Increased resistance against tellurite is conferred by a mutation in the promoter region of uncommon tellurite resistance gene tehB in the ter-negative Shiga toxin-producing Escherichia coli O157:H7.

Resistance to potassium tellurite (PT) is an important indicator in isolating Shiga toxin-producing Escherichia coli (STEC) O157:H7 and other major STEC serogroups. Common resistance determinant genes are encoded in the ter gene cluster. We found an O157:H7 isolate that does not harbor ter but is resistant to PT. One nonsynonymous mutation was found in another PT resistance gene, tehA, through whole-genome sequence analyses. To elucidate the contribution of this mutation to PT resistance, complementation of tehA and the related gene tehB in isogenic strains and quantitative RT‒PCR were performed. The results indicated that the point mutation not only changed an amino acid of tehA, but also was positioned on a putative internal promoter of tehB and increased PT resistance by elevating tehB mRNA expression. Meanwhile, the amino acid change in tehA had negligible impact on the PT resistance. Comprehensive screening revealed that 2.3% of O157:H7 isolates in Japan did not harbor the ter gene cluster, but the same mutation in tehA was not found. These results suggested that PT resistance in E. coli can be enhanced through one mutational event even in ter-negative strains. IMPORTANCE: Selective agents are important for isolating Shiga toxin-producing Escherichia coli (STEC) because the undesirable growth of microflora should be inhibited. Potassium tellurite (PT) is a common selective agent for major STEC serotypes. In this study, we found a novel variant of PT resistance genes, tehAB, in STEC O157:H7. Molecular experiments clearly showed that one point mutation in a predicted internal promoter region of tehB upregulated the expression of the gene and consequently led to increased resistance to PT. Because tehAB genes are ubiquitous across E. coli, these results provide universal insight into PT resistance in this species.

Classifications of moderate to severe asthma phenotypes in Japan and analysis of serum biomarkers: A Nationwide Cohort Study in Japan (NHOM Asthma Study).

BACKGROUND: Asthma is a heterogeneous disease, and phenotyping can facilitate understanding of disease pathogenesis and direct appropriate asthma treatment. This nationwide cohort study aimed to phenotype asthma patients in Japan and identify potential biomarkers to classify the phenotypes. METHODS: Adult asthma patients (n = 1925) from 27 national hospitals in Japan were enrolled and divided into Global Initiative for Asthma (GINA) steps 4 or 5 (GINA 4, 5) and GINA Steps 1, 2, or 3 (GINA 1-3) for therapy. Clinical data and questionnaires were collected. Biomarker levels among GINA 4, 5 patients were measured. Ward's minimum variance hierarchical clustering method and tree analysis were performed for phenotyping. Analysis of variance, the Kruskal-Wallis, and chi-square tests were used to compare cluster differences. RESULTS: The following five clusters were identified: 1) late-onset, old, less-atopic; 2) late-onset, old, eosinophilic, low FEV1; 3) early-onset, long-duration, atopic, poorly controlled; 4) early-onset, young, female-dominant, atopic; and 5) female-dominant, T1/T2-mixed, most severe. Age of onset, disease duration, blood eosinophils and neutrophils, asthma control questionnaire Sum 6, number of controllers, FEV1, body mass index (BMI), and hypertension were the phenotype-classifying variables determined by tree analysis that assigned 79.5% to the appropriate cluster. Among the cytokines measured, IL-1RA, YKL40/CHI3L1, IP-10/CXCL10, RANTES/CCL5, and TIMP-1 were useful biomarkers for classifying GINA 4, 5 phenotypes. CONCLUSIONS: Five distinct phenotypes were identified for moderate to severe asthma and may be classified using clinical and molecular variables (Registered in UMIN-CTR; UMIN000027776.).

Large-scale genome analysis of bovine commensal Escherichia coli reveals that bovine-adapted E. coli lineages are serving as evolutionary sources of the emergence of human intestinal pathogenic strains.

