European Registry on Helicobacter pylori management: Single-capsule bismuth quadruple therapy is effective in real-world clinical practice.

BACKGROUND: There has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three-in-one single-capsule formulation. OBJECTIVE: To evaluate the effectiveness and safety of the single-capsule bismuth quadruple therapy. METHODS: Data were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention-to-treat and per-protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line. RESULTS: Finally, 2100 patients were prescribed single-capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention-to-treat effectiveness of 92% was achieved. Eradication was over 90% in first-line treatment (95% modified intention-to-treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention-to-treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention-to-treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases. CONCLUSIONS: Single-capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real-world clinical practice, both as a first-line and rescue treatment, with good compliance and a favourable safety profile.

Heterozygous mutations cause genetic instability in a yeast model of cancer evolution.

Genetic instability, a heritable increase in the rate of genetic mutation, accelerates evolutionary adaptation1 and is widespread in cancer2,3. In mammals, instability can arise from damage to both copies of genes involved in DNA metabolism and cell cycle regulation4 or from inactivation of one copy of a gene whose product is present in limiting amounts (haploinsufficiency5); however, it has proved difficult to determine the relative importance of these two mechanisms. In Escherichia coli6, the application of repeated, strong selection enriches for genetic instability. Here we have used this approach to evolve genetic instability in diploid cells of the budding yeast Saccharomyces cerevisiae, and have isolated clones with increased rates of point mutation, mitotic recombination, and chromosome loss. We identified candidate, heterozygous, instability-causing mutations; engineering these mutations, as heterozygotes, into the ancestral diploid strain caused genetic instability. Mutations that inactivated one copy of haploinsufficient genes were more common than those that dominantly altered the function of the mutated gene copy. The mutated genes were enriched for genes functioning in transport, protein quality control, and DNA metabolism, and have revealed new targets for genetic instability7-11, including essential genes. Although only a minority (10 out of 57 genes with orthologues or close homologues) of the targets we identified have homologous human genes that have been implicated in cancer2, the remainder are candidates to contribute to human genetic instability. To test this hypothesis, we inactivated six examples in a near-haploid human cell line; five of these mutations increased instability. We conclude that single genetic events cause genetic instability in diploid yeast cells, and propose that similar, heterozygous mutations in mammalian homologues initiate genetic instability in cancer.

Recurrent orthodeoxia and patent foramen ovale.

BACKGROUND: Patent foramen ovale (PFO) occurs in 25% of healthy adults. It can lead to paradoxical embolization, migraine and respiratory failure (RF). The authors present a case of RF and orthodeoxia due to a right-to-left shunt via a PFO without previous elevation of right atrial pressure. Closure of the PFO effectively resolved the RF. CASE REPORT: A 52-year-old man, with IgA-k multiple myeloma diagnosed one year before, was admitted for severe hypoxemic RF, with orthodeoxia and poor response to oxygen supplementation, after placement of a central venous catheter (CVC) in the right subclavian vein. The patient reported paresthesia and nonspecific visual changes after manipulation of the CVC. The RF suggested a shunt between the pulmonary and systemic circulations. There was no clinical or radiological evidence of an intrapulmonary shunt. Contrast echocardiography showed a right-to-left shunt and transesophageal echocardiography revealed a PFO. Cardiac catheterization, after spontaneous resolution of the RF, showed no shunt. A week later, severe RF recurred. Complete resolution of respiratory dysfunction and neurological symptoms was seen after PFO closure. DISCUSSION: RF due to an intracardiac shunt without increased right-sided pressure is hemodynamically difficult to interpret. A few reports (in adults) relate this entity to anatomical anomalies, which can lead to a shunt by directing blood flow preferentially to the PFO. Examples include right diaphragmatic paresis and ectasia of the ascending aorta, which were observed in this patient. The role of the CVC, which was placed immediately before the RF, is uncertain. Complete therapeutic success after closure of the PFO supports the diagnosis. CONCLUSION: Correct evaluation of RF (by investigating orthodeoxia and response to oxygen therapy) enables the suspicion of a shunt, which can be confirmed through simple, safe and cost-effective exams. Intracardiac shunt without increased right-sided pressure should be considered because it can be successfully treatment.