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Objective:  To compare the risk of severe maternal morbidity (SMM) from the delivery admission to 42 days' postdischarge among persons with sickle cell disease (SCD) to those without SCD., Study Design:  This retrospective cohort study included deliveries ≥20 weeks' gestation at an urban safety net hospital in Atlanta, GA from 2011 to 2019. The exposure was SCD diagnosis. The outcome was a composite of SMM from the delivery admission to 42 days' postdischarge. SMM indicators as defined by the Centers for Disease Control and Prevention were identified using the International Classification of Diseases, Ninth and Tenth Revisions (ICD-9/10) codes; transfusion of blood products and sickle cell crisis were excluded., Results:  Of N  = 17,354 delivery admissions, n  = 92 (0.53%) had SCD. Persons with SCD versus without SCD had an increased risk of composite SMM (15.22 vs. 2.29%, p  < 0.001), acute renal failure (6.52 vs. 0.71%, p  < 0.001), acute respiratory distress syndrome (4.35 vs. 0.17%, p  < 0.001), puerperal cerebrovascular disorders (3.26 vs. 0.10%, p  < 0.001), sepsis (4.35 vs. 0.42%, p  < 0.01), air and thrombotic embolism (5.43 vs. 0.10%, p  < 0.001), and ventilation (2.17 vs. 0.09%, p  < 0.01). Ultimately, those with SCD had an approximately 6-fold higher incidence risk ratio of SMM, which remained after adjustment for confounders (adjusted incidence risk ratio [aIRR]: 5.96, 95% confidence interval [CI]: 3.4-9.19, p  < 0.001). Persons with SCD in active vaso-occlusive crisis at the delivery admission had an approximately 9-fold higher risk of SMM up to 42 days' postdischarge compared with those with SCD not in crisis at the delivery admission (incidence: 25.71 vs. 8.77%, p  < 0.05; aIRR: 8.92, 95% CI: 4.5-10.04, p  < 0.05). Among those with SCD, SMM at the delivery admission was primarily related to renal and cerebrovascular events, whereas most postpartum SMM was related to respiratory events or sepsis., Conclusion:  SCD is significantly associated with an increased risk of SMM during the delivery admission and through 42 days' postdischarge. Active crisis at delivery further increases the risk of SMM., Key Points: · Sickle cell disease was associated with an approximately 6-fold increased risk of SMM.. · Active vaso-occlusive crisis at delivery was associated with an approximately 9-fold increased risk of SMM.. · 48% of SMM events in persons with SCD occurred postpartum and were respiratory- or sepsis-related.., Competing Interests: None declared., (Thieme. All rights reserved.)

The aim of this study was to evaluate the safety and efficacy of digital therapeutic application of Sleep Index-Based Treatment for Insomnia (dSIBT-I) and compare them with those of digital application of Cognitive Behavioural Therapy for Insomnia (dCBT-I). This randomised prospective pilot study was conducted at the Asan Medical Center. A total of 50 patients with insomnia were recruited between December 2022 and January 2023 and randomly allocated to the dSIBT-I or dCBT-I group. The study was carried out for one month. The primary outcome was the significant reduction in Insomnia Severity Index score at Week 4 compared to baseline, while the secondary outcome was proportion of participants whose Insomnia Severity Index scores were reduced to <15 at Week 4. We performed linear mixed model and generalised estimating equation analyses. Both dSIBT-I and dCBT-I groups showed significant improvements in Insomnia Severity Index scores at Week 4. There was no significant difference between two groups in terms of Insomnia Severity Index scores at Week 4 (group × time effect, F = 1.07, p = 0.382) and proportion of participants whose Insomnia Severity Index scores were reduced to <15 at Week 4 (group × time effects, F = 1.80, p = 0.615). However, at Week 2, the dSIBT-I group showed better results than the dCBT-I group in terms of both Insomnia Severity Index scores (p = 0.044) and proportion of participants whose Insomnia Severity Index scores were reduced to <15 (82.6% vs. 48.0%, p = 0.017). No treatment-emergent adverse events were reported in either group. The dSIBT-I is a safe and effective therapy for insomnia, with rapid treatment effects., (© 2023 European Sleep Research Society.)

Background: The roles of tight junction (TJ) proteins in peritoneal membrane transport and peritoneal dialysis (PD) require further characterisation. Dipeptidyl peptidase-4 is expressed in mesothelial cells, and its activity may affect peritoneal membrane function and morphology., Methods: Human peritoneal mesothelial cells (HPMCs) were isolated and cultured from omentum obtained during abdominal surgery, and paracellular transport functions were evaluated by measuring transmesothelial electrical resistance (TMER) and dextran flux. Sprague-Dawley rats were infused daily with 4.25% peritoneal dialysate with and without sitagliptin administration for 8 weeks. At the end of this period, rat peritoneal mesothelial cells (RPMCs) were isolated to evaluate TJ protein expression., Results: In HPMCs, the protein expression of claudin-1, claudin-15, occludin and E-cadherin was decreased by TGF-β treatment but reversed by sitagliptin co-treatment. TMER was decreased by TGF-β treatment but improved by sitagliptin co-treatment. Consistent with this, dextran flux was increased by TGF-β treatment and reversed by sitagliptin co-treatment. In the animal experiment, sitagliptin-treated rats had a lower D2/D0 glucose ratio and a higher D2/P2 creatinine ratio than PD controls during the peritoneal equilibration test. Protein expression of claudin-1, claudin-15 and E-cadherin decreased in RPMCs from PD controls but was not affected in those from sitagliptin-treated rats. Peritoneal fibrosis was induced in PD controls but ameliorated in sitagliptin-treated rats., Conclusion: The expression of TJ proteins including claudin-1 and claudin-15 was associated with transport function both in HPMCs and in a rat model of PD. Sitagliptin prevents peritoneal fibrosis in PD and can potentially restore peritoneal mesothelial cell TJ proteins., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: We investigated sarcopenia prevalence using various diagnostic criteria based on dual-energy X-ray absorptiometry (DXA) and computed tomography (CT) in gastric cancer patients who underwent gastrectomy, and evaluated the association between sarcopenia and perioperative complications., Methods: This retrospective study included consecutive patients with gastric cancer who underwent gastrectomy, and preoperative DXA and CT from January 2013 to November 2020. Body composition was measured using DXA and CT. Height-adjusted DXA-based Appendicular Skeletal Muscle Mass Index (ASMI) and CT-based skeletal muscle cross-sectional area at the L3 level (SMI) were measured. Sarcopenia and sarcopenic obesity were defined using reported cutoff values. The chi-square test and univariate analysis were performed to determine risk factors for significant and severe perioperative complications (Clavien-Dindo Grades ≥ 2 and ≥ 3, respectively)., Results: In total, 77 males and 43 females aged 61.4 ± 11.0 years were included. ASMI and SMI were correlated (r = 0.819), but sarcopenia prevalence varied (20.0-63.3%), depending on the criteria applied. Univariate analysis revealed sarcopenia defined using the Asian Working Group on Sarcopenia (AWGS) criteria and sarcopenic obesity as risk factors for significant (odds ratio [OR] 2.76, p = 0.030 vs. OR 4.31, p = 0.002) and severe perioperative complications (OR 3.77, p = 0.036 vs. OR 4.78, p = 0.010). In subgroup analyses, sarcopenia and sarcopenic obesity were significantly associated with perioperative complications only in males., Conclusion: Perioperative complication risk can be predicted from sarcopenia defined using the AWGS criteria and sarcopenic obesity measured using DXA and CT, particularly in males., Key Points: • The prevalence of sarcopenia varies due to definition differences. • Sarcopenia and sarcopenic obesity are risk factors for significant and severe perioperative complications, particularly in males. • Our results suggest that physicians need to pay attention to perioperative complications after surgical treatment of male patients with sarcopenia and sarcopenic obesity., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

The dominant method for generating Chinese hamster ovary (CHO) cell lines that produce high titers of biotherapeutic proteins utilizes selectable markers such as dihydrofolate reductase (Dhfr) or glutamine synthetase (Gs), alongside inhibitory compounds like methotrexate or methionine sulfoximine, respectively. Recent work has shown the importance of asparaginase (Aspg) for growth in media lacking glutamine-the selection medium for Gs-based selection systems. We generated a Gs/Aspg double knockout CHO cell line and evaluated its utility as a novel dual selectable system via co-transfection of Gs-Enbrel and Aspg-Enbrel plasmids. Using the same selection conditions as the standard Gs system, the resulting cells from the Gs/Aspg dual selection showed substantially improved specific productivity and titer compared to the standard Gs selection method, however, with reduced growth rate and viability. Following adaptation in the selection medium, the cells improved viability and growth while still achieving ~5-fold higher specific productivity and ~3-fold higher titer than Gs selection alone. We anticipate that with further optimization of culture medium and selection conditions, this approach would serve as an effective addition to workflows for the industrial production of recombinant biotherapeutics., (© 2022 Wiley Periodicals LLC.)

