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Supplemental material, sj-docx-2-dhj-10.1177_20552076231187247 for Mortality risk prediction of the electrocardiogram as an informative indicator of cardiovascular diseases by Dung-Jang Tsai, Yu-Sheng Lou, Chin-Sheng Lin, Wen-Hui Fang, Chia-Cheng Lee, Ching-Liang Ho, Chih-Hung Wang and Chin Lin in DIGITAL HEALTH

Supplemental material, sj-docx-2-dhj-10.1177_20552076231187247 for Mortality risk prediction of the electrocardiogram as an informative indicator of cardiovascular diseases by Dung-Jang Tsai, Yu-Sheng Lou, Chin-Sheng Lin, Wen-Hui Fang, Chia-Cheng Lee, Ching-Liang Ho, Chih-Hung Wang and Chin Lin in DIGITAL HEALTH

Supplemental material, sj-docx-1-dhj-10.1177_20552076231187247 for Mortality risk prediction of the electrocardiogram as an informative indicator of cardiovascular diseases by Dung-Jang Tsai, Yu-Sheng Lou, Chin-Sheng Lin, Wen-Hui Fang, Chia-Cheng Lee, Ching-Liang Ho, Chih-Hung Wang and Chin Lin in DIGITAL HEALTH

Supplemental material, sj-docx-1-dhj-10.1177_20552076221143249 for Artificial intelligence-enabled electrocardiogram screens low left ventricular ejection fraction with a degree of confidence by Chun-Ho Lee, Wei-Ting Liu, Yu-Sheng Lou, Chin-Sheng Lin and Wen-Hui Fang, Chia-Cheng Lee, Ching-Liang Ho, Chih-Hung Wang, Chin Lin in Digital Health

Insulin secretion in pancreatic β-cells is regulated by cortical complexes that are enriched at the sites of adhesion to extracellular matrix facing the vasculature. Many components of these complexes, including Bassoon, RIM, ELKS and liprins, are shared with neuronal synapses. Here, we show that insulin secretion sites also contain non-neuronal proteins LL5β and KANK1, which in migrating cells organize exocytotic machinery in the vicinity of integrin-based adhesions. Depletion of LL5β or focal adhesion disassembly triggered by myosin II inhibition perturbed the clustering of secretory complexes and attenuated the first wave of insulin release. While previous analyses in vitro and in neurons suggested that secretory machinery might assemble through liquid-liquid phase separation, analysis of endogenously labeled ELKS in pancreatic islets indicated that its dynamics is inconsistent with such a scenario. Instead, fluorescence recovery after photobleaching and single molecule imaging showed that ELKS turnover is driven by binding and unbinding to low-mobility scaffolds. Both the scaffold movements and ELKS exchange were stimulated by glucose treatment. Our findings help to explain how integrin-based adhesions control spatial organization of glucose-stimulated insulin release.

BACKGROUND Helicobacter pylori (H pylori) treatment remains a challenge for penicillin-allergic patients. AIM To evaluate the efficacy and tolerability of susceptibility-guided first-line and rescue treatment in H pylori-infected penicillin-allergic patients. METHODS Consecutive H pylori-infected patients with penicillin allergy received a 14-day triple or quadruple therapy based on susceptibility to clarithromycin, levofloxacin, and metronidazole. All received esomeprazole 20 mg twice a day. Metronidazole-susceptible infections received metronidazole plus clarithromycin or levofloxacin triple therapy if susceptible. Clarithromycin- and levofloxacin-resistant infections received metronidazole plus tetracycline triple therapy. Metronidazole-resistant infections received a bismuth-high-dose metronidazole plus clarithromycin or levofloxacin quadruple therapy. Triple-resistant infections received classical bismuth quadruple therapy with high-dose metronidazole. Antimicrobial susceptibility was assessed using the E test method. RESULTS 112 patients were entered (34.8% men, average 47.1 years). Infections in 83.8% (31/37) of treatment-naive subjects and 12.0% (9/75) (P

Additional file 1: Table S1. DEGs involved in the special pathways of E. harbinense under different pH conditions. Table S2. KEGG pathway analysis of differentially expressed new transcripts in E. harbinense strains involved in pH response. Figure S1. The pH changes in E. harbinense fermentation broth under different initial pH conditions. Figure S2. Correlation analysis and expression distribution of E. harbinense transcriptomes under different initial pH conditions. Figure S3. Gene co-expression network analysis of E. harbinense transcriptomes under different initial pH conditions. Figure S4. Differentially expressed genes of E. harbinense involved in the PTS system. Figure S5. Differentially expressed new transcripts of E. harbinense involved in pH response.

