Background Endoscopic submucosal dissection (ESD) permits en bloc removal of superficial esophageal squamous cell carcinoma. However, postprocedure stricture is common after ESD for extensive tumors, ...and multiple endoscopic balloon dilation (EBD) is required for recalcitrant cases. Objective To evaluate the effectiveness of oral prednisolone in controlling postprocedure esophageal stricture. Design Retrospective study. Setting Endoscopy department at a university hospital. Patients Patients who underwent complete circular or semicircular ESD for esophageal squamous cell carcinoma involving more than three fourths of the lumen were treated with either pre-emptive EBD or oral prednisolone. Intervention Preemptive EBD was started on the third day post-ESD and continued twice weekly for 8 weeks. Oral prednisolone was started at 30 mg/day on the third day post-ESD , tapered gradually, and then discontinued 8 weeks later. An additional EBD was performed on demand in both groups whenever dysphagia appeared. Main Outcome Measurement The incidence of esophageal stricture and number of EBD sessions required to relieve dysphagia. Results Stricture at 3 months after ESD was found in 7 of 22 patients in the preemptive EBD group but only 1 of 19 in the oral prednisolone group ( P < .05). The average number of EBD sessions required was 15.6 in the preemptive EBD group and 1.7 in the oral prednisolone group ( P < .0001). After complete circular ESD, 32.7 EBD sessions were needed on average in the preemptive EBD group, whereas fewer were needed in the oral prednisolone group ( P < .05). Limitations Nonrandomized study. Conclusions Post-ESD esophageal strictures were persistent even if treated preemptively with multiple EBD sessions, but oral prednisolone may offer a useful preventive option.
The study was conducted to determine expression patterns of microRNA (miRNA), a non‐coding RNA that controls gene expression mainly through translational repression, in gastric mucosa infected with ...Helicobacter pylori. Using endoscopic biopsy specimens, miRNA expression patterns in H. pylori‐infected gastric mucosa were determined by microarray. The differentially expressed miRNAs were quantitated by real‐time reverse‐transcriptase polymerase chain reaction (RT‐PCR). An in vitro infection model was assessed to monitor the regulation of miRNAs in gastric epithelium in response to H. pylori. The comprehensive method unraveled the expression profiles; among 470 human miRNAs loaded, 55 were differentially expressed between H. pylori‐positive and ‐negative subjects. The expression levels were significantly decreased in 30 miRNAs, whereas hsa‐miRNA‐223 was the only miRNA to be overexpressed on quantitative RT‐PCR. Eight miRNAs enabled discrimination of H. pylori status with acceptable accuracy. Gastritis scores of activity and chronic inflammation according to the updated Sydney system correlated significantly with the expression levels of diverse miRNAs. Cure of the infection with an anti‐H. pylori regimen restored decreased expression in 14 of the 30 miRNAs. Expression levels of some miRNAs, including let‐7 family members, were significantly altered following infection with a virulent H. pylori strain carrying intact cag pathogenicity island including cagA but not isogenic mutants. These results provide insights into miRNA involvement in the pathogenesis of H. pylori‐associated gastritis. cagA may be involved in cellular regulation of certain miRNAs in the gastric epithelium.
Gastrointestinal colonization has been considered as the primary source of candidaemia; however, few established mouse models are available that mimic this infection route. We therefore developed a ...reproducible mouse model of invasive candidiasis initiated by fungal translocation and compared the virulence of six major pathogenic Candida species. The mice were fed a low-protein diet and then inoculated intragastrically with Candida cells. Oral antibiotics and cyclophosphamide were then administered to facilitate colonization and subsequent dissemination of Candida cells. Mice infected with Candida albicans and Candida tropicalis exhibited higher mortality than mice infected with the other four species. Among the less virulent species, stool titres of Candida glabrata and Candida parapsilosis were higher than those of Candida krusei and Candida guilliermondii. The fungal burdens of C. parapsilosis and C. krusei in the livers and kidneys were significantly greater than those of C. guilliermondii. Histopathologically, C. albicans demonstrated the highest pathogenicity to invade into gut mucosa and liver tissues causing marked necrosis. Overall, this model allowed analysis of the virulence traits of Candida strains in individual mice including colonization in the gut, penetration into intestinal mucosa, invasion into blood vessels, and the subsequent dissemination leading to lethal infections.