Objective: To evaluate the association between sickle cell disease (SCD) and severe maternal morbidity (SMM) in a contemporary cohort of deliveries by non-Hispanic Black people., Methods: We retrospectively examined SMM by using electronic health record data on deliveries by non-Hispanic Black patients between 2011 and 2020 at a single tertiary, public institution. Sickle cell disease was identified during the delivery admission by using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes. The primary outcome, SMM at delivery hospitalization, was ascertained using ICD-9-CM and ICD-10-CM codes and excluded sickle cell crisis as an indicator of SMM. We also constructed a secondary measure of SMM that excluded deliveries in which blood transfusion was the only indication of SMM. Poisson regression models were used to estimate risk ratios (RRs) and 95% CIs for the associations between SCD and SMM (overall and for individual indicators). Multivariable models adjusted for age, parity, insurance type, chronic conditions (chronic hypertension, diabetes mellitus, obesity), and multiple gestation., Results: Among 17,493 deliveries by non-Hispanic Black patients during the study period, 132 (0.8%) had a diagnosis of SCD. Of those patients, 87 (65.9%, 95% CI 57.2-73.9) with SCD and 2,035 (11.7%), 95% CI 11.2-12.2) without SCD had SMM. Sickle cell disease was associated with increased risk of SMM (87 vs 2,035, adjusted risk ratio [aRR] 5.4, 95% CI 4.6-6.3) and nontransfusion SMM (51 vs 1,057, aRR 6.0, 95% CI 4.6-8.0). Effect estimates were highest for cardiac arrest (3 vs 14, RR 28.2, 95% CI 3.8-209.3), air and thrombotic embolism (14 vs 72, RR 25.6, 95% CI 12.0-54.6), and puerperal cerebrovascular disorders (10 vs 53, RR 24.8, 95% CI 10.2-60.5)., Conclusion: Sickle cell disease was associated with a more than fivefold increased risk of SMM during the delivery hospitalization. Our data suggest cardiovascular morbidity as the driving major risk. The identification and monitoring of cardiovascular pathology in patients with SCD before and during pregnancy may reduce SMM., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2022 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Three unreported dammarane-type triterpenoids with rare skeletons (1-3), along with one undescribed gypenoside (4), were isolated from the aerial parts of Gynostemma pentaphyllum using diverse chromatographic materials and pre-HPLC. Their structures were elucidated on the basis of spectroscopic and spectrometric data, while the absolute configurations of 1-3 were assessed via electronic circular dichroism (ECD) analyses. Notably, compounds 1-3 possess a 3,19-hemiketal bridge in the A ring. Saponin 4 possesses an unreported 20,25-oxa structural moiety. Their antiproliferative effects against HepG2, MCF-7, and DU145 cell lines were screened. Compounds 1-3 displayed moderate cytotoxicity with IC 50 values ranging from 13.7 ± 0.2 to 32.0 ± 1.7 μM., Competing Interests: Declaration of Competing Interest The authors declared that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Objectives: Polysomnography is manually scored by sleep experts. However, manual scoring is a time-consuming and labor-intensive task. The goal of this study was to verify the accuracy of automated sleep-stage scoring based on a deep learning algorithm compared to manual sleep-stage scoring. Materials and Methods: A total of 602 polysomnography datasets from subjects (Male:Female = 397:205) aged 19 to 65 years (mean age, 43.8, standard deviation = 12.2) were included in the study. The performance of the proposed model was evaluated based on kappa value and bootstrapped point-estimate of median percent agreement with a 95% bootstrap confidence interval and R = 1000. The proposed model was trained using 482 datasets and validated using 48 datasets. For testing, 72 datasets were selected randomly. Results: The proposed model exhibited good concordance rates with manual scoring for stages W (94%), N1 (83.9%), N2 (89%), N3 (92%), and R (93%). The average kappa value was 0.84. For the bootstrap method, high overall agreement between the automated deep learning algorithm and manual scoring was observed in stages W (98%), N1 (94%), N2 (92%), N3 (99%), and R (98%) and total (96%). Conclusions: Automated sleep-stage scoring using the proposed model may be a reliable method for sleep-stage classification.

Background: External cephalic version (ECV) is a technique used to reduce the incidence of cesarean deliveries due to malpresentation. Nitrous oxide is an inhaled analgesic that may be used for pain relief for women undergoing external cephalic version., Objective: To compare the conversion rate of non-cephalic to cephalic presentation in ECV with and without nitrous oxide., Study Design: A retrospective cohort analysis was performed including all singleton, term gestation ECVs between January 2016 and June 2017 at a single institution. Multivariable logistic regression was used to compare women who had ECV with nitrous oxide versus ECV without nitrous oxide. The primary outcome was successful rate of conversion to cephalic presentation and the secondary outcome was the rate of vaginal delivery., Results: During the study period, 167 women underwent ECV: 77 with nitrous oxide and 90 without nitrous oxide. Of the 77 women who used nitrous oxide, 25 (32.5%) were successful and 17 of these women delivered vaginally (68%). Of the women who underwent ECV without nitrous oxide, 29 (32.2%) successfully converted and 21 of these delivered vaginally (72%). After controlling for confounders, the use of nitrous oxide had no clinically or statistically significant difference on ECV success rates (OR 1.08, 95% CI 0.52-2.23)., Conclusion: Nitrous oxide does not seem to affect conversion rate to cephalic presentation in ECV. Further studies are needed to determine the impact of nitrous oxide on women's decision to undergo ECV and on patient satisfaction and tolerability., (Copyright © 2022 Elsevier B.V. All rights reserved.)

There is no clear evidence that post-operative maintenance of thyroid-stimulating hormone (TSH) in the mid to lower reference range (0.5-2 mU/L) improves prognosis in patients undergoing thyroid lobectomy for low-risk differentiated thyroid cancer (DTC). The purpose of this systematic review and meta-analysis was to compare and analyze the recurrence rate according to whether the serum TSH level was maintained below 2 mU/L in patients who underwent thyroid lobectomy for low-risk DTC. Clinical data and outcomes were collected from MEDLINE, Embase, and the Cochrane Database of Systematic Reviews. The inclusion criteria were related studies on TSH maintenance or serum TSH concentration after surgery for DTC. Seven observational studies with a total of 3974 patients were included in this study. In the patients who received TSH maintenance less than 2 mU/L, the recurrence rate during the follow-up period was 2.3%. A subgroup analysis of five studies showed that the odds ratio for recurrence in patients who received TSH maintenance was 1.45 ( p -value = 0.45) compared to patients who did not receive TSH maintenance. In conclusion, the evidence for the effectiveness of post-operative TSH maintenance less than 2 mU/L in patients undergoing thyroid lobectomy for low-risk DTC is insufficient.