Aconitine (ACO), a main active ingredient of Aconitum, is well-known for its cardiotoxicity. However, the mechanisms of toxic action of ACO remain unclear. In the current study, we investigated the cardiac effects of ACO and mesaconitine (MACO), a structurally related analog of ACO identified in Aconitum with undocumented cardiotoxicity in guinea pigs. We showed that intravenous administration of ACO or MACO (25 μg/kg) to guinea pigs caused various types of arrhythmias in electrocardiogram (ECG) recording, including ventricular premature beats (VPB), atrioventricular blockade (AVB), ventricular tachycardia (VT), and ventricular fibrillation (VF). MACO displayed more potent arrhythmogenic effect than ACO. We conducted whole-cell patch-clamp recording in isolated guinea pig ventricular myocytes, and observed that treatment with ACO (0.3, 3 μM) or MACO (0.1, 0.3 μM) depolarized the resting membrane potential (RMP) and reduced the action potential amplitude (APA) and durations (APDs) in a concentration-dependent manner. The ACO- and MACO-induced AP remodeling was largely abolished by an I(Na) blocker tetrodotoxin (2 μM) and partly abolished by a specific Na(+)/K(+) pump (NKP) blocker ouabain (0.1 μM). Furthermore, we observed that treatment with ACO or MACO attenuated NKP current (I(Na/K)) and increased peak I(Na) by accelerating the sodium channel activation with the EC(50) of 8.36 ± 1.89 and 1.33 ± 0.16 μM, respectively. Incubation of ventricular myocytes with ACO or MACO concentration-dependently increased intracellular Na(+) and Ca(2+) concentrations. In conclusion, the current study demonstrates strong arrhythmogenic effects of ACO and MACO resulted from increasing the peak I(Na) via accelerating sodium channel activation and inhibiting the I(Na/K). These results may help to improve our understanding of cardiotoxic mechanisms of ACO and MACO, and identify potential novel therapeutic targets for Aconitum poisoning.

Background: Allogeneic chimeric antigen receptor (CAR) T cell therapy offers the prospect of readily accessible, CD19-directed cellular therapy with assured fitness and effector function for subjects with relapsed or refractory (R/R) B-cell malignancies. Using a single step process, the CD19 CAR is knocked-into the T-cell receptor alpha constant (TRAC) locus after editing with a TRAC-specific ARCUS nuclease, thereby preventing graft-versus-host disease through disruption of the endogenous T-cell receptor. To mitigate rejection of PBCAR0191, an enhanced lymphodepletion (LD) chemotherapy regimen (eLD) was investigated to improve PBCAR expansion and persistence by both deepening and extending the duration of LD without prolonged immune suppression. Here we present results of eLD conditioning in subjects with CD19 + NHL or ALL. Methods: Subjects with measurable CD19 + R/R B-ALL or NHL disease after two or more prior treatment regimens were enrolled; all without CNS disease, recent active infection, or other major medical comorbidities and no active GvHD. Prior autologous (auto) or allogeneic stem cell transplant and/or CD19-directed auto-CAR therapy was permitted. Lymphodepletion consisting of fludarabine 30 mg/m 2/day x 4 days plus cyclophosphamide 1000 mg/m 2/day x 3 days was administered prior to infusion of 3 x 10 6 cells/kg PBCAR0191 CAR T cells on day 0. CAR T cell expansion kinetics were assessed by flow cytometry and RT-PCR. Results: As of July 1, 2021, 21 subjects have been treated including 16 NHL (13 with Day 28 assessment) and 5 B-ALL. Subjects were heavily pretreated (median, 7 lines; max 15) with aggressive and advanced disease (Table 1), including six subjects who had progressed after treatment with an auto-CD19 CAR, and 8 after auto or allogeneic stem cell transplant. Most adverse events were mild. Grade 3 or greater neutropenia occurred in 2 NHL and 2 BALL subjects, and 1 Grade 3 self-limited ICANS with no evidence of Graft versus Host Disease (GvHD). There was 1 non-disease progression, infectious death at day 54 that was deemed possibly related to PBCAR0191 by the investigator. CAR T kinetics were profoundly improved compared to standard LD, with both peak cell expansion and area under the curve increasing 80-fold. Improved CAR T cell kinetics was associated with high rates of objective response. Overall, 15 of 18 (83%) evaluable subjects responded to PBCAR0191, including 11/13 (85%) NHL and 4/5 (80%) ALL subjects, with complete responses (CR/CRi) achieved in 8/13 (62%) NHL and 4 /5 (80%) ALL subjects. To date 3/15 responses are ongoing at > 6 months duration, 1 received consolidation with allo-SCT and 3 additional subjects have not yet reached the 6-month evaluation threshold at the time of abstract submission. Of note, there was no difference in the frequency of response among subjects who were CAR naïve compared to those who received a prior auto-CD19 CAR. Remarkably, among 6 subjects who progressed following an auto-CD19 CAR (5 NHL, 1 ALL), the ORR was 83% (5/6 pts) with 4 (67%) CRs, including an ongoing MRD - CR in an ALL subject of > 6 months. Conclusions: eLD mitigated PBCAR0191 rejection to markedly improve peak CAR T cell expansion and persistence with predictable and manageable toxicity. A single infusion of PBCAR0191 following eLD provided clinical benefit in the majority of subjects, yielding high rates of overall and complete response with promising activity in both CD19 CAR naïve subjects and those who progressed following auto-CD19 CAR therapy. Figure 1 Figure 1. Disclosures Shah: Pfizer: Consultancy, Other: Expenses; Amgen: Consultancy; Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; BeiGene: Consultancy, Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Servier Genetics: Other; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Novartis: Consultancy, Other: Expenses; Adaptive Biotechnologies: Consultancy. Jacobson: Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Nkarta: Consultancy, Honoraria; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Humanigen: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; Clinical Care Options: Speakers Bureau. Jain: Beigene: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria; Incyte: Research Funding; Genentech: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Pfizer: Research Funding; Servier: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; TG Therapeutics: Honoraria; Pharmacyclics: Research Funding. Johnson: Precision BioSciences, Inc: Current Employment, Current equity holder in publicly-traded company. Vainorius: Precision BioSciences: Current Employment, Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company; United Therapeautics: Current equity holder in publicly-traded company. Yu: Precision BioSciences: Current Employment, Current equity holder in publicly-traded company. Heery: Precision BioSciences: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Arcellx: Current Employment, Current holder of stock options in a privately-held company. List: Precision BioSciences: Current Employment, Current equity holder in publicly-traded company; CTI Biosciences: Consultancy; Halia Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company; Aileron Therapeutics: Consultancy. Reshef: Gilead and Novartis: Honoraria; ilead, BMS, Precision, Immatics, Atara, Takeda, Shire, Pharmacyclics, Incyte: Research Funding; Bayer: Consultancy; BMS, Regeneron, TScan, Synthekine, Atara, Jasper, Bayer: Consultancy. Akard: Takeda: Consultancy; Jazz Pharmaceuticals: Consultancy; Abbvie: Speakers Bureau; Astellas Pharma: Speakers Bureau; BMS: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau; Takeda: Speakers Bureau; Verastem: Speakers Bureau. Sauter: Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Gamida Cell: Consultancy; Celgene: Consultancy, Research Funding; Kite/Gilead: Consultancy. Olszewski: TG Therapeutics: Research Funding; PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding. Deol: Kite, a Gilead Company: Consultancy.