How pathogens evolve their virulence to humans in nature is a scientific issue of great medical and biological importance. Shiga toxin (Stx)-producing Escherichia coli (STEC) and enteropathogenic E. coli (EPEC) are the major foodborne pathogens that can cause hemolytic uremic syndrome and infantile diarrhea, respectively. The locus of enterocyte effacement (LEE)-encoded type 3 secretion system (T3SS) is the major virulence determinant of EPEC and is also possessed by major STEC lineages. Cattle are thought to be the primary reservoir of STEC and EPEC. However, genome sequences of bovine commensal E. coli are limited, and the emerging process of STEC and EPEC is largely unknown. Here, we performed a large-scale genomic comparison of bovine commensal E. coli with human commensal and clinical strains, including EPEC and STEC, at a global level. The analyses identified two distinct lineages, in which bovine and human commensal strains are enriched, respectively, and revealed that STEC and EPEC strains have emerged in multiple sublineages of the bovine-associated lineage. In addition to the bovine-associated lineage-specific genes, including fimbriae, capsule, and nutrition utilization genes, specific virulence gene communities have been accumulated in stx- and LEE-positive strains, respectively, with notable overlaps of community members. Functional associations of these genes probably confer benefits to these E. coli strains in inhabiting and/or adapting to the bovine intestinal environment and drive their evolution to highly virulent human pathogens under the bovine-adapted genetic background. Our data highlight the importance of large-scale genome sequencing of animal strains in the studies of zoonotic pathogens.

Clinical Characteristics of Severe Refractory Asthma Associated with the Effectiveness of Bronchial Thermoplasty.

We investigated the clinical characteristics of refractory asthma associated with the effectiveness of bronchial thermoplasty (BT). We retrospectively evaluated data from 10 patients who underwent BT between June 2016 and December 2017 at Okayama Medical Center. The following were measured before and 6 months post-BT: forced expiratory volume in 1.0 s (FEV1), fractional exhaled nitric oxide (FeNO), immunoglobulin E (IgE) level, blood eosinophil counts (Eosi), Asthma Quality of Life Questionnaire (AQLQ) score, and preventive medication use. At baseline, the mean post-bronchodilator FEV1 was 80.9% of the predicted value (range 45.6-115.7%). All patients were being treated with moderate- or high-dose inhaled corticosteroids and long-acting ß2 agonists. The AQLQ improved from 4.26±1.67 at baseline to 5.59±0.94 at 6 months post-BT (p<0.05). The %FEV1, FeNO, IgE, and Eosi did not change significantly between baseline and 6 months post-BT. No severe complications were reported. BT was effective for non-allergic and non-eosinophilic in 3 patients, and allergic or eosinophilic in 4 patients. Their AQLQ improved by > 0.5 points post-BT. For both allergic and eosinophilic asthmatics following mepolizumab, BT was not useful. BT was effective for non-allergic and non-eosinophilic or allergic asthmatics, but insufficient for both allergic and eosinophilic following mepolizumab.

Prediction of 1-year clinical outcomes using the SYNTAX score in patients with prior heart failure undergoing percutaneous coronary intervention: sub-analysis of the SHINANO registry.

Although coronary artery disease (CAD) is common in patients with heart failure (HF), little is known about the prognostic significance of coronary lesion complexity in patients with prior HF undergoing percutaneous coronary intervention (PCI). The aim of this study was to investigate whether the coronary Synergy between Percutaneous Coronary Intervention with TAXus and Cardiac Surgery (SYNTAX) score could improve risk stratification in HF patients with CAD. Two hundred patients (mean age 73 ± 11 years, left ventricular ejection fraction 49 ± 15 %) with prior HF who underwent PCI were divided into two groups stratified by SYNTAX score (median value 12) and tracked prospectively for 1 year. The study endpoint was the composite of major adverse cardiovascular events (MACE), including all-cause death, myocardial infarction, stroke, and hospitalization for worsening HF. Adverse events were observed in 39 patients (19.5 %). Patients with high SYNTAX scores (n = 100) showed worse prognoses than those with low scores (n = 100) (26.0 vs. 13.0 %, respectively, P = 0.021). In multivariate Cox-regression analysis, SYNTAX score ≥12 was significantly associated with MACE (hazard ratio: 1.99, 95 % confidence interval: 1.02-3.97; P = 0.045). In patients with prior HF and CAD, high SYNTAX scores predicted a high incidence of MACE. These results suggest that the SYNTAX score might be a useful parameter for improving risk stratification in these patients.

In-hospital clinical outcomes of elderly patients (≥80 years) undergoing percutaneous coronary intervention.

