospital in South Korea. The clinical characteristics and treatment outcomes of patients infected with rifampicin-resistant MRSA were compared with those of rifampicin-susceptible isolates. All-cause death and recurrence of MRSA infection were assessed for 90 days. RESULTS: Of the 961 patients with MRSA bacteraemia, 61 (6.3%) were infected by rifampicin-resistant isolates. The type of infection focus and duration of bacteraemia did not significantly differ between the two groups. Rifampicin-resistant MRSA isolates were more likely to have multidrug resistance and a higher vancomycin MIC relative to the rifampicin-susceptible isolates. The 90-day recurrence rate was higher in the patients infected with rifampicin-resistant MRSA compared with those with rifampicin-susceptible MRSA (18.0% versus 6.2%, P < 0.001), whereas the 90-day mortality was comparable between the two groups (27.9% versus 29.2%, P = 0.94). After adjusting for potential confounding factors, rifampicin resistance was significantly associated with 90-day recurrence (subdistributional HR: 2.31; 95% CI: 1.05-5.10; P = 0.04). CONCLUSIONS: Rifampicin-resistant MRSA isolates showed distinct microbiological features in terms of multidrug resistance and a high vancomycin MIC. Although the management of MRSA bacteraemia was not significantly different between the two groups, recurrence was significantly more common in the rifampicin-resistant group. Rifampicin resistance may play a significant role in infection recurrence.

Sophora flavescens Aiton methanol extract exerts anti-inflammatory effects via reduction of Src kinase phosphorylation.

ETHNOPHARMACOLOGICAL RELEVANCE: Sophora flavescens Aiton (Family: Leguminosae), an herbal plant, has been used in East Asian home remedies for centuries for treating ulcers, skin burns, fevers, and inflammatory disorders. In addition, the dried root of S. flavescens was also applied for antipyretic, analgesic, antihelmintic, and stomachic uses. AIM OF STUDY: Nonetheless, how this plant can show various pharmacological activities including anti-inflammatory responses was not fully elucidated. In this study, therefore, we aimed to investigate the curative effects of S. flavescens on inflammation and its molecular mechanism. MATERIALS AND METHODS: For reaching this aim, various in vitro and in vivo experimental models with LPS-treated RAW264.7 cells, HCl/EtOH-induced gastric ulcer, and LPS-triggered lung injury conditions were employed and anti-inflammatory activity of S. flavescens methanol extract (Sf-ME) was also tested. Fingerprinting profile of Sf-ME was identified via LC-MS analysis. Its anti-inflammatory molecular mechanism was also examined by immunoblotting analysis. RESULTS: Nitric oxide production and mRNA expression levels of iNOS, COX-2, IL-1ß, and TNF-α were decreased. Additionally, phosphorylation of Src in the signaling cascade was decreased, and activities of the transcriptional factor NF-κB were reduced as determined by a luciferase reporter assay. Moreover, in vivo, gastritis and lung injury lesions were attenuated by Sf-ME. CONCLUSION: Taken together, these findings suggest that Sf-ME could be a potential anti-inflammatory therapeutic agent via suppression of Src kinase activity and regulation of IL-1ß secretion.

Long-term outcomes of liver transplantation for biliary atresia and results of policy changes: over 20 years of follow-up experience.

Objective: Biliary atresia (BA) patients develop chronic liver disease after the Kasai operation and are eventually indicated for liver transplantation (LT). The purposes of this study were to analyze long-term outcomes after LT and risk factors that affect complications to reduce graft failure. Study design: Overall, 145 pediatric patients who underwent LT between June 1996 and June 2020 after a diagnosis of BA were included. We performed a retrospective analysis of medical records and evaluated patient and graft survival, cumulative incidence of complications, risk factors, and the results of policy changes. Results: Patient and graft survival rates in over 20 years were 95.8% and 91.0%, respectively. Post-transplantation lymphoproliferative disease was frequently observed in the early period of immunosuppression within the first 1-2 years after LT. The incidence of cholangitis and rejection steadily increased over time. Weight-to-portal vein size was evaluated as a risk factor for cholangitis and bile duct strictures (OR = 12.82, p = 0.006 and OR = 16.54, p = 0.015, respectively). When evaluated using 2013 as a reference point, the split graft indication was expanded and the group that received LT after 2013 had a significantly lower survival over time compared with that of the group that received LT before 2013 (p = 0.006). Conclusion: This study revealed time differences in prevalence of complications. The evaluation of weight-to-duct or vessel size is a more important factor in considering complications than the graft-to-recipient weight ratio. Survival outcomes may have been altered by a policy change that affects the donor type ratio in transplantation.