Amoxicillin, metronidazole, proton pump inhibitor, bismuth quadruple therapy had been shown to reliably achieve high eradication rates. The role of individual components remains undefined. To identify the additional benefit/role of bismuth in amoxicillin, metronidazole, proton pump inhibitor, bismuth quadruple therapy for Helicobacter pylori (H. pylori) treatment. This was a non-inferiority factorial design trial. Treatment-naive H. pylori-infected subjects were randomly (1:1) assigned to receive 14-day amoxicillin- and metronidazole-containing triple therapy consisting of esomeprazole 20 mg twice a day, amoxicillin 1 g, and metronidazole 400 mg both thrice daily with or without 220 mg bismuth twice a day. Six weeks after treatment, H. pylori eradication was assessed by 13C-urea breath test. Antimicrobial susceptibility was assessed by the twofold agar dilution method. From July 2018 to June 2019, a total of two hundred and sixteen subjects were randomized. Both therapies achieved high eradication rates. Per-protocol with bismuth = 97.9% (94/96, 95% CI 95.1–100%) and without bismuth = 94.7% (90/95, 95% CI 90.3–99.1%) (P = 0.43). Intent-to-treat analysis = 90.7% (98/108, 95% CI 85.2–96.2%) versus 88.9% (96/108, 95% CI 82.8–95.0%) with and without bismuth (P = 0.65). The two regimens were not inferior by intent-to-treat or per-protocol analyses. Metronidazole resistance did not affect the efficacy of either therapy. Neither the presence nor absence of bismuth or metronidazole resistance reduced the effectiveness of triple therapy containing esomeprazole 20 mg twice a day, amoxicillin 1 g, and metronidazole 400 mg thrice daily in this population. The clinical trial was registered with ClinicalTrials.gov, NCT03557437.

Background: Empirical therapy of Helicobacter pylori frequently results in treatment failure due to unrecognized antimicrobial resistance. The aim of this study was to investigate the effectiveness of susceptibility-guided therapy for rescue treatment of H. pylori infection in China. Methods: This was a prospective study of consecutive 200 patients infected with H. pylori with one or more treatment failures. The therapy chosen was susceptibility based using the most effective, best-tolerated regimens first and a locally proven, reliably effective regimen for multidrug-resistant infections. All patients received 14-day triple therapy, i.e. esomeprazole 20 mg and amoxicillin 1 g twice a day plus clarithromycin 500 mg twice a day, metronidazole 400 mg twice a day, or levofloxacin 500 mg daily, or, for multidrug-resistant infections, amoxicillin-containing bismuth quadruple therapy with esomeprazole 20 mg twice a day, bismuth 220 mg twice a day, amoxicillin 1 g three times a day, and metronidazole 400 mg four times a day. Antibiotic resistance was determined by agar dilution. Results: The eradication rate of susceptibility-guided therapy overall was 94.5% (189/200, 95% confidence interval: 90.4–97.2%). Around 28% (56/200) of patients carried strains susceptible to one of the tested antibiotics and were prescribed the triple therapy. A total of 144 multidrug-resistant patients received bismuth quadruple therapy. The eradication rates were all greater than 90%, i.e. 91.7% (11/12), 92.3% (12/13), and 93.5% (29/31) in those who received clarithromycin, metronidazole, and levofloxacin-containing triple therapy and 95.1% (137/144) for the bismuth quadruple therapy. There were no differences in eradication rates between the subgroups. Conclusions: Although susceptibility-guided therapy proved high efficacious despite the high proportion of multidrug-resistant strains, the strategy suggested the best approach for this population would be empirical amoxicillin-containing bismuth quadruple therapy. ClinicalTrials.gov identifier: NCT03413020.