Chinese hamster ovary (CHO) cells are the most widely used mammalian host cells for the commercial production of therapeutic proteins. Fed-batch culture is widely used to produce therapeutic proteins, including monoclonal antibodies, because of its operational simplicity and high product titer. Despite technical advances in the development of culture media and cell cultures, it is still challenging to maintain high productivity in fed-batch cultures while also ensuring good product quality. In this review, factors that affect the quality attributes of therapeutic proteins in recombinant CHO (rCHO) cell culture, such as glycosylation, charge variation, aggregation, and degradation, are summarized and categorized into three groups: culture environments, chemical additives, and host cell proteins accumulated in culture supernatants. Understanding the factors that influence the therapeutic protein quality in rCHO cell culture will facilitate the development of large-scale, high-yield fed-batch culture processes for the production of high-quality therapeutic proteins., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Trimethylamine N-oxide (TMAO), a gut microbe-dependent metabolite, has been implicated as a novel risk factor for cardiovascular events related to obesity and type 2 diabetes mellitus (T2DM). The aim of the study was to test the hypothesis if TMAO is associated with the reduction of cardiovascular disease in the Korean obese patients who underwent bariatric surgery. From a subgroup of a multicenter, nonrandomized, controlled trial, titled KOBESS, 38 obese patients, 18 with and 20 without T2DM, who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) were investigated. Bariatric surgery is indicated for Korean patients with a body mass index (BMI) ≥ 35 kg/m 2 or for Korean patients with a BMI ≥ 30 kg/m 2 who have comorbidities. Serum levels of TMAO and its precursors, betaine, carnitine, and choline were measured before and six months after bariatric surgery. The levels of TMAO and its precursors did not differ between obese patients with T2DM and non-T2DM at baseline. However, TMAO increased more than twofold in patients with T2DM after RYGB surgery, but not in patients without T2DM. Choline levels were decreased by half in all patients after RYGB. In patients with T2DM who underwent SG, TMAO, betaine, and carnitine levels did not change after the surgery. Furthermore, in obese patients who underwent bariatric surgery, increased TMAO levels were associated with both T2DM and RYGB, while reduced choline levels were associated with RYGB. These associations need to be further elucidated in follow-up studies to gain further insights into the relationship between TMAO levels and bariatric surgery outcomes.

Purpose: The aim of this study was to show that bariatric surgery (BS) is more effective than medical therapy (MT) in Asian obese patients., Methods: In this prospective, multicenter, nonrandomized, controlled trial, obese patients with body mass index of ≥35 kg/m 2 or 30.0-34.9 kg/m 2 with obesity-related comorbidities were assigned to undergo BS, such as laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass, or MT. Patients who underwent BS were evaluated 4, 12, 24, and 48 weeks after surgery, whereas patients who received MT were monitored at a hospital every 6 weeks for 1 year. At each visit, weight, waist and hip circumference, and blood pressure were measured, and patients underwent physical examination and laboratory testing. Health-related quality of life (HQOL) was investigated using Euro QOL-5 Dimension, Impact of Weight on Quality of Life questionnaire-Lite and Obesity-related Problems scale., Results: The study included 264 patients from 13 institutions; of these, 64 underwent BS and 200 received MT. Of the patients who underwent BS, 6.3% experienced early complications. Relative weight changes from baseline to 48 weeks were significantly greater in the BS than in the MT group (26.9% vs. 2.1%, P < 0.001), as were the rates of remission of diabetes (47.8% vs. 16.7%, P = 0.014), hypertension (60.0% vs. 26.1%, P < 0.001), and dyslipidemia (63.2% vs. 22.0%, P < 0.001). HQOL was better in the BS than in the MT group at 48 weeks., Conclusion: BS was safe and effective in Korean obese patients, with greater weight reduction, remission of comorbidities, and quality of life improvement than MT., Competing Interests: Conflict of Interest: No potential conflict of interest relevant to this article was reported., (Copyright © 2021, the Korean Surgical Society.)

Introduction: Bariatric surgery is known to be the most effective treatment for weight loss in obese patients and for the rapid remission of obesity-related comorbidities. These short-term improvements result from not only limited digestion or absorption but also dynamic changes in metabolism throughout the whole body. However, short-term metabolism studies associated with bariatric surgery in Asian individuals have not been reported., Objectives: The aim of this study was to investigate the short-term metabolome changes in the serum promoted by laparoscopic sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) and to determine the underlying mechanisms that affect obesity-related comorbidities., Methods: Serum samples were collected from Korean patients who underwent RYGB or SG before and 4 weeks after the surgery. Metabolomic and lipidomic profiling was performed using UPLC-Orbitrap-MS, and data were analyzed using statistical analysis., Results: Metabolites mainly related to amino acids, lipids (fatty acids, glycerophospholipids, sphingolipids, glycerolipids) and bile acids changed after surgery, and these changes were associated with the lowering of risk factors for obesity-related diseases such as nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D) and atherosclerosis. Interestingly, the number of significantly altered metabolites related to the lipid metabolism were greater in SG than in RYGB. Furthermore, the metabolites related to amino acid metabolism were significantly changed only after SG, whereas bile acid changed significantly only following RYGB., Conclusion: These differences could result from anatomical differences between the two surgeries and could be related to the gut microbiota. This study provides crucial information to expand the knowledge of the common but different molecular mechanisms involved in obesity and obesity-related comorbidities affected by each bariatric procedure., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We previously reported that the duodenal-jejunal bypass (DJB) surgery altered transsulfuration and purine metabolism via flux changes in 1-carbon metabolism in the liver. In this study, we extended our study to gain further insight into mechanistic details of how the DJB-induced flux changes in 1-carbon metabolism contributes to the improvement of diet-induced nonalcoholic fatty liver disease. Rodents were subjected to surgical (sham operation and DJB) or dietary (reduced food supply to follow the weight changes in the DJB group) interventions. The microscopic features of the liver were examined by immunohistochemistry. The expressions of genes in lipid synthesis and in 1-carbon cycle in the liver were analyzed by real-time polymerase chain reaction and western blotting. Metabolic changes in the liver were determined. We observed that DJB reduces hepatic steatosis and improves insulin sensitivity in both high-fat diet-fed rats and mice. Metabolic analyses revealed that the possible underlying mechanism may involve decreased S-adenosylmethionine (SAM)-to-S-adenosylhomocysteine ratio via downregulation of SAM synthesizing enzyme and upregulation of SAM catabolizing enzyme. We also found in mice that DJB-mediated attenuation of hepatic steatosis is independent of weight loss. DJB also increased hepatic expression levels of GNMT while decreasing those of PEMT and BHMT, a change in 1-carbon metabolism that may decrease the ratio of SAM to S-adenosylhomocysteine, thereby resulting in the prevention of fat accumulation in the liver. Thus, we suggest that the change in 1-carbon metabolism, especially the SAM metabolism, may contribute to the improvement of diet-induced fatty liver disease after DJB surgery., (Copyright © 2021 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS., (© 2021 Wiley Periodicals LLC.)

Purpose: Recently, more than 10 models have been developed to predict remission of type 2 diabetes mellitus (T2DM) after metabolic surgery. The ABCD score was compared to the individualized metabolic surgery (IMS) score in terms of prediction of T2DM remission, but which of the two scoring systems is better remains controversial., Methods: Patient data from 463 obese East Asian patients who underwent laparoscopic Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), or SG with duodenojejunal bypass (SG-DJB) as a primary operation and were followed for at least 3 years were retrospectively collected from 24 institutions. The correlation between the ABCD and IMS scoring systems and the discrimination power of the models was evaluated. The cut-off point for the IMS stage of T2DM severity was also revised to adjust the scoring system to obese East Asian patients., Results: The two scoring systems were significantly well correlated. The IMS scoring system showed significant differences in T2DM remission rates between the procedures in the moderate stage, but the ABCD score showed no significant differences in each category. The discrimination power of the IMS score was comparable to that of the ABCD score at both 3 and 5 years. The revised IMS scoring system showed that SG-DJB had significantly higher T2DM remission rates in the moderate stage at 5 years than RYGB or SG., Conclusion: IMS score may be comparable to ABCD score to predict T2DM remission in obese East Asian patients. The revised IMS scoring system may also select candidates for SG or SG-DJB.

