[EFFECTIVENESS OF ADD-ON SUBLINGUAL IMMUNOTHERAPY FOR THE TREATMENT OF JAPANESE CEDAR POLLINOSIS-ASSOCIATED ALLERGIC ASTHMA IS IT POSSIBLE TO REDUCE THE DOSE OF INHALED CORTICOSTEROID BY ADDING SUBLINGUAL IMMUNOTHERAPY?]

BACKGROUND: This study investigated the effect of adjuvant sublingual immunotherapy (SLIT) on inhaled corticosteroid (ICS) dose in patients with pollinosis-associated asthma. METHODS: We retrospectively evaluated patients with cedar pollinosis-associated asthma who initiated pharmacotherapy with or without adjuvant SLIT therapy from December 2014 to December 2016 and who continued treatment for 3 years. Changes in ICS dose (fluticasone propionate or its equivalent), antihistamine use, leukotriene antagonist use and intranasal corticosteroid (INCS) use over the 3-year period were compared. RESULTS: The study included 36 and 35 patients in the add-on SLIT and standard treatment groups, respectively. At 3 years, the add-on SLIT group showed a significant decline in ICS dose (p = 0.024). Although leukotriene antagonist use and INCS use did not differ between the two groups, the percentage of patients using antihistamines at 3 years was significantly lower in the add-on SLIT group than in the standard treatment group (p = 0.009); one in three patients on adjuvant SLIT therapy was able to discontinue ICS treatment. Patients who discontinued ICS treatment were younger (44.6±13.3 years vs. 55.0±14.1 years, p = 0.042), had a higher FEV1% predicted (109.9±14.4 vs. 94.8±18.6, p = 0.02), and were on a lower treatment step (2.1±0.7 vs. 3.0±0.8, p = 0.002) than those who did not. CONCLUSION: The addition of SLIT to standard pharmacotherapy resulted in a significant reduction in ICS dose at 3 years.

Effect of Vonoprazan, a Potassium-Competitive Acid Blocker, on the 13C-Urea Breath Test in Helicobacter pylori-Positive Patients.

BACKGROUND AND AIM: Vonoprazan (VPZ) is a new oral potassium-competitive acid blocker that has recently become available. The aim of this study was to investigate the effects of VPZ on the urease activity of H. pylori as measured by the 13C-urea breath test (13C-UBT). PATIENTS AND METHODS: A total of 60 patients (26 men, 34 women; mean age 53.2 ± 13.6 years) who were diagnosed as H. pylori-positive were recruited. The patients were randomly allocated to three treatment groups: lansoprazole (LPZ) 30 mg (n = 20), VPZ 20 mg (n = 20) once daily for 3 weeks, or the control group (n = 20). The 13C-UBT was carried out at baseline and after 3 weeks of treatment, and the baseline and after treatment results then compared. Δ13C‰ ≥ 2.5‰ was considered H. pylori-positive. RESULTS: Four patients failed to complete the medication and were omitted from the analysis; data from the LPZ group (n = 18), VPZ group (n = 18), and control group (n = 20) were analyzed. The control group showed no significant change in 13C-UBT data between baseline and the completion of 3-week treatment (baseline: 26.6 ± 23.0‰, completion: 21.1 ± 13.1‰). The 13C-UBT data at week 3 were significantly decreased in both the VPZ group (baseline: 32.8 ± 22.7‰, completion: 7.6 ± 9.2‰, p = 0.0002) and the LPZ group (baseline: 41.8 ± 33.4‰; completion: 9.6 ± 8.8‰, p = 0.0006) compared to baseline. CONCLUSIONS: VPZ treatment reduced the value of UBT, warning that UBT for patients with VPZ treatment should be evaluated carefully.

[A clinical study of pulmonary Mycobacterium abscessus infection].