Background A reliably highly effective high-dose proton-pump inhibitor plus amoxicillin (dual Helicobacter pylori therapy) has remained elusive. We compared whether the addition of bismuth to high-dose dual therapy would improve the efficacy of high-dose dual therapy as first-line treatment. Methods This was an open-label, randomized single-center study of 160 treatment-naive patients with H. pylori infection who were randomly assigned to 14-day therapy with esomeprazole 40 mg twice a day plus amoxicillin 1 g three times a day with or without bismuth potassium citrate 600 mg (elemental bismuth 220 mg) twice a day. Antibiotic resistance was determined by agar dilution method and eradication by 13 C-urea breath test. Results The per-protocol eradication rates were 96.1%; 95% CI = 88.9%-99.2% (73/76) without bismuth vs 93.3%; 95% CI = 85.1%-97.8% (70/75) with bismuth (P = 0.494). The intention-to-treat eradication rates were 92.5%; 95% CI = 84.4%-97.2% (74/80) without bismuth and 88.8%; 95% CI = 79.7%-94.7% (71/80) with bismuth (P = 0.416). Resistance to amoxicillin, clarithromycin, metronidazole, and levofloxacin was 0%, 31.7%, 81.4%, and 40.7%, respectively. Smoking reduced treatment effectiveness limited to those not receiving bismuth. The per-protocol eradication rates were 70% (7/10) vs 100% (66/66) in smokers vs non-smokers without bismuth (P = 0.002), and 100% (10/10) in smokers vs 92.3% (60/65) in non-smokers with bismuth (P = 1.0). The adverse event rates were 7.5% (6/80) without bismuth vs 11.3% (9/80) with bismuth (P = 0.416). Conclusions Fourteen-day high-dose dual therapy was both effective and safe for first-line treatment in a region of high prevalence antibiotic resistance. Adding bismuth only improved treatment effectiveness among smokers.

Background Increasing Helicobacter pylori resistance has led to decreases in treatment effectiveness. Aim To test the effectiveness of susceptibility-guided therapy vs a locally highly effective empiric modified bismuth quadruple therapy for first-line H pylori treatment in a region with high antimicrobial resistance. Methods We compared 14-day susceptibility-guided with empiric therapy using a multicentre superiority-design trial, which randomised H pylori infected subjects 3:1 to (a) susceptibility-guided therapies contained esomeprazole 20 mg and amoxicillin 1 g b.d. plus clarithromycin 500 mg, metronidazole 400 mg b.d., or levofloxacin 500 mg daily for susceptible infections or bismuth 220 mg b.d. and metronidazole 400 mg q.d.s. for triple-resistant infections; (b) Empiric therapy contained esomeprazole 20 mg, bismuth 220 mg b.d., amoxicillin 1 g and metronidazole 400 mg t.d.s. Primary outcome was H pylori eradication. Results Between February 2017 and March 2018, 491 subjects were screened and 382 were randomised. Both the susceptibility-guided and the empiric regimens were highly successful with per-protocol eradication rates of 97.7% (250/256) vs 97.6% (81/83, P = 1.00) and intent-to-treat eradication rates of 91.6% (262/286) vs 85.4% (82/96, P = 0.12). Overall, susceptibility-guided therapy was not superior to empiric therapy with 0.1% per-protocol (95% CI -3.1% to 3.2%) and 6.2% intent-to-treat (-0.3% to 12.7%) eradication difference. Both approaches had high adherence and low adverse event rates. Conclusions Both susceptibility-guided and empiric therapies provided excellent eradication rates. Clinically, the choice would hinge on availability of susceptibility testing and/or a locally highly effective empiric therapy.

Background A reliably highly effective high-dose proton-pump inhibitor plus amoxicillin (dual Helicobacter pylori therapy) has remained elusive. We compared whether the addition of bismuth to high-dose dual therapy would improve the efficacy of high-dose dual therapy as first-line treatment. Methods This was an open-label, randomized single-center study of 160 treatment-naive patients with H. pylori infection who were randomly assigned to 14-day therapy with esomeprazole 40 mg twice a day plus amoxicillin 1 g three times a day with or without bismuth potassium citrate 600 mg (elemental bismuth 220 mg) twice a day. Antibiotic resistance was determined by agar dilution method and eradication by 13 C-urea breath test. Results The per-protocol eradication rates were 96.1%; 95% CI = 88.9%-99.2% (73/76) without bismuth vs 93.3%; 95% CI = 85.1%-97.8% (70/75) with bismuth (P = 0.494). The intention-to-treat eradication rates were 92.5%; 95% CI = 84.4%-97.2% (74/80) without bismuth and 88.8%; 95% CI = 79.7%-94.7% (71/80) with bismuth (P = 0.416). Resistance to amoxicillin, clarithromycin, metronidazole, and levofloxacin was 0%, 31.7%, 81.4%, and 40.7%, respectively. Smoking reduced treatment effectiveness limited to those not receiving bismuth. The per-protocol eradication rates were 70% (7/10) vs 100% (66/66) in smokers vs non-smokers without bismuth (P = 0.002), and 100% (10/10) in smokers vs 92.3% (60/65) in non-smokers with bismuth (P = 1.0). The adverse event rates were 7.5% (6/80) without bismuth vs 11.3% (9/80) with bismuth (P = 0.416). Conclusions Fourteen-day high-dose dual therapy was both effective and safe for first-line treatment in a region of high prevalence antibiotic resistance. Adding bismuth only improved treatment effectiveness among smokers.