In the search for antiviral cyclopeptides against influenza A virus, five unprecedented Caryophyllaceae-type cyclopeptides ( 1 - 5 ) were isolated from the leaves of Melicope pteleifolia . Their chemical structures and absolute configurations were unambiguously determined by means of advanced Marfey's analysis and comprehensive spectroscopic analyses including two-dimensional nuclear magnetic resonance and MS/MS fragmentation. Interestingly, compounds 3 - 5 contain an unusual heterocycle, a 3a-hydroxypyrroloindole moiety, which was biosynthetically formed by a nucleophilic cyclization from the least abundant amino acid, tryptophan, precursor and has aroused a great interest in the aspect of chemical diversity and biological activity. All isolates ( 1 - 5 ) were evaluated for their protective effects against influenza A viruses H1N1 and H9N2 in MDCK cells. All isolated cyclopeptides exhibited strong anti-influenza activity, especially against H1N1. Compound 3 showed the most potent CPE inhibition effect, which was stronger than that of the positive control ribavirin against H1N1, with an EC 50 (μM) of 2.57 ± 0.45 along with higher selectivity.

Background: Amino acid metabolites (AAMs) have been linked to glucose homeostasis and type 2 diabetes (T2D). We investigated whether (1) baseline AAMs predict T2D remission 12 months after bariatric surgery and (2) whether AAMs are superior for predicting T2D remission postoperatively compared with existing prediction models., Methods: Among 24 participants undergoing bariatric surgery, 16 diabetes-related AAMs were quantified at baseline and postoperative 3 and 12 months. Existing prediction models included the ABCD, DiaRem, and IMS models., Results: Baseline L-dihydroxyphenylalanine (L-DOPA) (areas under receiver operating characteristic curves (AUROC), 0.92; 95% confidence interval (CI), 0.75 to 1.00) and 3-hydroxyanthranilic acid (3-HAA) (AUROC, 0.85; 95% CI, 0.67 to 1.00) better predicted T2D remission 12 months postoperatively than the ABCD model (AUROC, 0.81; 95% CI, 0.54 to 1.00), which presented the highest AUROC value among the three models. The superior prognostic performance of L-DOPA (AUROC at 3 months, 0.97; 95% CI, 0.91 to 1.00) and 3-HAA (AUROC at 3 months, 0.86; 95% CI, 0.63 to 1.00) continued until 3 months postoperatively., Conclusions: The AAM profile predicts T2D remission after bariatric surgery more effectively than the existing prediction models.

The present study was designed to determine the effects of pineal gland‑derived melatonin on obesity by employing a rat pinealectomy (Pnx) model. After 10 weeks of a high‑fat diet, rats received sham or Pnx surgery followed by a normal chow diet for 10 weeks. Reverse transcription‑quantitative PCR, western blotting analysis, immunohistochemistry and ELISA were used to determine the effects of Pnx. Pnx decreased the expression of melatonin receptor (MTNR)1A and MTNR1B, in brown adipose tissues (BAT) and white adipose tissues (WAT). Pnx rats showed increased insulin sensitivity compared with those that received sham surgery. Leptin levels were significantly decreased in the serum of the Pnx group. In addition, Pnx stimulated thermogenic genes in BAT and attenuated lipogenic genes in both WAT and the liver. Histological analyses revealed a marked decrease in the size of lipid droplets and increased expression of uncoupling protein 1 in BAT. In the liver of the Pnx group, the size and number of lipid droplets had also decreased. In conclusion, the results presented in the current study suggested that Pnx increases thermogenesis in BAT and decreases lipogenesis in WAT and the liver.

Purpose: Quality of life (QOL) has become important in the trend of emphasizing patient satisfaction. This study aimed to evaluate the QOL in patients who underwent laparoscopic or robotic gastrectomy for gastric cancer., Methods: A prospective trial was performed involving patients who underwent laparoscopic or robotic gastrectomy for primary gastric cancer at 11 hospitals in Korea. Within this comparative trial, QOL, postoperative pain, and long-term complications were exanimated. The quality-of-life questionnaire (QLQ)-C30 and QLQ-STO22 developed by the European Organization for Research and Treatment of Cancer were used for the QOL survey. We compared the data after dividing it into several types of characteristics as follows; device (robotic or laparoscopic), operation type, pathological stage, and sex. Biased components were extracted by logistic regression analysis. Propensity score matching was applied to the data set with the biased components., Results: In total, 434 patients (211 for laparoscopic surgery and 223 for robotic surgery) were enrolled, out of which 321 patients who responded to both preoperative and postoperative surveys were selected for analysis. Robotic gastrectomy was not different from laparoscopic gastrectomy with respect to postoperative QOL. Distal gastrectomy showed better scores than total gastrectomy in terms of role functioning, social functioning, fatigue, nausea/vomiting, pain, dyspnea, constipation, financial difficulties, dysphagia, eating restrictions, anxiety, taste, and body image. Male patients showed better scores on the 19 scales compared to female patients., Conclusion: Robotic and laparoscopic approaches for gastric cancer surgery did not differ from each other with respect to QOL. Distal gastrectomy resulted in better QOL than total gastrectomy., Competing Interests: Conflict of interest: No potential conflict of interest relevant to this article was reported., (Copyright © 2020, the Korean Surgical Society.)

Alzheimer's disease (AD), a neurocognitive impairment affecting human mental capacity, is related to the accumulation of amyloid-β peptide (Aβ) and the hyperphosphorylation of tau protein. In addition to modern therapies approved for AD treatment, natural products with antioxidant and anti-inflammatory properties have been studied for their potential to prevent AD pathogenesis. Six new noroleanane triterpenoids from the fruit peels of Camellia japonica were isolated, and their structures were determined by diverse spectroscopic methods. The neuroprotective effects of the six new compounds were tested against Aβ-induced neurotoxicity and neuroinflammation in mouse hippocampal and microglial cells. In the model of HT22-transfected cells, compounds 1 - 4 showed strongly neuroprotective effects via antioxidant response element gene activation and decreased the level of glutamate uptake. Compounds 1 - 4 also appeared to have strong inhibitory effects on NO production in Aβ 1-42 -transfected BV2 microglial cells. A docking simulation study was used to explain the inhibitory effects of compounds 1 - 4 on β-secretase 1 (BACE1). Noroleanane triterpenoids 1 - 4 had potential neuroprotective and anti-inflammatory effects against Aβ-induced neuronal damage. The structure-activity relationships of the 30 oleanane triterpenoids from C. japonica were assessed in a model of Aβ 1-42 -transfected HT22 cells.

Objective: This study aimed to compare ultrasonography (US) features and the Korean-Thyroid Imaging Reporting and Data System (K-TIRADS) categories for diagnosing isthmic and lobar papillary thyroid carcinomas (PTC). Methods: From January 2009 to December 2012, 163 patients who underwent thyroid surgery and were confirmed with a post-operative histopathological diagnosis of isthmic PTC were retrospectively included. Fifty-nine patients were excluded because their tumor size was <0.5 cm or because of other reasons. The control group comprised of 145 patients who underwent thyroid surgery from January to April 2013 for a classic type of PTC, with the largest diameter being ≥ 0.5 cm and located in the thyroid lobe. A single radiologist retrospectively reviewed the US features and K-TIRADS categories of each nodule using a picture archiving and communication system. Results: Among 104 patients with isthmic PTC, 95 and 9 had primary and secondary cancers, respectively. On the other hand, all 145 patients with lobar PTC had primary cancers. Isthmic PTC showed a lower prevalence of non-parallel orientation than lobar PTC (23.1 and 71%). Nodule orientation was the only US feature statistically different between the two groups ( p < 0.0001). However, there was no significant difference in patient age, sex, nodule size, composition, echogenicity, microcalcification, spiculated/microlobulated margin, and K-TIRADS category between the two groups ( p > 0.05). Conclusions: K-TIRADS may be useful in the diagnosis of both isthmic and lobar PTC., (Copyright © 2020 Lee, Kim, Shin, Park, Choo, Park, Ha, Kim, Jung, Park, Moon, Ahn and Baek.)