BACKGROUND: The clinical outcomes of elderly patients (≥80 years old) undergoing percutaneous coronary intervention (PCI) has not been well established, despite recent advances in both devices and techniques. METHODS AND RESULTS: We recruited patients from the SHINANO Registry, a prospective, observational, multicenter, cohort study. From August 2012 to July 2013, a total of 1,923 consecutive patients with 2,250 elective/urgent PCIs (2,105 admissions) (mean age, 71±11 years; ≥80 years, 23%; men, 77%) were enrolled. The primary endpoint was procedural success. The secondary endpoints were in-hospital death and in-hospital major adverse cardiovascular events (MACE). The procedural success rate was significantly lower (83.7% vs. 89.1%, P=0.0001), and the rates of in-hospital mortality and MACE were significantly higher in elderly than in non-elderly patients (3.6% vs. 1.5%, P=0.005; 4.4% vs. 2.3%, P=0.016, respectively). For elective PCI, the rates of procedural success and in-hospital MACE were similar between groups (90.3% vs. 91.3%, P=0.65, 2.3% vs. 1.2%, P=0.2, respectively). On multivariate analysis, being elderly was not an independent predictor of procedural failure (OR, 1.15; CI, 0.81-1.61; P=0.43). CONCLUSIONS: In elderly patients, PCI is safe and feasible. The presence of comorbidities is a more important factor than age alone.

N-glycosylation at noncanonical Asn-X-Cys sequences in plant cells.

The vesicular transport pathway in plant cells is often used for higher accumulation of recombinant proteins. In the endoplasmic reticulum, which acts as a gateway to the vesicular transport pathway, N-glycosylation occurs on specific Asn residues. This N-glycosylation in recombinant proteins must be carefully regulated as it can impact their enzymatic activity, half lives in serum when injected, structural stability, etc. In eukaryotic cells, including plant cells, N-glycans were found to be attached to Asn residues in Asn-X-Ser/Thr (X ≠ Pro) sequences. However, recently, N-glycosylations at noncanonical Asn-X-Cys sequences have been found in mammals and yeast. Our laboratory has discovered that N-glycans are attached to Asn residues at Asn-Thr-Cys sequences of double-repeated B subunit of Shiga toxin 2e produced in plant cells, the first reported case of N-glycosylation at a noncanonical Asn-X-Cys sequence in plant cells.

Production of double repeated B subunit of Shiga toxin 2e at high levels in transgenic lettuce plants as vaccine material for porcine edema disease.

Pig edema disease is a bacterial disease caused by enterohemorrhagic Escherichia coli. E. coli produces Shiga toxin 2e (Stx2e), which is composed of one A subunit (Stx2eA) and five B subunits (Stx2eB). We previously reported production of Stx2eB in lettuce plants as a potential edible vaccine (Matsui et al. in Biosci Biotechnol Biochem 73:1628-1634, 2009). However, the accumulation level was very low, and it was necessary to improve expression of Stx2eB for potential use of this plant-based vaccine. Therefore, in this study, we optimized the Stx2eB expression cassette and found that a double repeated Stx2eB (2× Stx2eB) accumulates to higher levels than a single Stx2eB in cultured tobacco cells. Furthermore, a linker peptide between the two Stx2eB moieties played an important role in maximizing the effects of the double repeat. Finally, we generated transgenic lettuce plants expressing 2× Stx2eB with a suitable linker peptide that accumulate as much as 80 mg per 100 g fresh weight, a level that will allow us to use these transgenic lettuce plants practically to generate vaccine material.

A case of colorectal cancer with double-activating epidermal growth factor receptor mutations.

We describe the case of a 72-year-old woman with locally advanced lung tumor mimicking primary lung cancer. She was diagnosed with rectal cancer at the age of 65 years and was initially treated with platinum-based chemotherapy and thoracic irradiation as a treatment for primary lung cancer. One year later, a thyroid tumor was detected in her right thyroid lobe and was confirmed to have metastasized from rectal cancer based on pathological findings. Therefore, we suspected that she had metachronous double cancers and treated her with conventional chemotherapy for colorectal cancer. However, new life-threatening multiple lung metastases appeared. We treated her with the drug erlotinib because additional genetic analysis against primary lung tumor revealed typical double-activating epidermal growth factor receptor mutations. Histological review by immunostaining concluded that the primary lung tumor was composed of metastatic tumors from rectal cancer. In addition, genetic analysis revealed that the primary rectal cancer contained nearly the same types of double-activating epidermal growth factor receptor mutations as were present in the lung tumor. This is the first report of a case of rectal adenocarcinoma with double-activating epidermal growth factor receptor mutations.

Removal of viable bacteria and endotoxins by Electro Deionization (EDI).

