Comparison of lansoprazole-based triple and dual therapy for treatment of Helicobacter pylori-related duodenal ulcer: An Asian multicentre double-blind randomized placebo controlled study

Background: In Asian countries with limited resources, clarithromycin-based triple therapy may not be readily available. There are also few direct comparisons of different regimens in Asia. Aim: To compare two lansoprazole-based non-clarithromycin triple therapies and one dual therapy in a prospective double-blind placebo-controlled study of Helicobacter pylori eradication and duodenal ulcer healing. Methods: Fourteen centres in Asia participated in this study. Patients with acute duodenal ulcer who were H. pylori-positive were recruited. They were randomized to receive: (a) lansoprazole 30 mg b.d., amoxycillin 1 g b.d. and metronidazole 500 mg b.d. for 2 weeks (LAM-2 W), or (b) LAM for 1 week and placebo (LAM-1 W), or (c) lansoprazole 30 mg b.d., amoxycillin 1 g b.d. and placebo for 2 weeks (LA-2 W). Upper endoscopy was repeated at week 6 to check for duodenal ulcer healing. Symptoms and side-effects were recorded. Results: A total of 228 patients were recruited, and two patients took less than 50% of the drugs. H. pylori eradication rates (intention-to-treat) were 68 out of 82 (83%) with LAM-2 W, 55 out of 71 (78%) with LAM-1 W and 43 out of 75 (57%) with LA-2 W. There were significant differences (P = 0.001) in eradication rates when comparing either LAM-2 W or LAM-1 W with LA-2 W. The eradication rate in patients with metronidazole resistant H. pylori strains were significantly lower than those with metronidazole sensitive strains (P = 0.0001). The duodenal ulcer healing rates at week 6 were 85%, 85% and 72% in LAM-2 W, LAM-1 W and LA-2 W, respectively (P = 0.065). Side-effects occurred in 13%, 11% and 9% in LAM-2 W, LAM-1 W and LA-2 W, respectively. H. pylori eradication and initial ulcer size were factors affecting duodenal ulcer healing. Conclusions: This Asian multicentre study showed that 1-week lansoprazole-based triple therapy without clarithromycin has similar efficacy in H. pylori eradication and ulcer healing compared with a 2-week regimen. Both triple therapies were significantly better than dual therapy in H. pylori eradication. Therefore, 1-week lansoprazole-based triple therapy is as safe and effective as 2-week therapy in eradication of a pylori infection and healing of duodenal ulcer in these Asian centres.postprin

Structure of Human DNA Polymerase κ Inserting dATP Opposite an 8-OxoG DNA Lesion

Background: Oxygen-free radicals formed during normal aerobic cellular metabolism attack bases in DNA and 7,8-dihydro-8-oxoguanine (8-oxoG) is one of the major lesions formed. It is amongst the most mutagenic lesions in cells because of its dual coding potential, wherein 8-oxoG(syn) can pair with an A in addition to normal base pairing of 8-oxoG(anti) with a C. Human DNA polymerase κ (Polκ) is a member of the newly discovered Y-family of DNA polymerases that possess the ability to replicate through DNA lesions. To understand the basis of Polκ\u27s preference for insertion of an A opposite 8-oxoG lesion, we have solved the structure of Polκ in ternary complex with a template-primer presenting 8-oxoG in the active site and with dATP as the incoming nucleotide. Methodology and Principal Findings: We show that the Polκ active site is well-adapted to accommodate 8-oxoG in the syn conformation. That is, the polymerase and the bound template-primer are almost identical in their conformations to that in the ternary complex with undamaged DNA. There is no steric hindrance to accommodating 8-oxoG in the syn conformation for Hoogsteen base-paring with incoming dATP. Conclusions and Significance: The structure we present here is the first for a eukaryotic translesion synthesis (TLS) DNA polymerase with an 8-oxoG:A base pair in the active site. The structure shows why Polκ is more efficient at inserting an A opposite the 8-oxoG lesion than a C. The structure also provides a basis for why Polκ is more efficient at inserting an A opposite the lesion than other Y-family DNA polymerases

A Field Trial of Alternative Targeted Screening Strategies for Chagas Disease in Arequipa, Peru

In the wake of emerging T. cruzi infection in children of periurban Arequipa, Peru, we conducted a prospective field trial to evaluate alternative targeted screening strategies for Chagas disease across the city. Using insect vector data that is routinely collected during Ministry of Health insecticide application campaigns in 3 periurban districts of Arequipa, we separated into 4 categories those households with 1) infected vectors; 2) high vector densities; 3) low vector densities; and 4) no vectors. Residents of all infected-vector households and a random sample of those in the other 3 categories were invited for serological screening for T. cruzi infection. Subsequently, all residents of households within a 15-meter radius of detected seropositive individuals were invited to be screened in a ring case-detection scheme. Of 923 participants, 21 (2.28%) were seropositive. There were no significant differences in prevalence across the 4 screening strategies, indicating that household entomologic factors alone could not predict the risk of infection. Indeed, the most predictive variable of infection was the number of years a person lived in a location with triatomine insects. Therefore, a simple residence history questionnaire may be a useful screening tool in large, diverse urban environments with emerging Chagas disease

A phase 1/2, open-label, multicenter study of isatuximab in combination with cemiplimab in patients with lymphoma