Background: There are 2 prediction nomograms for vaginal birth after cesarean delivery. The first is based on variables that are available at the first prenatal visit, and the second includes variables at the time of admission., Objective: The purpose of this study was to compare the accuracy of prediction scores that are calculated by the intake and admission prediction nomograms in a modern cohort of racially and ethnically diverse women., Study Design: This is a retrospective cohort study that analyzed the data for women with at least 1 previous cesarean delivery who attempted a trial of labor from 2007-2016 at a tertiary medical center. Participants were stratified into 3 probability-of-success groups: low (<35%), moderate (35-65%), and high (>65%). The primary outcome was the difference between the intake- and admission-predicted success scores in the 3 groups. Secondary outcomes were characteristics that were associated with successful vaginal birth after cesarean delivery ., Results: Of the 614 women included in the analysis, 444 (72.3%) had a successful vaginal birth after cesarean delivery . Predicted vaginal birth after cesarean delivery success rate ranged from 14.4-96.2%. Patients were stratified into 3 groups by intake predicted success rates: low (<35%; n=21), moderate (35-65%; n=136), and high (>65%; n=457). The change in predicted success rates was compared between the intake and admission nomograms. Women in the low and moderate groups improved their prediction score by approximately 7-8% when variables at the time of admission were included. As a result, more than one-half of these women (172/307; 56%) shifted to a higher predicted success group. The admission nomogram, as compared with the intake nomogram, more accurately predicted vaginal birth after cesarean delivery success in all groups. Analysis of admission variables showed that cervical dilation >2 cm compared with a closed cervix was the strongest predictor of successful vaginal birth after cesarean delivery (relative risk, 1.79; 95% confidence interval, 1.11-2.89)., Conclusion: The admission prediction nomogram was more accurate and showed higher predicted success compared with the intake nomogram for the same cohort. Because prediction scores may improve at the time of admission, additional counseling on the risks and benefits of trial of labor may be helpful at that time., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The relationship between radioactive iodine therapy (RIT) and prevalence of thyroglossal duct cysts (TGDC) on ultrasonography (US) has not been reported. We assessed the prevalence and US features of TGDC according to RIT. Methods: From July 2017 to June 2018, 3,146 subjects underwent thyroid or neck US at our center. The presence or absence of TGDCs was prospectively investigated based on real-time US examination. Among the 3,146 subjects, 261 subjects were excluded because of <18 years of age, unclear information of RIT, or the presence of a radiation therapy history to the neck. Eventually, 2,885 subjects were included in this study. Results: Of the 2,885 subjects finally included, 126 (4.4%) showed a TGDC on US. Those with RIT history showed a higher prevalence of TGDCs than those without (no statistical difference, p = 0.062). In 697 male subjects, there were statistical differences in type of surgery, RIT history, and session number of RIT between those with or without TGDCs ( p < 0.0001). In 126 subjects with TGDCs, only sex showed a significant difference between those with or without RIT history ( p = 0.015). However, there were no significant differences in the location, size, and shape of TGDCs ( p > 0.05). The common US features of TGDC were suprahyoid location, ~1 centimeter, and flat-to-ovoid or round shape. Conclusions: RIT may increase the prevalence of TGDCs, particularly in men., (Copyright © 2020 Park, Kim, Shin, Park, Lee, Choo, Park, Ha, Kim, Jung, Moon, Ahn and Baek.)

Sialic acid, a terminal monosaccharide present in N-glycans, plays an important role in determining both the in vivo half-life and the therapeutic efficacy of recombinant glycoproteins. Low sialylation levels of recombinant human erythropoietin (rhEPO) in recombinant Chinese hamster ovary (rCHO) cell cultures are considered a major obstacle to the production of rhEPO in fed-batch mode. This is mainly due to the accumulation of extracellular sialidases released from the cells. To overcome this hurdle, three sialidase genes (Neu1, 2, and 3) were initially knocked-out using the CRISPR/Cas9-mediated large deletion method in the rhEPO-producing rCHO cell line. Unlike wild type cells, sialidase knockout (KO) clones maintained the sialic acid content and proportion of tetra-sialylated rhEPO throughout fed-batch cultures without exhibiting a detrimental effect with respect to cell growth and rhEPO production. Additional KO of two pro-apoptotic genes, BAK and BAX, in sialidase KO clones (5X KO clones) further improved rhEPO production without any detrimental effect on sialylation. On day 10 in fed-batch cultures, the 5X KO clones had 1.4-times higher rhEPO concentration and 3.0-times higher sialic acid content than wild type cells. Furthermore, the proportion of tetra-sialylated rhEPO on day 10 in fed-batch cultures was 42.2-44.3% for 5X KO clones while it was only 2.2% for wild type cells. Taken together, KO of sialidase and pro-apoptotic genes in rCHO cells is a useful tool for producing heavily sialylated glycoproteins such as rhEPO in fed-batch mode., (Copyright © 2019 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.)

BACKGROUND This study aimed to evaluate the prevalence of thyroglossal duct cysts (TGDCs) on ultrasonography (US) and US features of TGDCs in adults, and to assess whether the prevalence or size of TGDCs increases after radioactive iodine ablation (RIA). MATERIAL AND METHODS Between July and December 2018, 2820 patients underwent thyroid or neck US examination, performed by 2 radiologists, at our center. On the basis of real-time US, the presence or absence of TGDCs was prospectively investigated by 2 radiologists. Among the 2820 patients, 54 patients who were <19 years of age or had a radiation therapy history to the neck were excluded. Eventually, 2766 patients were included. RESULTS Of the 2766 patients, 160 (5.8%) showed a TGDC on US. The mean size of TGDCs in RIA history (+) (n=36) and RIA history (-) (n=124) groups was 0.92±0.41 cm and 0.86±0.45 cm, respectively. There was no significant difference in size of TGDCs between RIA history (+) and RIA history (-) groups (p=0.684). Between the TGDC (+) and TGDC (-) groups, there was no significant difference in patient age, gender, reason for thyroid/neck US, type of thyroid surgery, and session number and application/no application of RIA (p>0.05). The prevalence rate of TGDCs in radiologist A and B was 4.9% (70/1427) and 6.7% (90/1339), respectively. TGDCs were more common in the suprahyoid neck, and the common shapes of TGDCs were flat-to-ovoid and round. CONCLUSIONS RIA may not be associated with the prevalence or enlargement of TGDCs.

Chinese hamster ovary (CHO) cells are the preferred host for producing biopharmaceuticals. Amino acids are biologically important precursors for CHO metabolism; they serve as building blocks for proteogenesis, including synthesis of biomass and recombinant proteins, and are utilized for growth and cellular maintenance. In this work, we studied the physiological impact of disrupting a range of amino acid catabolic pathways in CHO cells. We aimed to reduce secretion of growth inhibiting metabolic by-products derived from amino acid catabolism including lactate and ammonium. To achieve this, we engineered nine genes in seven different amino acid catabolic pathways using the CRISPR-Cas9 genome editing system. For identification of target genes, we used a metabolic network reconstruction of amino acid catabolism to follow transcriptional changes in response to antibody production, which revealed candidate genes for disruption. We found that disruption of single amino acid catabolic genes reduced specific lactate and ammonium secretion while specific growth rate and integral of viable cell density were increased in many cases. Of particular interest were Hpd and Gad2 disruptions, which show unchanged AA uptake rates, while having growth rates increased up to 19%, and integral of viable cell density as much as 50% higher, and up to 26% decrease in specific ammonium production and to a lesser extent (up to 22%) decrease in lactate production. This study demonstrates the broad potential of engineering amino acid catabolism in CHO cells to achieve improved phenotypes for bioprocessing., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

We describe an overgrowth condition associated with X-linked copy number variation. Three brothers displayed an overgrowth pattern at birth that continued postnatally. Clinical findings included macrocephaly, distinctive facial features, developmental delay and variable clubfoot. Normal fetal growth was noted until the third trimester by Hadlock standards, revealing a late gestational overgrowth pattern. Microarray analysis in the family showed a maternally inherited 680 kb copy number duplication at Xq26.1-q26.2 in all three brothers. Molecular sequencing for known overgrowth conditions including GPC3, Sotos 1 (NSD1), Malan (NFIX), Perlman (DIS3L2), Weaver (EZH2), Opitz-Kaveggia (MED12) loci were negative. BWS IC1 and IC2 methylation and CDKN1C testing was also negative. Normal IGF1 levels excluded X-linked acrogiantism. The duplicated region Xq26.1-q26.2 contained IGSF1 and at least part of the lncRNA FIRRE. IGSF1, a highly expressed pituitary immunoglobulin superfamily gene, was recently implicated in a genome-wide association study of canine size. IGSF1 variants were associated with large canine breeds compared to smaller breeds. Our findings support the hypothesis that an X-linked variant encompassing the IGSF1 region may be associated with body size. Although IGSF1 loss has been noted in human hypothyroidism, this is the first reported phenotype in a family with copy number duplication in the region. Our findings suggest that prenatal evaluation, cross-species evaluation, Mendelian, and GWAS studies may describe a distinctive familial condition and its corresponding phenotypic features., (© 2019 Wiley Periodicals, Inc.)