Pulmonary Mycobacterium abscessus infection is resistant to many antibiotics and is difficult to treat. We retrospectively analyzed the clinical characteristics of pulmonary infection due to M. abscessus. Eleven cases diagnosed as having pulmonary M. abscessus infection at Osaka Red Cross Hospital from January. 2008, to June, 2012 were enrolled in this study. The average age of the 11 cases was 63 years (all were females). Nine cases showed underlying diseases, comprising 5 cases with Mycobacterium avium complex lung infection, 3 with old pulmonary tuberculosis, and 3 with bronchiectasis. The radiological examination revealed that 10 cases showed the small nodular type, 7 showed the bronchiectatic type, 4 showed a cavity lesion and 4 showed infiltrative shadows. A microbiological definite diagnosis was made from sputum in 10 cases and bronchial lavage fluid in one. As treatment for M. abscessus pulmonary infection, combined multi-drug chemotherapy was carried out in 7 of the 11 cases. No patients were successfully treated with antibiotics alone, whereas 4 patients had no exacerbation of radiological findings without any treatment. One patient received antibiotics including clarithromycin, amikacin and levofloxacin for 2 to 12 months following surgical excision and her sputum cultures have been maintained as negative over the long-term. During the study, none of the 11 patients were known to have died. In this study, we found that M. abscessus pulmonary infection is more common among females, and is found frequently in patients with M. avium complex lung infection. We also found that the clinical course of M. abscessus pulmonary infection was different among patients. We think this is because M. abscessus was shown to comprise three closely related species. M. abscessus is extremely difficult to eradicate, and surgical resection of localized disease or the main lesion or cavity may be significantly effective in preventing the progression of disease.

Relationship between oral health and prognosis in patients with empyema: Single center retrospective study with propensity score matching analysis.

BACKGROUND: Empyema is a life-threatening infection often caused by oral microbiota. To the best of our knowledge, no reports have investigated the association between the objective assessment of oral health and prognosis in patients with empyema. MATERIALS AND METHODS: A total of 63 patients with empyema who required hospitalization at a single institution were included in this retrospective study. We compared non-survivors and survivors to assess risk factors for death at three months, including the Renal, age, pus, infection, diet (RAPID) score, and Oral Health Assessment Tool (OHAT) score. Furthermore, to minimize the background bias of the OHAT high-score and low-score groups determined based on the cut-off value, we also analyzed the association between the OHAT score and death at 3 months using the propensity score matching method. RESULTS: The 3-month mortality rate was 20.6% (13 patients). Multivariate analysis showed that a RAPID score ≥5 points (odds ratio (OR) 8.74) and an OHAT score ≥7 points (OR 13.91) were significantly associated with death at 3 months. In the propensity score analysis, a significant association was found between a high OHAT score (≥7 points) and death at 3 months (P = 0.019). CONCLUSION: Our results indicated that oral health assessed using the OHAT score may be a potential independent prognostic factor in patients with empyema. Similar to the RAPID score, the OHAT score may become an important indicator for the treatment of empyema.

Application of QUBO solver using black-box optimization to structural design for resonance avoidance.

Quadratic unconstrained binary optimization (QUBO) solvers can be applied to design an optimal structure to avoid resonance. QUBO algorithms that work on a classical or quantum device have succeeded in some industrial applications. However, their applications are still limited due to the difficulty of transforming from the original optimization problem to QUBO. Recently, black-box optimization (BBO) methods have been proposed to tackle this issue using a machine learning technique and a Bayesian treatment for combinatorial optimization. We propose a BBO method based on factorization machine to design a printed circuit board for resonance avoidance. This design problem is formulated to maximize natural frequency and simultaneously minimize the number of mounting points. The natural frequency, which is the bottleneck for the QUBO formulation, is approximated to a quadratic model in the BBO method. For the efficient approximation around the optimum solution, in the proposed method, we probabilistically generate the neighbors of the optimized solution of the current model and update the model. We demonstrated that the proposed method can find the optimum mounting point positions in shorter calculation time and higher success probability of finding the optimal solution than a conventional BBO method. Our results can open up QUBO solvers' potential for other applications in structural designs.