Background The high prevalence of Helicobacter pylori (H pylori) infection in China results in a substantial public health burden. Medical experts have not agreed on the best solution of population intervention for this problem. We presented a health economic evaluation of a population-based H pylori screen-and-treat strategy for preventing gastric cancer, peptic ulcer disease (PUD), and nonulcer dyspepsia (NUD). Materials and methods Decision trees and Markov models were developed to evaluate the cost-effectiveness of H pylori screening followed by eradication treatment in asymptomatic Chinese. The modeled screen-and-treat strategy reduced the risk of gastric cancer, PUD, and NUD. The main outcomes were the costs, effectiveness, and the incremental cost-effectiveness ratio. Uncertainty was explored by one-way and probabilistic sensitivity analyses. Results For preventing gastric cancer, PUD, and NUD together in a cohort of 10 million asymptomatic Chinese at the age of 20 years, the H pylori screen-and-treat strategy saved 288.1 million dollars, 28 989 life years, and 111 663 quality-adjusted life years, and prevented 11 611 gastric cancers, 5422 deaths from gastric cancer, and 1854 deaths from PUD during life expectancy. Uncertainty of screening age from 20 to 60 did not affect the superiority of the screen-and-treat strategy over the no-screen strategy. The one-way and probabilistic sensitivity analyses confirmed the robustness of our study's results. Conclusions Compared with the no-screen strategy, population-based screen-and-treat strategy for H pylori infection proved cheaper and more effective for preventing gastric cancer, PUD, and NUD in Chinese asymptomatic general population.

Background Helicobacter pylori (H. pylori) eradication has become increasingly difficult especially for penicillin allergy patients. Aims To evaluate the efficacy of adding bismuth or high-dose metronidazole to an H. pylori eradication regimen containing a proton-pump inhibitor, clarithromycin, and metronidazole in patients allergic to penicillin. Methods Pilot study in which penicillin-allergic, treatment-naive subjects were randomized (1:1) to 14-day esomeprazole (20 mg q12h), clarithromycin (500 mg q12h), and high dose of metronidazole (400 mg q6h) with (BECM group) or without (ECM group) bismuth (600 mg q12h). Eradication was confirmed by 13 C-urea breath test 6 weeks after therapy. Antimicrobial susceptibility was assessed by the agar dilution method. Adverse events were recorded. Results Sixty-six subjects were randomized, four were lost to follow-up and eight violated the protocol. The eradication rates were 63.6% (95% CI: 47.2%-80.0%) for ECM vs 84.8% (95% CI 72.6%-97.1%) (p = .049) for BECM by intention-to-treat, 67.7% (95% CI 51.3%-84.2%) vs 90.3% (95% CI 79.9%-100%) (p = .029) by modified ITT, and 70% (95% CI 53.6%-86.4%) vs 96% (95% CI 88.3%-100%) (P = .033) by per-protocol. Metronidazole, clarithromycin, and dual-resistant rates were 74.2%, 24.2%, and 18.2%, respectively. The cure rates were significantly improved by the addition of bismuth for both clarithromycin-resistant isolates (100% vs 25%, P = .024) and metronidazole-resistant isolates (94.7% vs 63.6%, P = .043). Adverse events were reported by 45.5% of subjects in ECM group and 48.5% in the BECM group (P = .805). Conclusions This prospective trial demonstrated that while high-dose metronidazole could not completely overcome metronidazole resistance, bismuth was additive and improved the overall cure rates by 21%-26%.

This first-time-in-human, randomized, double-blind, placebo-controlled, dose-escalation study assessed the safety, tolerability, pharmacokinetics, and antiviral activity of GSK2485852, a hepatitis C virus (HCV) NS5B inhibitor, in 27 chronically infected HCV genotype-1 subjects. Subjects received GSK2485852 70, 420, and 70 mg with a moderate fat/caloric meal. Safety, pharmacokinetics, antiviral activity, HCV genotype/phenotype, and interleukin 28B genotype were evaluated. A statistically significant reduction in HCV ribonucleic acid (RNA) was observed after a single dose of 420 mg GSK2485852 (−1.33 log10 IU/mL) compared with placebo (−0.09 log10 IU/mL) at 24 hours post-dose. Subjects receiving 70 mg GSK2485852 were exposed to concentrations above the protein-adjusted 90% effective concentration for a short time; none experienced a significant decline in HCV RNA (−0.47 log10 copies/mL). GSK2485852 was readily absorbed; however, the observed geometric mean maximum plasma concentration (Cmax) and area under the curve (AUC) values were significantly lower than expected due to a higher-than-predicted-oral clearance. Co-administration with food reduced the AUC and Cmax of GSK2485852 by 40% and 70%, respectively. Two metabolites were detected in human blood with one having approximately 50% higher concentrations than those of the parent. GSK2485852 was well-tolerated and exhibited antiviral activity after a single 420 mg dose in HCV subjects.