Objective: This study aimed to compare the ultrasonography (US) features of diffuse thyroid disease (DTD) and normal thyroid parenchyma (NTP), and to propose a structured imaging reporting system for detecting DTD. Methods: This retrospective study assessed the findings for 270 consecutive patients who underwent thyroid US before thyroid surgery. The following US data were analyzed: DTD-specific features, parenchymal echotexture and echogenicity, anteroposterior diameter, glandular margin, and parenchymal vascularity. Univariate and multivariate analyses with generalized estimating equations were performed to investigate the relationship between US features and DTD. The fitted probability of DTD was analyzed by using a regression equation. Results: Of the 270 patients, there were NTP ( n = 193), Hashimoto thyroiditis ( n = 24), non-Hashimoto lymphocytic thyroiditis ( n = 51), Graves' disease ( n = 1), and diffuse hyperplasia ( n = 1). The following US features were significantly associated with DTD: decreased or increased parenchymal echogenicity, coarse parenchymal echotexture, increased anteroposterior diameter, lobulated glandular margin, and increased parenchymal vascularity. Of these, coarse parenchymal echotexture was the most significant independent predictor of DTD. The numbers of abnormal US features were positively correlated with the fitted probability and risk of DTD. The diagnostic indices were highest when the chosen cut-off criterion was category III with the largest Az value (0.867, 95% confidence interval: 0.820-0.905), yielding a sensitivity of 68.8%, specificity of 92.2%, positive predictive value of 77.9%, negative predictive value of 88.1%, and accuracy of 85.6% ( p < 0.001). Conclusions: Our sonographic reporting and data system may be useful for detecting DTD., (Copyright © 2019 Baek, Kim, Ryu, Shin, Park, Lee, Choo, Park, Ha, Kim, Jung, Park, Moon and Ahn.)

Developmental and epileptic encephalopathies are genetic disorders in which both the developmental disability and the frequent epileptic activity are the effect of a specific gene variant. While heterozygous variants in SCN1B have been described in families with generalized epilepsy with febrile seizures plus, Type 1, only three cases of homozygous, missense variants in SCN1B have been reported in association with autosomal recessive inheritance of a severe developmental and epileptic encephalopathy. We present two siblings who are homozygous for a novel, missense variant in SCN1B, c.265C>T, predicting p.Arg89Cys. The proband is an 11-year-old female with infantile-onset, fever-induced, intractable generalized tonic-clonic seizures, myoclonic seizures, and developmental slowing and autism spectrum disorder occurring later in the course of the disease. Her 4-year-old brother had a similar epilepsy phenotype, but still displays normal development. This variant has not been previously reported in the homozygous state in control databases. The variant was predicted to be damaging and occurred in the vicinity of other epileptic encephalopathy-associated missense variants that are biallelic and located in the extracellular immunoglobulin loop domain of the protein, which mediates interaction of the beta-1 subunit with cellular adhesion molecules. Our report is the first set of siblings with homozygosity for the p.Arg89Cys variant in SCN1B and further implicates biallelic mutations in this gene as a cause of epileptic encephalopathy mimicking Dravet syndrome. Interestingly, the phenotype we observed was milder compared to that previously described in patients with recessive SCN1B mutations., (© 2019 Wiley Periodicals, Inc.)

In this study, the sintering behaviors of Nb-6Mo-20Si-3Cr (at percentage) in situ composite powders were studied. The Nb alloy powder was fabricated by a hydrogenation-dehydrogenation method, and both the alloy ingot and powders consisted of two phases: An Nb metal phase and the α-Nb 5 Si 3 phase. Consolidation of the alloy powders was performed at 1500, 1600, and 1700 °C using spark plasma sintering, and the microstructures and phases formed at various sintering temperatures were analyzed. Micropores were observed in the compact sintered at 1500 °C due to the lack of complete densification at that temperature. The densification was completed at 1600 °C and the microstructure was slightly coarsened at 1700 °C compared to the microstructure of the compact sintered at 1600 °C. The microstructures prepared by the powder metallurgy method were finer than the microstructure of the ingot prepared by the casting method. The phase formation behavior varied according to the sintering temperature. Specifically, the α-Nb 5 Si 3 phase, which is a stable structure of the Nb 5 Si 3 phase at a low temperature, was transformed to the β-Nb 5 Si 3 phase (which is stable at a high temperature) with an increasing sintering temperature.

Objective: This study aimed to evaluate factors influencing the successful maintenance of postoperative euthyroidism in patients who did not undergo immediate thyroid hormone replacement after lobectomy for papillary thyroid microcarcinoma (PTMC). Methods: From September 2015 to June 2017, 186 patients underwent lobectomy for PTMC in our hospital. Patients taking medications for hypothyroidism and hyperthyroidism before and after lobectomy were excluded. Multiple parameters, including sex, age, pre-operative free thyroxine (T4), thyroid-stimulating hormone (TSH), thyroglobulin (TG), and thyroid autoantibody levels, body mass index (BMI), postoperative histopathology of the thyroid gland, remnant thyroid gland volume, and session number of levothyroxine discontinuation were retrospectively evaluated. These factors were compared between groups based on the maintenance of postoperative euthyroidism. Results: In 88 of the 175 patients (50.3%), postoperative euthyroidism was successfully maintained without thyroid hormone replacement during the first year after lobectomy. There were significant differences in sex ( P = .003), pre-operative TSH levels ( P = .002), and histopathology of the thyroid gland ( P = .035) between the groups showing maintenance success and failure. The group showing successful maintenance had a higher percentage of male patients, lower levels of pre-operative TSH, and normal parenchymal histology of the thyroid gland. However, there were no significant between-group differences in age, pre-operative free T4, TG, and thyroid autoantibody levels, BMI, remnant thyroid gland volume, and session number of levothyroxine discontinuation. Conclusion: Patient sex, pre-operative TSH levels, and histopathology of the thyroid gland may influence the maintenance of postoperative euthyroidism after lobectomy. Abbreviations: BMI = body mass index; PTMC = papillary thyroid microcarcinoma; RR = reference range; T4 = thyroxine; TFT = thyroid function test; TG = thyroglobulin; TSH = thyroid-stimulating hormone.