Viable bacteria and endotoxins in water sometimes cause problems for human health. Endotoxins are major components of the outer cell wall of gram-negative bacteria (lipopolysaccharides). In medical procedures, especially haemodialysis (HD) and related therapies (haemodiafiltration (HDF), haemofiltration (HF)), endotoxins in the water for haemodialysis can permeate through the haemodialysis membrane and cause microinflammation or various haemodialysis-related illnesses. To decrease such a biological risk, RO and UF membranes are generally used. Also, hot water disinfection or the chemical disinfection is regularly executed to kill bacteria which produce endotoxins. However, simple treatment methods and equipment may be able to decrease the biological risk more efficiently. In our experiments, we confirmed that viable bacteria and endotoxins were removed by Electro Deionization (EDI) technology and also clarified the desorption mechanisms.

[A case of small cell lung cancer that presented with paraneoplastic syndrome].

A 65-year-old man had suffered from systemic erythema from November 2008 and had noticed gradually progressing weakness in the upper and lower limbs. He received medical treatment in another hospital but his symptoms did not improve. He was admitted to our hospital for treatment of diabetes in June 2009, and his chest X-ray images and CT scans showed a mass shadow in the right upper lobe with hilar and mediastinal lymphadenopathy. We performed bronchoscopy, and diagnosed small cell lung cancer (T2N2M1, stage IV). However, he had hand grip weakness and continuing upper and lower limb muscle weakness, and therefore electromyography was performed, which showed the presence of waxing in the right leg. Subsequently, a diagnosis of Lambert-Eaton myasthenic syndrome was made. As he also showed ataxia of the left lower extremity, we also diagnosed paraneoplastic cerebellar degeneration. We gave the patient chemotherapy consisting of carboplatin and etoposide which resulted in the disappearance of his waxing, and his grip strength and erythema immediately improved with regression of the tumor after 1 course of chemotherapy. We report a case of small cell lung cancer associated with Lambert-Eaton myasthenic syndrome, paraneoplastic cerebellar degeneration and erythema which presented as paraneoplastic syndrome, which improved with chemotherapy.

Shiga toxin 2eB-transgenic lettuce vaccine: N-glycosylation is important for protecting against porcine edema disease.

Porcine edema disease (ED) is a life-threatening toxemia caused by enteric infection with Shiga toxin 2e (Stx2e)-producing Escherichia coli (STEC) in weaned piglets. We previously reported that the stx2eB-transgenic lettuce 2BH strain shows potential for use as an oral vaccine candidate against ED. However, the 2BH strain expressed a hemagglutinin (HA)-tag together with Stx2eB and contained non-canonical N-glycosylation. Therefore, we developed two Stx2eB-lettuce strains, the 3 (G+) strain in which the HA-tag was removed from 2BH, and the 3 (G-) lettuce strain, in which the 73rd Asn was replaced with Ser to prevent non-canonical N-glycosylation of Stx2eB from the 3 (G+) strain. We examined the protective effect of these newly developed two strains compared with the previous 2BH strain against ED using a colostrum-deprived piglet STEC infection model. We found that the N-glycosylated 2BH and 3 (G+) strains relieved the pathogenic symptoms of ED in STEC-challenged piglets, whereas the non-glycosylated 3 (G-) strain did not. N-Glycosylation of the Stx2eB product in lettuce may be involved in the immune response in piglets.

An orally applicable Shiga toxin neutralizer functions in the intestine to inhibit the intracellular transport of the toxin.

Shiga toxin 2 (Stx2) is a major virulence factor in infections with Stx-producing Escherichia coli (STEC), which causes gastrointestinal diseases and sometimes fatal systemic complications. Recently, we developed an oral Stx2 inhibitor known as Ac-PPP-tet that exhibits remarkable therapeutic potency in an STEC infection model. However, the precise mechanism underlying the in vivo therapeutic effects of Ac-PPP-tet is unknown. Here, we found that Ac-PPP-tet completely inhibited fluid accumulation in the rabbit ileum caused by the direct injection of Stx2. Interestingly, Ac-PPP-tet accumulated in the ileal epithelial cells only through its formation of a complex with Stx2. The formation of Ac-PPP-tet-Stx2 complexes in cultured epithelial cells blocked the intracellular transport of Stx2 from the Golgi apparatus to the endoplasmic reticulum, a process that is essential for Stx2 cytotoxicity. Thus, Ac-PPP-tet is the first Stx neutralizer that functions in the intestine by altering the intracellular transport of Stx2 in epithelial cells.

Medical students' attitudes towards peer physical examination: findings from an international cross-sectional and longitudinal study.