Background: Empirical therapy of Helicobacter pylori frequently results in treatment failure due to unrecognized antimicrobial resistance. The aim of this study was to investigate the effectiveness of susceptibility-guided therapy for rescue treatment of H. pylori infection in China. Methods: This was a prospective study of consecutive 200 patients infected with H. pylori with one or more treatment failures. The therapy chosen was susceptibility based using the most effective, best-tolerated regimens first and a locally proven, reliably effective regimen for multidrug-resistant infections. All patients received 14-day triple therapy, i.e. esomeprazole 20 mg and amoxicillin 1 g twice a day plus clarithromycin 500 mg twice a day, metronidazole 400 mg twice a day, or levofloxacin 500 mg daily, or, for multidrug-resistant infections, amoxicillin-containing bismuth quadruple therapy with esomeprazole 20 mg twice a day, bismuth 220 mg twice a day, amoxicillin 1 g three times a day, and metronidazole 400 mg four times a day. Antibiotic resistance was determined by agar dilution. Results: The eradication rate of susceptibility-guided therapy overall was 94.5% (189/200, 95% confidence interval: 90.4–97.2%). Around 28% (56/200) of patients carried strains susceptible to one of the tested antibiotics and were prescribed the triple therapy. A total of 144 multidrug-resistant patients received bismuth quadruple therapy. The eradication rates were all greater than 90%, i.e. 91.7% (11/12), 92.3% (12/13), and 93.5% (29/31) in those who received clarithromycin, metronidazole, and levofloxacin-containing triple therapy and 95.1% (137/144) for the bismuth quadruple therapy. There were no differences in eradication rates between the subgroups. Conclusions: Although susceptibility-guided therapy proved high efficacious despite the high proportion of multidrug-resistant strains, the strategy suggested the best approach for this population would be empirical amoxicillin-containing bismuth quadruple therapy. ClinicalTrials.gov identifier: NCT03413020.

Signcryption, which was introduced by ZHENG, is a cryptographic primitive that fulfils the functions of both digital signature and encryption and guarantees confidentiality, integrity and non-repudiation in a more efficient way. Certificateless signcryption and proxy signcryption in identity-based cryptography were proposed for different applications. Most of these schemes are constructed by bilinear pairings from elliptic curves. However, some schemes were recently presented without pairings. In this paper, we present a certificateless proxy identity-based signcryption scheme without bilinear pairings, which is efficient and secure.

Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-alpha 1/beta 1 and the components of the LL5 beta-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.

The vesicle-associated membrane protein (VAMP) associated protein B (VAPB) is an integral membrane protein localized to the endoplasmic reticulum (ER). The P56S mutation in VAPB has been linked to motor neuron degeneration in amyotrophic lateral sclerosis type 8 (ALS8) and forms ER-like inclusions in various model systems. However, the role of wild-type and mutant VAPB in neurons is poorly understood. Here, we identified Yip1-interacting factor homologue A (YIF1A) as a new VAPB binding partner and important component in the early secretory pathway. YIF1A interacts with VAPB via its transmembrane regions, recycles between the ER and Golgi and is mainly localized to the ER-Golgi intermediate compartments (ERGICs) in rat hippocampal neurons. VAPB strongly affects the distribution of YIF1A and is required for intracellular membrane trafficking into dendrites and normal dendritic morphology. When VAPB-P56S is present, YIF1A is recruited to the VAPB-P56S clusters and loses its ERGIC localization. These data suggest that both VAPB and YIF1A are important for ER-to-Golgi transport and that missorting of YIF1A may contribute to VAPB-associated motor neuron disease.

How stem cells maintain their identity and potency as tissues change during growth is not well understood. In mammalian hair, it is unclear how hair follicle stem cells can enter an extended period of quiescence during the resting phase but retain stem cell potential and be subsequently activated for growth. Here, we use lineage tracing and gene expression mapping to show that the Wnt target gene Axin2 is constantly expressed throughout the hair cycle quiescent phase in outer bulge stem cells that produce their own Wnt signals. Ablating Wnt signaling in the bulge cells causes them to lose their stem cell potency to contribute to hair growth and undergo premature differentiation instead. Bulge cells express secreted Wnt inhibitors, including Dickkopf (Dkk) and secreted frizzled-related protein 1 (Sfrp1). However, the Dickkopf 3 (Dkk3) protein becomes localized to the Wnt-inactive inner bulge that contains differentiated cells. We find that Axin2 expression remains confined to the outer bulge, whereas Dkk3 continues to be localized to the inner bulge during the hair cycle growth phase. Our data suggest that autocrine Wnt signaling in the outer bulge maintains stem cell potency throughout hair cycle quiescence and growth, whereas paracrine Wnt inhibition of inner bulge cells reinforces differentiation.