Prolonged endoplasmic reticulum (ER) stress reduces protein synthesis and induces apoptosis in mammalian cells. When dimethyl sulfoxide (DMSO), a specific monoclonal antibody productivity (q mAb )-enhancing reagent, is added to recombinant Chinese hamster ovary (rCHO) cell cultures (GSR cell line), it induces ER stress and apoptosis in a dose-dependent manner. To determine an effective ER stress inhibitor, three ER stress inhibitors (BiP inducer X [BIX], tauroursodeoxycholic acid, and carbazole) are examined and BIX shows the best production performance. Coaddition of BIX (50 μm) with DMSO extends the culture longevity and enhances q mAb . As a result, the maximum mAb concentration is significantly increased with improved galactosylation. Coaddition of BIX significantly increases the expression level of binding immunoglobulin protein (BiP) followed by increased expression of chaperones (calnexin and GRP94) and galactosyltransferase. Furthermore, the expression levels of CHOP, a well-known ER stress marker, and cleaved caspase-3 are significantly reduced, suggesting that BIX addition reduces ER stress-induced cell death by relieving ER stress. The beneficial effect of BIX on mAb production is also demonstrated with another q mAb -enhancing reagent (sodium butyrate) and a different rCHO cell line (CS13-1.00). Taken together, BIX is an effective ER stress inhibitor that can be used to increase mAb production in rCHO cells., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

BACKGROUND This study aimed to assess the utility and characteristics of preoperative ultrasonography (US) in patients transferred to referral hospitals from local clinics with a diagnosis of malignancy on US-guided fine-needle aspiration cytology of thyroid nodules. MATERIAL AND METHODS From January 2018 to June 2018, 109 transferred patients underwent preoperative US in our hospital for suspected thyroid malignancy on cytological analysis after US-guided fine-needle aspiration of thyroid nodules in local clinics. Preoperative US was performed by a single radiologist in all patients. Among them, 6 were excluded from the study because of refusal of thyroid surgery. Preoperative US and histopathological results were compared in all patients. RESULTS After thyroid surgery, pathological examination revealed papillary thyroid carcinoma (PTC) (n=98), follicular adenoma (n=1), and nodular hyperplasia (n=4). Of the 103 patients, 91 exhibited suspicious US findings on the preoperative US, whereas 12 did not. In the 91 patients with suspicious US findings, PTC (n=90) and follicular adenoma (n=1) were confirmed after thyroid surgery. In the 12 patients with no suspicious US findings, PTC (n=8) and nodular hyperplasia (n=4) were confirmed after thyroid surgery. On repeat analysis of the cytological slides of the 4 nodular hyperplasia cases from the local clinics, Bethesda category II (n=1) and III (n=3) were determined. CONCLUSIONS In the transferred patients with a malignant cytology, preoperative US might be helpful to detect false-positive cytology cases.

This study aimed to assess the prevalence of tumor recurrence/persistence and determine the appropriate frequency and interval of follow-up neck ultrasonography (US) in papillary thyroid microcarcinoma (PTMC) patients who underwent hemithyroidectomy and long-term follow-up US. From January 2005 to December 2006, 179 patients underwent a hemithyroidectomy for the treatment of PTMC and at least 1 postoperative US surveillances. The postoperative follow-up US was performed by 2 radiologists for all patients. Based on the US and histopathologic results, tumor recurrence/persistence was determined. Of the 179 patients, the following results were determined after hemithyroidectomy: all patients exhibited T1 stage, while nodal metastasis to the ipsilateral level VI node (n = 27) and ipsilateral multifocality (n = 16) were found. Tumor recurrence was found in 5 (2.8%) of 179 and tumor persistence in 2 (1.1%) of 179. In the tumor recurrence cases, all patients underwent US-guided fine-needle aspiration for the newly detected thyroid nodule because of suspicious features on postoperative follow-up US (8-, 24-, 36-, 87-, and 96-month intervals). Differences were observed in the number of follow-up US sessions (mean, 5.2; range, 1-13) and in the interval period to the last follow-up (mean, 80.7 months; range, 8-138 months). Among the patients, 82 (45.8%) had a more than 120-month interval to the last follow-up US after hemithyroidectomy. In conclusion, the PTMC tumor recurrence rate was low, indicating that only 1 or 2 sessions of postoperative US follow-up may be sufficient to detect tumor recurrence within the first 10 years after hemithyroidectomy in PTMC patients.

Oligostilbenes are polyphenol oligomers derived from resveratrol and are commonly produced by members of the Gnetaceae family, and many researchers have focused on their anti-inflammatory activities. The EtOAc fraction of a Gnetum latifolium extract showed inhibitory activity against neuroinflammation induced by the transfection of Aβ 1-42 into microglial BV-2 cells. The bioassay-guided isolation of the 70% EtOH extract of this plant resulted in three previously undescribed resveratrol oligostilbenes and ten known stilbene derivatives. The structures of the isolated compounds were established based on extensive NMR spectroscopic analysis. The absolute configurations of the three undescribed compounds were confirmed by comparison with available compounds with known stereochemistry and by ECD calculations and molecular modelling. Latifoliols A and B are the first reported oligostilbenes with a bridged 3-oxabicyclo[3.3.0]octane moiety, and latifoliol C was formed by the condensation of gnemontanin G with oxyresveratrol. Moreover, the hypothetical biogenetic pathway of latifoliols A, B and C was proposed. The potential anti-inflammatory activities of the thirteen isolated compounds were tested by measuring their effect on the secreted NO concentrations induced by transfection with plasmids expressing the Aβ 1-42 gene in the BV-2 cell line. Interestingly, cis- and trans-shegansu B and latifolol, whose structures contained double bonds, strongly inhibited NO secretion in BV-2 cells, supporting the double binding effect of the stilbene derivative on inhibitory activity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

In this study, we compared ultrasound (US) features between normal parotid parenchyma (NPP) and incidental diffuse parotid disease (DPD). From January 2008 to December 2017, 180 patients underwent neck US before parotid surgery at our hospital. From these, 82 were excluded because of the lack of histopathological data concerning the parotid parenchyma or inadequate US images. A single radiologist blinded to the clinicoserological data and histopathological results, retrospectively investigated all US features and categorizations for the parotid glands using a picture archiving and communication system. Retrospective histopathological analysis of the parotid parenchyma was performed by a single pathologist. On the basis of the histopathological analyses, the 98 patients were divided into NPP (n = 70) and DPD (n = 28) groups. Among US features, parenchymal echogenicity and echotexture showed statistically significant differences between the two groups (p < 0.0001), whereas the gland size, margin, and vascularity showed no significant differences (p > 0.05). The US-based categorization significantly differentiated between NPP and DPD (p < 0.0001), and receiver operating characteristic curve analysis revealed that US categorization based on ≥2 abnormal US features showed the best diagnostic performance for detecting DPD. Thus, US can aid in differentiating DPD from NPP., Competing Interests: The authors have declared that no competing interests exist.

Objective: This study aimed to evaluate the ultrasonography (US), cytology, and thyroglobulin (Tg) measurement results of nodal metastasis in patients showing unclear US or cytology results of primary papillary thyroid carcinoma (PTC). Methods: From January 2016 to December 2018, 179 patients underwent US-guided fine-needle aspiration (FNA) to diagnose lymphadenopathy in the neck. Among them, 36 patients underwent subsequent total thyroidectomy and nodal dissection, and cervical lymph node (LN) metastasis from PTC was confirmed. However, two patients were excluded because of mismatch between the US and pathological findings of LNs. US images and cytological slides for metastatic LNs were retrospectively analyzed, and serum and FNA Tg levels for metastatic LNs were investigated using data from the electric medical records. Primary PTC patients with suspicious results on both US and cytology were classified as the clear group, and the remaining patients were classified as the unclear group. Results: Of the 34 patients, 24 had clear results of primary PTC on both US and cytology (clear group), whereas 10 had unclear results of primary PTC on US or cytology (unclear group). Of the 10 patients in the unclear group, seven had suspicious nodal metastasis from PTC on cytology after US-guided FNA of the cervical LN, and the remaining three had negative cytology but a positive Tg measurement. Metastatic LNs with cystic change tended to show a positive Tg measurement but negative cytology. Conclusions: The combination of US, cytology, and Tg measurement is necessary for diagnosing nodal metastasis from PTC. In cases with unclear primary PTC on US or cytology, the detection of nodal metastasis may be helpful for assessing primary PTC.

Porcine epidemic diarrhea virus (PEDV), a serious swine epidemic, has been rampant in Asia since the 1990s. Despite the widespread use of PEDV vaccines, the occurrence of PEDV variants requires the discovery of new substances that inhibit these viruses. During a search for PEDV inhibitory materials from natural sources, seven new sabphenosides (1-7) and a new flavonoid (8), as well as eight known phenolic compounds (9-16), were obtained from the leaves of Sabia limoniacea. The structural determination of the new phenolic derivatives (1-8) was accomplished using comprehensive spectroscopic methods. Their absolute configurations were assigned by a combination of the ECD exciton chirality method following selective reduction and calculation of their ECD spectra. The bioactivities of the isolated compounds were measured based on their abilities to inhibit viral replication of PEDV. Among the test compounds, 15 and 16 exhibited the most promising antiviral activities, with IC 50 values of 7.5 ± 0.7 μM and 8.0 ± 2.5 μM against PEDV replication. This study suggests that compounds 15 and 16 could serve as new scaffolds for the treatment of PEDV infection through the inhibition of PEDV replication.