Duodenal cholinergic tuft cell number is increased in functional dyspepsia.

BACKGROUND: Low-grade duodenal inflammation has recently been identified in patients with functional dyspepsia (FD). Chemosensory tuft cells were reported to be associated with gastrointestinal diseases. We therefore assessed duodenal tuft cell density and microinflammation in patients with FD to determine whether these measures could serve as useful biomarkers, and also correlated tuft cell density and microinflammation in FD patients. METHODS: Duodenal biopsy specimens were obtained from patients with FD and from controls. Tuft cells, eosinophils, and mast cells were immunochemically stained with specific antibodies. Tuft cells were identified by immunostaining for doublecortin-like kinase 1 (DCLK1); cholinergic tuft cells were assessed by double staining for choline acetyltransferase (ChAT) and DCLK1. Immune-type tuft cells were assessed by IL-25 mRNA expression using real-time PCR. KEY RESULTS: The density of intramucosal eosinophils and mast cells was significantly higher in the duodenum of FD patients than in controls. The density of tuft cells was significantly higher in the duodenum of FD patients compared with controls, and significantly correlated with eosinophil density in the duodenum of FD patients and controls. Moreover, a fraction of ChAT-positive cells was DCLK1 positive; all duodenal DCLK1+ tuft cells were ChAT-immunoreactive in FD and in control subjects. CONCLUSIONS AND INFERENCES: Cholinergic tuft cell density was higher in the duodenum of patients with FD and significantly correlated with eosinophil density. Further studies are needed to investigate the pathophysiological significance of tuft cells in FD and may provide valuable clues to the pathophysiology of FD.

[A case of eosinophilic pneumonia which occurred after bone marrow transplantation for acute myeloid leukemia].

A 37-year-old woman with acute myeloid leukemia received allogeneic bone marrow transplantation (BMT) after systemic chemotherapy and total body irradiation. Soon after BMT both cutaneous and gastrointestinal graft-versus-host disease (GVHD) developed, but she was successfully treated with corticosteroids and tacrolimus. Thereafter, about 6 months after BMT a dry cough developed, and chest computed tomography (CT) showed a consolidated shadow in the right lower lobe which was resistant to antibiotics, and we finally diagnosed eosinophilic pneumonia based on a bronchoalveolar lavage analysis of the eosinophilia. The eosinophilic pneumonia in this case might have been associated with GVHD, because cutaneous GVHD simultaneously recurred. We report the details of this case because only a few such reports of eosinophilic pneumonia associated with GVHD have been previously described, and such cases may increase with the growing use of transplantations.

Counterfactual Explanation of Brain Activity Classifiers Using Image-To-Image Transfer by Generative Adversarial Network.

Deep neural networks (DNNs) can accurately decode task-related information from brain activations. However, because of the non-linearity of DNNs, it is generally difficult to explain how and why they assign certain behavioral tasks to given brain activations, either correctly or incorrectly. One of the promising approaches for explaining such a black-box system is counterfactual explanation. In this framework, the behavior of a black-box system is explained by comparing real data and realistic synthetic data that are specifically generated such that the black-box system outputs an unreal outcome. The explanation of the system's decision can be explained by directly comparing the real and synthetic data. Recently, by taking advantage of advances in DNN-based image-to-image translation, several studies successfully applied counterfactual explanation to image domains. In principle, the same approach could be used in functional magnetic resonance imaging (fMRI) data. Because fMRI datasets often contain multiple classes (e.g., multiple behavioral tasks), the image-to-image transformation applicable to counterfactual explanation needs to learn mapping among multiple classes simultaneously. Recently, a new generative neural network (StarGAN) that enables image-to-image transformation among multiple classes has been developed. By adapting StarGAN with some modifications, here, we introduce a novel generative DNN (counterfactual activation generator, CAG) that can provide counterfactual explanations for DNN-based classifiers of brain activations. Importantly, CAG can simultaneously handle image transformation among all the seven classes in a publicly available fMRI dataset. Thus, CAG could provide a counterfactual explanation of DNN-based multiclass classifiers of brain activations. Furthermore, iterative applications of CAG were able to enhance and extract subtle spatial brain activity patterns that affected the classifier's decisions. Together, these results demonstrate that the counterfactual explanation based on image-to-image transformation would be a promising approach to understand and extend the current application of DNNs in fMRI analyses.