Patients with relapsed or refractory lymphoma have limited treatment options, requiring newer regimens. In this Phase 1/2 study (NCT03769181), we assessed the safety, efficacy, and pharmacokinetics of isatuximab (Isa, anti-CD38 antibody) in combination with cemiplimab (Cemi, anti-programmed death-1 [PD-1] receptor antibody; Isa + Cemi) in patients with classic Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL), and peripheral T-cell lymphoma (PTCL). In Phase 1, we characterized the safety and tolerability of Isa + Cemi with planned dose de-escalation to determine the recommended Phase 2 dose (RP2D). Six patients in each cohort were treated with a starting dose of Isa + Cemi to determine the RP2D. In Phase 2, the primary endpoints were complete response in Cohort A1 (cHL anti-PD-1/programmed death-ligand 1 [PD-L1] naïve), and objective response rate in Cohorts A2 (cHL anti-PD-1/PD-L1 progressors), B (DLBCL), and C (PTCL). An interim analysis was performed when the first 18 (Cohort A1), 12 (Cohort A2), 17 (Cohort B), and 11 (Cohort C) patients in Phase 2 had been treated and followed up for 24 weeks. Isa + Cemi demonstrated a manageable safety profile with no new safety signals. No dose-limiting toxicities were observed at the starting dose; thus, the starting dose of each drug was confirmed as the RP2D. Based on the Lugano 2014 criteria, 55.6% (Cohort A1), 33.3% (Cohort A2), 5.9% (Cohort B), and 9.1% (Cohort C) of patients achieved a complete or partial response. Pharmacokinetic analyses suggested no effect of Cemi on Isa exposure. Modest clinical efficacy was observed in patients with cHL regardless of prior anti-PD-1/PD-L1 exposure. In DLBCL or PTCL cohorts, interim efficacy analysis results did not meet prespecified criteria to continue enrollment in Phase 2 Stage 2. Isa + Cemi did not have a synergistic effect in these patient populations

A History of Chagas Disease Transmission, Control, and Re-Emergence in Peri-Rural La Joya, Peru

The historically rural problem of Chagas disease is increasing in urban areas in Latin America. Peri-rural development may play a critical role in the urbanization of Chagas disease and other parasitic infections. We conducted a cross-sectional study in an urbanizing rural area in southern Peru, and we encountered a complex history of Chagas disease in this peri-rural environment. Specifically, we discovered: (1) long-standing parasite transmission leading to substantial burden of infection; (2) interruption in parasite transmission resulting from an undocumented insecticide application campaign; (3) relatively rapid re-emergence of parasite-infected vector insects resulting from an unsustained control campaign; (4) extensive migration among peri-rural inhabitants. Long-standing parasite infection in peri-rural areas with highly mobile populations provides a plausible mechanism for the expansion of parasite transmission to nearby urban centers. Lack of commitment to control campaigns in peri-rural areas may have unforeseen and undesired consequences for nearby urban centers. Novel methods and perspectives are needed to address the complexities of human migration and erratic interventions

A nucleotide binding rectification Brownian ratchet model for translocation of Y-family DNA polymerases

Y-family DNA polymerases are characterized by low-fidelity synthesis on undamaged DNA and ability to catalyze translesion synthesis over the damaged DNA. Their translocation along the DNA template is an important event during processive DNA synthesis. In this work we present a Brownian ratchet model for this translocation, where the directed translocation is rectified by the nucleotide binding to the polymerase. Using the model, different features of the available structures for Dpo4, Dbh and polymerase ι in binary and ternary forms can be easily explained. Other dynamic properties of the Y-family polymerases such as the fast translocation event upon dNTP binding for Dpo4 and the considerable variations of the processivity among the polymerases can also be well explained by using the model. In addition, some predicted results of the DNA synthesis rate versus the external force acting on Dpo4 and Dbh polymerases are presented. Moreover, we compare the effect of the external force on the DNA synthesis rate of the Y-family polymerase with that of the replicative DNA polymerase

An Active Site Aromatic Triad in Escherichia coli DNA Pol IV Coordinates Cell Survival and Mutagenesis in Different DNA Damaging Agents

DinB (DNA Pol IV) is a translesion (TLS) DNA polymerase, which inserts a nucleotide opposite an otherwise replication-stalling N2-dG lesion in vitro, and confers resistance to nitrofurazone (NFZ), a compound that forms these lesions in vivo. DinB is also known to be part of the cellular response to alkylation DNA damage. Yet it is not known if DinB active site residues, in addition to aminoacids involved in DNA synthesis, are critical in alkylation lesion bypass. It is also unclear which active site aminoacids, if any, might modulate DinB's bypass fidelity of distinct lesions. Here we report that along with the classical catalytic residues, an active site “aromatic triad”, namely residues F12, F13, and Y79, is critical for cell survival in the presence of the alkylating agent methyl methanesulfonate (MMS). Strains expressing dinB alleles with single point mutations in the aromatic triad survive poorly in MMS. Remarkably, these strains show fewer MMS- than NFZ-induced mutants, suggesting that the aromatic triad, in addition to its role in TLS, modulates DinB's accuracy in bypassing distinct lesions. The high bypass fidelity of prevalent alkylation lesions is evident even when the DinB active site performs error-prone NFZ-induced lesion bypass. The analyses carried out with the active site aromatic triad suggest that the DinB active site residues are poised to proficiently bypass distinctive DNA lesions, yet they are also malleable so that the accuracy of the bypass is lesion-dependent

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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