Generation of recombinant Chinese hamster ovary (rCHO) cell lines is critical for the production of therapeutic proteins. However, the high degree of phenotypic heterogeneity among generated clones, referred to as clonal variation, makes the rCHO cell line development process inefficient and unpredictable. Here, we investigated the major genomic causes of clonal variation. We found the following: (1) consistent with previous studies, a strong variation in rCHO clones in response to hypothermia (33 vs 37 °C) after random transgene integration; (2) altered DNA sequence of randomly integrated cassettes, which occurred during the integration process, affecting the transgene expression level in response to hypothermia; (3) contrary to random integration, targeted integration of the same expression cassette, without any DNA alteration, into three identified integration sites showed the similar response of transgene expression in response to hypothermia, irrespective of integration site; (4) switching the promoter from CMV to EF1α eliminated the hypothermia response; and (5) deleting the enhancer part of the CMV promoter altered the hypothermia response. Thus, we have revealed the effects of integration methods and cassette design on transgene expression levels, implying that rCHO cell line generation can be standardized through detailed genomic understanding. Further elucidation of such understanding is likely to have a broad impact on diverse fields that use transgene integration, from gene therapy to generation of production cell lines.

Background: No previous studies have investigated the feasibility of magnetic resonance imaging (MRI) diagnosis for detecting incidental diffuse thyroid disease (DTD). This study investigated MRI features of normal thyroid parenchyma and incidental DTD. Methods: From January 2008 to December 2017, 387 patients underwent neck MRI in our hospital due to tumor/nodal staging ( n = 137), lymphadenopathy ( n = 122), inflammatory neck lesion ( n = 85), congenital neck lesion ( n = 12), and patient request ( n = 31). Among them, 375 patients were excluded because of a lack of appropriate histopathological data on the thyroid parenchyma. Results: Among the patients included, 10 had normal thyroid parenchyma, 1 had Hashimoto thyroiditis, and 1 had diffuse hyperplasia. The common MRI features of normal thyroid parenchyma include iso-/slightly high and homogeneous signal intensity on T1/T2-weighted images, normal anteroposterior diameter of the thyroid gland, smooth margin, and homogeneously increased enhancement as compared to adjacent muscle. Hashimoto thyroiditis exhibited high and inhomogeneous signal intensity on T2-weighted images, while diffuse hyperplasia revealed an increased anteroposterior diameter and lobulated margin of the thyroid gland, and inhomogeneous enhancement. Conclusions: MRI may be helpful for detection of incidental DTD.

Background: Sirtuins mediate metabolic responses to nutrient availability and slow aging and accompanying decline in health. This study was designed to assess the expressions of sirtuin1 (SIRT1) and sirtuin3 (SIRT3) in the liver and hypothalamus after duodenal-jejunal bypass (DJB) surgery in rats., Methods: A total of 38 rats were randomly assigned to either sham group (n=8) or DJB group (n=30). DJB group was again divided into three groups according to the elapsed time after surgery (10 weeks, DJB10; 16 week, DJB16; 28 week, DJB28). The mRNA and protein expressions of SIRT1 and SIRT3 in the liver and hypothalamus were measured by reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry analyses. NAD + /NADH ratio was also measured., Results: We found increased mRNA and protein expression levels of SIRT1 in the liver of DJB16 and DJB28 groups compared with those of sham group. The mRNA and protein expressions of SIRT3 in the liver of DJB group increased proportionally to the elapsed time after DJB surgery. The mRNA expression levels of SIRT1 in the hypothalamus increased in DJB16 and DJB28 groups and protein expression levels of SIRT1 in the hypothalamus increased in DJB10, DBJ16, and DJB28 groups compared with sham group. We observed that mRNA and protein levels of SIRT3 in the hypothalamus of DJB group were not changed., Conclusion: This study proves that DJB increases SIRT1 and SIRT3 expressions in the liver and SIRT1 expression in the hypothalamus. These results suggest the possibility of sirtuins being involved in bypass surgery-induced metabolic changes., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflict of interest.

Purpose: Acute normovolemic hemodilution (ANH) is an autologous transfusion method, using blood collected during surgery, to reduce the need for allogeneic blood transfusion. ANH is controversial because it may lead to various complications. Among the possible complications, anastomotic leakage is one that would have a significant effect on the operation outcome. However, the relationship between ANH and anastomotic site healing requires additional research. Therefore, we conducted this prospective study of ANH, comparing it with standard intraoperative management, undergoing gastric anastomosis in rats., Methods: Sixteen Sprague-Dawley rats were randomly assigned to three groups: group A, surgery with ANH; group N, surgery with standard intraoperative management; and group C, sham surgery with standard intraoperative management. ANH was performed in group A animals by, removing 5.8-6.6 mL of blood and replacing it with 3 times as much crystalloid. All rats were enthanized on postoperative day 6, and histopathologic analyses were performed., Results: The mean hematocrit values, after hemodilution were 22.0% (range, 18.0%-29.0%), group A; 33.0% (29.0%-35.0%), group N; and 32.5% (29.0%-34.0%), group C. There were significant differences between groups A and N (P = 0.019, P = 0.009, P = 0.004, P = 0.039, and P = 0.027), and between groups N and C (P = 0.006, P = 0.027, P = 0.04, P = 0.008, and P = 0.009) with respect to inflammatory cell numbers, neovascularization, fibroblast numbers, edema and necrosis, respectively; there were no differences between groups A and N., Conclusion: In rat model, anastomotic complications did not increase in the ANH group, compared with the standard intraoperative management group., Competing Interests: CONFLICTS OF INTEREST: No potential conflict of interest relevant to this article was reported.

This study investigated the role of BRAF mutation analysis in thyroid fine-needle aspiration (FNA) samples compared to ultrasonographic and cytological diagnoses. A total 316 patients underwent ultrasonography (US)-guided FNA with BRAFV600E mutation analysis to diagnose thyroid nodules. One hundred sixteen patients with insufficient US images (n = 6), follow-up loss (n = 43), or unknown final diagnosis (n = 67) were excluded from the study. Comparisons between US diagnoses, cytological diagnoses, and BRAF mutation analysis were performed. Of 200 thyroid nodules, there was US diagnosis with 1 false negative and 11 false positive cases, cytological diagnosis with 10 false negative and 2 false positive cases, and BRAFV600E mutation analysis with 19 false negative and 2 false positive cases. The sensitivity, specificity, positive and negative predictive values, and accuracy of BRAFV600E mutation analysis were 83.2%, 98.1%, 97.5%, 86.6%, and 91%, respectively. Of the 18 nodules with Bethesda category III, 9 were true positive, 6 were true negative, 3 was a false negative, and none were false positive on BRAF mutation analysis. In conclusion, we recommend that BRAFV600E mutation analysis only be performed for evaluating thyroid nodules with Bethesda category III, regardless of US diagnosis., Competing Interests: The authors have declared that no competing interests exist.

Rationale: Based on imaging and biopsy results, surgical removal of mediastinal nodular hyperplasia (MNH) may be unnecessary, and mediastomy may be avoidable., Patient Concerns: We report three cases of nodular hyperplasia presenting as a mediastinal mass on imaging studies during a health check-up or for the evaluation of known abscess in the right masticator and submandibular spaces., Interventions: In the first two cases, surgical excision was performed, and in the third case, US-guided core needle biopsy was performed., Diagnoses: Histopathological examination revealed MNH in the first two cases, and histologic examination suggested MNH., Outcomes: In the first two cases, there were no associated complications after successful surgical removal. In the third case, surgery was not performed because of old age and no associated symptoms., Lessons: MNH may mimic mediastinal tumors on imaging studies. Accordingly, awareness of imaging features, interval changes, associated symptoms, and biopsy results may be necessary for the appropriate management of MNH.