Duodenal Dual-Wavelength Photobiomodulation Improves Hyperglycemia and Hepatic Parameters with Alteration of Gut Microbiome in Type 2 Diabetes Animal Model.

BACKGROUND: Recently, the duodenum has garnered interest for its role in treating metabolic diseases, including type 2 diabetes (T2DM). Multiple sessions of external photobiomodulation (PBM) in previous animal studies suggested it resulted in improved hyperglycemia, glucose intolerance, and insulin resistance with a multifactorial mechanism of action, despite the target organ of PBM not being clearly proven. This study aimed to determine whether a single session of a duodenal light-emitting diode (LED) PBM may impact the T2DM treatment in an animal model. METHODS: Goto-Kakizaki rats as T2DM models were subjected to PBM through duodenal lumen irradiation, sham procedure, or control in 1-week pilot (630 nm, 850 nm, or 630/850 nm) and 4-week follow-up (630 nm or 630/850 nm) studies. Oral glucose tolerance tests; serum glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide, and insulin levels; liver chemistry and histology; and gut microbiome in the PBM, sham control, and control groups were evaluated. RESULTS: In the 1-week study, duodenal dual-wavelength (D, 630/850 nm) LED PBM showed improved glucose intolerance, alkaline phosphatase and cholesterol levels, and weight gain than other groups. The D-LED PBM group in the 4-week study also showed improved hyperglycemia and liver enzyme levels, with relatively preserved pancreatic islets and increased serum insulin and GLP-1 levels. Five genera (Bacteroides, Escherichia, Parabacteroides, Allobaculum, and Faecalibaculum) were significantly enriched 1 week after the D-LED PBM. Bacteroides acidifaciens significantly increased, while Lachnospiraceae significantly decreased after 1 week. CONCLUSION: A single session of D-LED PBM improved hyperglycemia and hepatic parameters through the change of serum insulin, insulin resistance, insulin expression in the pancreatic ß-cells, and gut microbiome in T2DM animal models.

MAX: a simple, affordable, and rapid tissue clearing reagent for 3D imaging of wide variety of biological specimens.

Transparency of biological specimens is crucial to obtaining detailed 3-dimensional images and understanding the structure and function of biological specimens. This transparency or tissue clearing can be achieved by adjusting the refractive index (RI) with embedding media and removing light barriers such as lipids, inorganic deposits, and pigments. Many currently available protocols consist of multiple steps to achieve sufficient transparency, making the process complex and time-consuming. Thus, in this study, we tailored the recipe for RI adjustment media named MAX based on the recently reported MACS protocol to achieve a single-step procedure, especially for ECM-rich tissues. This was achieved by the improvement of the tissue penetrability of the RI-matching reagent by combining MXDA with sucrose or iodixanol. While this was sufficient for the 3D imaging in many applications, MAX can also be combined with modular processes for de-lipidation, de-coloration, and de-calcification to further maximize the transparency depending on the special features of the tissues. Our approach provides an easy alternative for tissue clearing and 3D imaging.

Cytokine Profile at Diagnosis Affecting Trough Concentration of Infliximab in Pediatric Crohn's Disease.

BACKGROUND: This study aims to measure the concentration of cytokines produced during the inflammation process to investigate if there are any differences in response to treatment of pediatric Crohn's disease and to determine if the initial tumor necrosis factor-alpha (TNF-α) level affected the trough concentration of infliximab (IFX). METHODS: This study included 30 pediatric patients with moderate-to-severe Crohn's disease. At the time of diagnosis, blood samples were collected for the measurement of cytokines (IL-6, TNF-α, IL-17A, and IL-10). Blood samples were extracted from patients who had begun IFX treatment to measure the IFX trough concentration immediately before the fourth dose administration. RESULTS: All cytokines (TNF-α, IL-6, IL-10, and IL-17A) were significantly higher in patients who did not achieve clinical or biochemical remission than in those who did (p = 0.027, 0.006, 0.017, 0.032, respectively). TNF-α had a negative correlation with the IFX trough concentration (Pearson coefficient = -0.425, p = 0.034). The diagnostic capability of the initial TNF-α concentration to predict under the therapeutic IFX trough concentration, defined as less than 3 µg/mL, had an area under the receiver operating characteristic of 0.730 (p = 0.049). The TNF-α concentration was set at 27.6 pg/mL as the cutoff value. CONCLUSIONS: Measuring cytokines at the time of diagnosis can be used to predict the treatment response. Measuring the initial TNF-α concentration may help to predict the treatment response to IFX. When the initial TNF-α concentration is greater than 27.6 pg/mL, a higher dose of IFX may be more appropriate than routinely administering 5 mg/kg of IFX to maintain the therapeutic concentration.