Abstract
Background
Pneumonia is a common, serious illness in the elderly, with a poorly characterized long-term impact on health-related quality of life (HRQoL). The Japanese Goto Epidemiology Study ...is a prospective, active, population-based surveillance study of adults with X-ray/CT scan–confirmed community-onset pneumonia, assessing the HRQoL outcome quality-adjusted life-years (QALYs). We report QALY scores and losses among a subset of participants in this study.
Methods
QALYs were derived from responses to the Japanese version of the EuroQol-5D-5L health-state classification instrument at days 0, 7, 15, 30, 90, 180, and 365 after pneumonia diagnosis from participants enrolled from June 2017 to May 2018. We used patients as their own controls, calculating comparison QALYs by extrapolating EuroQol-5D-5L scores for day −30, accounting for mortality and changes in scores with age.
Results
Of 405 participants, 85% were aged ≥65 years, 58% were male, and 69% were hospitalized for clinically and radiologically confirmed pneumonia. Compliance with interviews by patients or proxies was 100%. Adjusted EuroQol-5D-5L scores were 0.759, 0.561, 0.702, and 0.689 at days −30, 0 (diagnosis), 180, and 365, respectively. Average scores at all time points remained below the average day −30 scores (P ≤ .001). Pneumonia resulted in a 1-year adjusted loss of 0.13 QALYs (~47.5 quality-adjusted days) (P < .001).
Conclusions
Substantial QALY losses were observed among Japanese adults following pneumonia diagnosis, and scores had not returned to prediagnosis levels at 1 year postdiagnosis. QALY scores and cumulative losses were comparable to those in US adults with chronic heart failure, stroke, or renal failure.
This prospective study evaluated quality-adjusted life-year (QALY) scores and losses due to pneumonia among adults in Japan. The average 1-year QALY loss was 0.13 (P < .001), which is larger than many evaluations of pneumonia-prevention programs assume.
Abstract
Background
Empiric therapy of pneumonia is currently based on the site of acquisition (community or hospital), but could be chosen, based on risk factors for multidrug-resistant (MDR) ...pathogens, independent of site of acquisition.
Methods
We prospectively applied a therapeutic algorithm based on MDR risks, in a multicenter cohort study of 1089 patients with 656 community-acquired pneumonia (CAP), 238 healthcare-associated pneumonia (HCAP), 140 hospital-acquired pneumonia (HAP), or 55 ventilator-associated pneumonia (VAP).
Results
Approximately 83% of patients were treated according to the algorithm, with 4.3% receiving inappropriate therapy. The frequency of MDR pathogens varied, respectively, with VAP (50.9%), HAP (27.9%), HCAP (10.9%), and CAP (5.2%). Those with ≥2 MDR risks had MDR pathogens more often than those with 0–1 MDR risk (25.8% vs 5.3%, P < .001). The 30-day mortality rates were as follows: VAP (18.2%), HAP (13.6%), HCAP (6.7%), and CAP (4.7%), and were lower in patients with 0–1 MDR risks than in those with ≥2 MDR risks (4.5% vs 12.5%, P < .001). In multivariate logistic regression analysis, 5 risk factors (advanced age, hematocrit <30%, malnutrition, dehydration, and chronic liver disease), as well as hypotension and inappropriate therapy were significantly correlated with 30-day mortality, whereas the classification of pneumonia type (VAP, HAP, HCAP, CAP) was not.
Conclusions
Individual MDR risk factors can be used in a unified algorithm to guide and simplify empiric therapy for all pneumonia patients, and were more important than the classification of site of pneumonia acquisition in determining 30-day mortality.