As networks and the development of information technology, the traditional machinery hard in some areas has been unable to satisfy the speed and performance requirements, and appeared SSD（solid state disk）. This article describes the design of a high-performance SSD control chip,the SSD control chip intergrate internal ARM7 processor, by AHB bus to rapid implement the dma data transmission, the interface with nandflash adopted eight, which can achieve on the parallel operation and improve nandflash interface speed. With the host interface uses sata2.Firmware use of the FTL algorithms, including and of the operation of the mapping. A balanced mix of wear and tear, a bad piece of management and garbage collection, and more efficient to access to SSD, improved ssd life. That the SSD chip for reading speed 200MB/S, the maximum writing speed is 140MB/s.

Steel-concrete composite beams are composed of concrete slabs and steel girders by shear connectos. Due to the shear lag effect, the longitudinal normal stress of cross section is nonuniform distribution,and it is difficult to analyse the effect of that by ordinary beam theory. A differential equation of equilibrium is constituted corresponding to the compatibility of deformation and the equilibrium of forces about steel-concrete composite beams under particular assumed condition. The method of variable-separating is applied to solve the differential equation with the simply supported boundary condition. An example of steel-concrete composite box girder is given to analyse the effect of shear lag on its stress and approve its applicability.

To observe the effect of acupuncture on simple adiposis. 121 cases of simple adiposis were divided into 6 groups and treated with acupuncture, dietotherapy and motortherapy. Weight and waistline were observed. Acupuncture had a markedly curative effect on adiposis and 97.8% patients after the treatment did not relapse.

This first-time-in-human, randomized, double-blind, placebo-controlled, dose-escalation study assessed the safety, tolerability, pharmacokinetics, and antiviral activity of GSK2485852, a hepatitis C virus (HCV) NS5B inhibitor, in 27 chronically infected HCV genotype-1 subjects. Subjects received GSK2485852 70, 420, and 70 mg with a moderate fat/caloric meal. Safety, pharmacokinetics, antiviral activity, HCV genotype/phenotype, and interleukin 28B genotype were evaluated. A statistically significant reduction in HCV ribonucleic acid (RNA) was observed after a single dose of 420 mg GSK2485852 (-1.33 log10 IU/mL) compared with placebo (-0.09 log10 IU/mL) at 24 hours post-dose. Subjects receiving 70 mg GSK2485852 were exposed to concentrations above the protein-adjusted 90% effective concentration for a short time; none experienced a significant decline in HCV RNA (-0.47 log10 copies/mL). GSK2485852 was readily absorbed; however, the observed geometric mean maximum plasma concentration (Cmax ) and area under the curve (AUC) values were significantly lower than expected due to a higher-than-predicted-oral clearance. Co-administration with food reduced the AUC and Cmax of GSK2485852 by 40% and 70%, respectively. Two metabolites were detected in human blood with one having approximately 50% higher concentrations than those of the parent. GSK2485852 was well-tolerated and exhibited antiviral activity after a single 420 mg dose in HCV subjects.

In reference to Jupiter south polar quasi-periodic 40-50 min (QP-40) activities and the model scenario for global QP-40 oscillations of the Jovian inner radiation belt (IRB), we validate relevant predictions and confirmations by amassing empirical evidence from Ulysses, Cassini, Chandra, Galileo, XMM-Newton, and Advanced Composition Explorer for Jupiter north polar QP-40 activities. We report ground 6cm radio observations of Jupiter by Urumqi 25m telescope for synchrotron intensity bursty variations of the Jovian IRB and show their likely correlations with the recurrent arrival of high-speed solar winds at Jupiter.

Microtubule organization and dynamics are controlled by a large set of cellular factors. An important group of microtubule regulators is microtubule plus-end-tracking proteins (+TIPs), which accumulate specifically at the growing microtubule ends, affect different phases of dynamic instability, and link microtubules to various cellular structures. +TIPs include a very diverse set of proteins with widely different structural properties. One of the most conserved and ubiquitous +TIP families are end-binding (EB) proteins, which can track growing microtubule ends autonomously in the absence of any other factors. In contrast, the majority of other known +TIPs cannot recognize the growing microtubule plus ends on their own; instead, they "hitchhike" to the plus ends by interacting with one of the members of the EB family. Therefore, the association with EBs and the ability to track growing microtubule ends are tightly linked, and binding to the EBs can be used to identify new +TIPs. In this chapter, we describe two affinity purification techniques, glutathione S-transferase and biotinylation tag-based pull-down assays that proved to be very useful for the identification of new EB-interacting +TIPs and their binding partners by mass spectrometry. We also discuss cytological techniques that can be applied to confirm plus-end localization of newly identified proteins.