Although studies have begun to shed light on medical students' attitudes towards peer physical examination (PPE), they have been conducted at single sites, and have generally not examined changes in medical students' attitudes over time. Employing both cross-sectional and longitudinal designs, the current study examines medical students' attitudes towards PPE at schools from different geographical and cultural regions and assess changes in their attitudes over their first year of medical study. Students at six schools (Peninsula, UK; Durham, UK; Auckland, New Zealand; Flinders, Australia; Sapporo, Japan and Li Ka Shing, Hong Kong) completed the Examining Fellow Students (EFS) questionnaire near the start of their academic year (T1), and students at four schools (Peninsula, Durham, Auckland and Flinders) completed the EFS for a second time, around the end of their academic year (T2). Univariate and multivariate analyses revealed a high level of acceptance for PPE of non-intimate body regions amongst medical students from all schools (greater than 83%, hips, at T1 and 94.5%, hips and upper body, at T2). At T1 and T2, students' willingness to engage in PPE was associated with their gender, ethnicity, religiosity and school. Typically, students least comfortable with PPE at T1 and T2 were female, non-white, religious and studying at Auckland. Although students' attitudes towards PPE were reasonably stable over their first year of study, and after exposure to PPE, we did find some statistically significant differences in attitudes between T1 and T2. Interestingly, attitude changes were consistently predicted by gender, even when controlling for school. While male students' attitudes towards PPE were relatively stable over time, females' attitudes were changeable. In this paper, we discuss our findings in light of existing research and theory, and discuss their implications for educational practice and further research.

[Patient with autoimmune alveolar proteinosis who did not respond to GM-CSF inhalation therapy and underwent repeated whole-lung lavage].

A 63-year-old man visited our department due to dry cough in September 2005. Chest radiography showed an infiltrative shadow extending from the bilateral hila to the peripheral areas. Chest CT scanning revealed a crazy-paving appearance. Bronchoalveolar lavage and transbronchial lung biopsy confirmed alveolar proteinosis. In addition, based on the absence of an underlying disease and a high titer of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody, a diagnosis of autoimmune alveolar proteinosis was made. His course was observed on an outpatient basis because of mild symptoms, but dyspnea on exertion gradually increased. In July 2007, GM-CSF inhalation therapy was initiated in another hospital, but no improvement was observed. In November of the same year, he underwent whole-lung lavage for one lung followed by that for the other at our department. The symptoms rapidly improved after the lavage but were aggravated again after 6 months. In May 2008, whole-lung lavage was performed again. There have been no reports of adults with autoimmune alveolar proteinosis who did not respond to GM-CSF inhalation therapy and who underwent whole-lung lavage twice. GM-CSF inhalation therapy for autoimmune alveolar proteinosis is a pathogenesis-based epoch-making therapy, but the response rate is about 60%. In patients with treatment-resistant autoimmune alveolar proteinosis showing repeated aggravation of symptoms, whole-lung lavage under general anesthesia is a reliable therapeutic method.

[Pleomorphic carcinoma of the lung with uncommon initial manifestation of intestinal perforation].

A 47-year-old woman suddenly developed abdominal pain and visited the emergency room of our hospital. Chest and abdominal CT scan revealed free air in the abdominal cavity and a bulky pulmonary tumor in the right middle lobe. The perforated sigmoid colon was removed in an emergency operation. Histological examination of the resected tissue revealed undifferentiated carcinoma, but the histological differentiation could not be determined. We used immunohistochemical staining to distinguish primary non-small cell lung cancer from colon cancer; the resected tumor was positive for TTF-1 and CK7, but negative for CK20. Therefore, by using immunohistochemical staining we could diagnose the tumor of the large intestine as metastasis from non-small cell lung cancer. After the operation, systemic chemotherapy with carboplatin and docetaxel was repeated, but the lung tumor did not regress and the patient died. Autopsy examination confirmed the histology of the lung tumor as pleomorphic carcinoma. Morphological characteristics and the immunohistochemical staining pattern of the pulmonary tumor were consistent with that of the colon tumor. In Japan, this is the first report in which the initial manifestation of lung cancer was perforation of the large intestine due to metastasis.

[Pulmonary carcinomatous lymphangiosis from recurrent breast cancer 10 years after resection of the primary tumor].