Clinical Trials Registration
JMA-IIA00146.
We applied a single algorithm to all forms of pneumonia, which was followed in 82.5% of a cohort of 1089 patients. Only 4.3% received inappropriate therapy; in multivariate analysis, site of pneumonia acquisition was not predictive of 30-day mortality.
Proper protein folding in the endoplasmic reticulum (ER) is vital in all eukaryotes. When misfolded proteins accumulate in the ER lumen, the transmembrane kinase/endoribonuclease Ire1 initiates ...splicing of HAC1 mRNA to generate the bZIP transcription factor Hac1, which subsequently activates its target genes to increase the protein-folding capacity of the ER. This cellular machinery, called the unfolded protein response (UPR), is believed to be an evolutionarily conserved mechanism in eukaryotes. In this study, we comprehensively characterized mutant phenotypes of IRE1 and other related genes in the human fungal pathogen Candida glabrata. Unexpectedly, Ire1 was required for the ER stress response independently of Hac1 in this fungus. C. glabrata Ire1 did not cleave mRNAs encoding Hac1 and other bZIP transcription factors identified in the C. glabrata genome. Microarray analysis revealed that the transcriptional response to ER stress is not mediated by Ire1, but instead is dependent largely on calcineurin signaling and partially on the Slt2 MAPK pathway. The loss of Ire1 alone did not confer increased antifungal susceptibility in C. glabrata contrary to UPR-defective mutants in other fungi. Taken together, our results suggest that the canonical Ire1-Hac1 UPR is not conserved in C. glabrata. It is known in metazoans that active Ire1 nonspecifically cleaves and degrades a subset of ER-localized mRNAs to reduce the ER load. Intriguingly, this cellular response could occur in an Ire1 nuclease-dependent fashion in C. glabrata. We also uncovered the attenuated virulence of the C. glabrata Δire1 mutant in a mouse model of disseminated candidiasis. This study has unveiled the unique evolution of ER stress response mechanisms in C. glabrata.
The objective of this open-label, randomised (i.e. 2:1 ratio), Phase 3 study was to compare the efficacy and safety of tedizolid phosphate 200 mg, once-daily treatment with that of linezolid 600 mg, ...twice-daily treatment for 7–14 days in Japanese adult patients (N = 125) with skin and soft tissue infections (SSTIs) and/or for 7–21 days for those with SSTI-related bacteraemia, caused by confirmed or highly suspected methicillin-resistant Staphylococcus aureus (MRSA).
Primary outcome was clinical cure rate at test-of-cure (TOC, in SSTI: 7–14 days, in bacteraemia: 4–6 weeks after end-of-therapy EOT) time point in the microbiologically evaluable MRSA (ME-MRSA) population (N = 39). Secondary endpoints were clinical and microbiological response rates at EOT. Safety parameters were evaluated in the safety analysis population up to follow up. Data analysis was descriptive in nature.
Baseline characteristics of patients were similar between treatment groups. At TOC in the ME-MRSA population, clinical cure rate was similar in tedizolid phosphate (92.6%) and linezolid (88.9%) groups. At EOT, clinical cure (tedizolid phosphate: 93.1%, linezolid: 90.0%) and microbiological success (tedizolid phosphate: 93.1%, linezolid: 100.0%) rates were similar in the ME-MRSA population.
Both treatments were well tolerated; overall treatment-emergent adverse events (TEAEs) in tedizolid phosphate (79.5%) and linezolid (75.6%) treatment groups were similar. Drug-related TEAEs were numerically lower with tedizolid phosphate versus linezolid (30.1%; 39.0%, respectively), as well as gastrointestinal (21.7%; 26.8%) and myelosuppression-related (2.4%; 22.0%) TEAEs. One death occurred in the linezolid group.
Tedizolid phosphate may be an appropriate antibiotic for the treatment of SSTIs in Japanese adult patients.
International clinical trial registration number: NCT01967225.
Japanese clinical trial registration number: JapicCTI-132308.
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