SummaryRab6 is a conserved small GTPase that localizes to the Golgi apparatus and cytoplasmic vesicles and controls transport and fusion of secretory carriers [1]. Another Rab implicated in trafficking from the trans-Golgi to the plasma membrane is Rab8 [2–5]. Here we show that Rab8A stably associates with exocytotic vesicles in a Rab6-dependent manner. Rab8A function is not needed for budding or motility of exocytotic carriers but is required for their docking and fusion. These processes also depend on the Rab6-interacting cortical factor ELKS [1], suggesting that Rab8A and ELKS act in the same pathway. We show that Rab8A and ELKS can be linked by MICAL3, a member of the MICAL family of flavoprotein monooxygenases [6]. Expression of a MICAL3 mutant with an inactive monooxygenase domain resulted in a strong accumulation of secretory vesicles that were docked at the cell cortex but failed to fuse with the plasma membrane, an effect that correlated with the strongly reduced mobility of MICAL3. We propose that the monooxygenase activity of MICAL3 is required to regulate its own turnover and the concomitant remodeling of vesicle-docking protein complexes in which it is engaged. Taken together, the results of our study illustrate cooperation of two Rab proteins in constitutive exocytosis and implicates a redox enzyme in this process.

Microtubule organization and dynamics are controlled by a large set of cellular factors. An important group of microtubule regulators is microtubule plus-end-tracking proteins (+TIPs), which accumulate specifically at the growing microtubule ends, affect different phases of dynamic instability, and link microtubules to various cellular structures. +TIPs include a very diverse set of proteins with widely different structural properties. One of the most conserved and ubiquitous +TIP families are end-binding (EB) proteins, which can track growing microtubule ends autonomously in the absence of any other factors. In contrast, the majority of other known +TIPs cannot recognize the growing microtubule plus ends on their own; instead, they "hitchhike" to the plus ends by interacting with one of the members of the EB family. Therefore, the association with EBs and the ability to track growing microtubule ends are tightly linked, and binding to the EBs can be used to identify new +TIPs. In this chapter, we describe two affinity purification techniques, glutathione S-transferase and biotinylation tag-based pull-down assays that proved to be very useful for the identification of new EB-interacting +TIPs and their binding partners by mass spectrometry. We also discuss cytological techniques that can be applied to confirm plus-end localization of newly identified proteins.

A spherically symmetric hydrodynamic stellar core collapse under gravity is time-dependent and may become unstable once disturbed. Specifically for a homologously collapse of stellar core characterized by a polytropic exponent \Gamma=4/3, we examine oscillations and/or instabilities of three dimensional (3D) general polytropic perturbations. For compressible 3D perturbations, the polytropic index \gamma of perturbations can differ from \Gamma=4/3 of the general polytropic hydrodynamic background flow. Our model formulation here is more general and allows the existence of internal gravity g(-)-modes and/or g(+)-modes. Eigenvalues and eigen-functions of various oscillatory and unstable perturbation modes are computed. As studied in several specialized cases of Goldreich & Weber and of Cao & Lou, we further confirm that acoustic p-modes and surface f-modes remain stable in the current more general situations. In comparison, g(-)-modes and sufficiently high radial order g(+)-modes are unstable, leading to inevitable convective motions within the collapsing stellar interior. Unstable growths of 3D g-mode disturbances are governed dominantly by the angular momentum conservation and modified by the gas pressure restoring force. We note in particular that unstable temporal growths of 3D vortical perturbations exist even when the specific entropy distribution becomes uniform and \gamma=\Gamma=4/3. Conceptually, unstable g-modes might bear conceivable physical consequences on supernova explosions, the initial kicks of nascent proto-neutron stars (PNSs) and break-ups of the collapsing core, while unstable growths of vortical perturbations can lead to fast spins of compact objects and other relevant results., Comment: 16 pages, MNRAS(to be published)

For dynamic background models of Goldreich & Weber and Lou & Cao, we examine 3-dimensional perturbation properties of oscillations and instabilities in a general polytropic homologously collapsing stellar core of a relativistic hot medium with a polytropic index of 4/3. We identify acoustic p-modes and surface f-modes as well as internal gravity g$^{+}-$ and g$^{-}-$modes. We demonstrate that the global energy criterion of Chandrasehkar is insufficient to warrant the stability of general polytropic equilibria. We confirm the acoustic p-mode stability of Goldreich & Weber, even though their p-mode eigenvalues appear in systematic errors. Unstable modes include g$^{-}-$modes and high-order g$^{+}-$modes. Such instabilities occur before the stellar core bounce, in contrast to instabilities in other models of supernova explosions. The breakdown of spherical symmetry happens earlier than expected in numerical simulations so far. The formation and motion of the central compact object are speculated to be much affected by such g-mode instabilities. By estimates of typical parameters, unstable low-order l=1 g-modes may produce initial kicks of the central compact object.

We propose self-similar shocked flow models for certain dynamical evolution phases of young stellar objects (YSOs), `champagne flows' of H {\sevenrm II} regions surrounding OB stars and shaping processes of planetary nebulae (PNe). We analyze an isothermal fluid of spherical symmetry and construct families of similarity shocked flow solutions featured by: 1. either a core expansion with a finite central density or a core accretion at constant rate with a density scaling $\propto r^{-3/2}$; 2. a shock moving outward at a constant speed; 3. a preshock gas approaching a constant speed at large $r$ with a density scaling $\propto r^{-2}$. In addition to testing numerical codes, our models can accommodate diverse shocked flows with or without a core collapse or outflow and an envelope expansion or contraction. As an application, we introduce our model analysis to observations of Bok globule B335., Comment: ApJL accepted