A 55-year-old woman had a history of left mastectomy due to early breast cancer in 1998. She had been suffering from dyspnea on effort and dry cough since August in 2007, and visited our hospital 6 months later because the symptoms had been becoming worse. She was hypoxic and her chest radiograph showed bilateral diffuse shadows, so she was hospitalized. The specimen of transbronchial lung biopsy showed undifferentiated adenocarcinoma cells in lymphatics identified by lymphatic endothelium antibody D2-40 stain, so we diagnosed carcinomatous lymphangiosis. It also revealed the cells staining positive for Cytokeratin 7, negative for Cytokeratin 20, and positive for both estrogen receptor and progesterone receptor. These features were identical to the immunohistological findings of the specimen from the previously resected breast cancer. Chemotherapy with docetaxel was effective and improved her respiratory condition and the chest radiograph. The immunohistological findings are useful for diagnosis and selection of cancer therapy. We cannot find any case reports of recurrence with carcinomatous lymphangiosis over 10 years after resection of breast cancer in Japan. We must keep in mind that some cancers relapse after a long disease-free interval.

Shiga toxin 2eB-transgenic lettuce vaccine is effective in protecting weaned piglets from edema disease caused by Shiga toxin-producing Escherichia coli infection.

Porcine edema disease (ED) is a toxemia that is caused by enteric infection with Shiga toxin 2e (Stx2e)-producing Escherichia coli (STEC) and is associated with high mortality. Since ED occurs most frequently during the weaning period, preweaning vaccination of newborn piglets is required. We developed stx2eB-transgenic lettuce as an oral vaccine candidate against ED and examined its protective efficacy using a piglet STEC infection model. Two serially developed Stx2eB-lettuce strains, 2BN containing ingredient Stx2eB constituting a concentration level of 0.53 mg Stx2eB/g of powdered lettuce dry weight (DW) and 2BH containing ingredient Stx2eB constituting a concentration level of 2.3 mg of Stx2eB/g of powdered lettuce DW, were evaluated in three sequential experiments. Taken the results together, oral administration of Stx2eB-lettuce vaccine was suggested to relieve the pathogenic symptoms of ED in piglets challenged with virulent STEC strain. Our data suggested that Stx2eB-lettuce is a promising first oral vaccine candidate against ED.

[Treatment-refractory-dental-extraction-associated pyothorax involving infection by 2 species of oral originated bacteria requires surgical debridement by video assisted thoracoscopic surgery (VATS)].

Cases of septic pulmonary embolism (SPE) diagnosed clinically by CT after dental extraction rarely include verification of bacteria from the local infection site. We report the case of a 70-year-old man without background disease suffering severe pyothrax after dental extraction. We detected two species of oral bacteria from his pleural effusion. Treatment was so difficult that it required surgical debridement by video assisted thoracoscopic surgery (VATS), even after the appropriate administration of antibiotics. According to the American Heart Association (AHA) prophylaxis guidelines for preventing infective endocarditis indicate that it is uncommon to prescribe antibiotics to patients without background disease after dental extraction. No appropriate Japanese guidelines exist considering the prevention of SPE causing severe pyothorax as in our case. The hematogenous spread of bacteria such as SPE caused by sepsis after tooth extraction thus requires more attended careful consideration in clinical practice if patients are to be properly protected against potentially serious complications.

Low Variability in Peak Expiratory Flow Predicts Successful Inhaled Corticosteroid Step-Down in Adults with Asthma.

BACKGROUND: The prognosis for patients beyond 1 year after reduction of their inhaled corticosteroid (ICS) dose remains unknown. Predictive factors that can be evaluated before the initiation of asthma treatment or at ICS dose reduction are unknown. METHODS: We prospectively studied 223 patients in 6 hospitals in the National Hospital Organization of Japan during the 36 months after 50% reduction of their daily ICS dose. All patients recorded their morning and evening peak expiratory flows (PEFs) in their diaries. Lung function, bronchial hyperresponsiveness, fractional nitric oxide levels, number of eosinophils in sputum, and serum IgE levels were measured in most patients. Serum levels of IL-10, IL-33, and thymic stromal lymphopoietin before ICS dose reduction were measured in all patients. RESULTS: During the 36-month study period, asthma control was retained in 127 (59.6%) of the 213 enrolled patients who underwent ICS dose reduction. Multivariate logistic regression analysis revealed that, at the initiation of dose reduction, the factors most predictive of maintenance of asthma control after ICS dose reduction were a low serum IL-33 level (P < .01), low PEF variability over 1 week (P = .014), childhood onset of asthma (at age <10 years) (P = .03), and high serum IL-10 level (P = .035). CONCLUSIONS: We demonstrated that low PEF variability over 1 week, high serum IL-10 level, and low serum IL-33 concentration were useful factors for predicting that an adult's asthma will remain in control for months to years after a 50% reduction in the daily ICS dose.