The utility of serial procalcitonin measurements in addition to pneumonia severity scores in hospitalised community-acquired pneumonia: A multicentre, prospective study.

OBJECTIVES: The usefulness of serial procalcitonin (PCT) measurements for predicting the prognosis and treatment efficacy for hospitalised community-acquired pneumonia (CAP) patients was investigated. METHODS: This prospective, multicentre, cohort study enrolled consecutive CAP patients who were hospitalised at 10 hospitals in western Japan from September 2013 to September 2016. PCT and C-reactive protein (CRP) were measured on admission (PCT D1 and CRP D1), within 48-72 h after admission (PCT D3 and CRP D3), and within 144-192 h after admission. CURB-65 and the Pneumonia Severity Index (PSI) were assessed on admission. The primary outcome was 30-day mortality; secondary outcomes were early and late treatment failure rates. RESULTS: A total of 710 patients were included. The 30-day mortality rate was 3.1%. On multivariate analysis, only PCT D3/D1 ratio >1 [odds ratio (95% confidence interval): 4.33 (1.46-12.82),P = 0.008] and PSI [odds ratio (95% confidence interval): 2.32 (1.07-5.03), P = 0.03] were significant prognostic factors. Regarding treatment efficacy, PCT D3/D1 >1 was a significant predictor of early treatment failure on multivariate analysis. PCT D3/D1 with the PSI significantly improved the prognostic accuracy over that of the PSI alone. CONCLUSIONS: PCT should be measured consecutively, not only on admission, to predict the prognosis and treatment efficacy in CAP.

Duodenal low-grade inflammation and expression of tight junction proteins in functional dyspepsia.

BACKGROUND: Duodenal changes in functional dyspepsia (FD) might be related to the development of symptoms. However, relationships among low-grade inflammation, Helicobacter pylori infection, and protein expression by tight junctions (TJs) in the duodenum are unclear. We therefore aimed to determine whether duodenal inflammation and genes associated with TJ proteins are associated with FD. METHODS: We evaluated inflammatory cell infiltration of the duodenum, H pylori infection, and genes associated with TJ proteins in duodenal biopsy specimens from 35 patients with FD according to the Rome III diagnostic questionnaire and from 31 asymptomatic controls without structural diseases. We immunohistochemically detected eosinophils and mast cells and counted them. The expression of claudins, occludin, and zonula occludens (ZO)-1 mRNA was evaluated using quantitative RT-PCR. Infection with H pylori was determined by measuring serum antibodies, rapid urease or urea breath tests, and endoscopic findings. RESULTS: Sex, age, and H pyloriinfection rates did not differ between patients with FD and controls. The numbers of eosinophils and mast cells were significantly increased in patients with FD compared with controls and were significantly correlated. Inflammatory cell counts in the duodenum were not associated with H pylori infection status. Claudin-3 mRNA expression was increased in the patients with FD. CONCLUSIONS: Subtle inflammation identified in the duodenum of patients with FD might be associated with the onset and persistence of dyspeptic symptoms.

Randomised clinical trial: vonoprazan versus lansoprazole for the initial relief of heartburn in patients with erosive oesophagitis.

BACKGROUND: Proton pump inhibitors (PPIs) are widely used to treat gastro-oesophageal reflux disease (GORD). However, the onset of action is considered slow and PPIs cannot completely block acid secretion at night. A new potassium-competitive acid blocker (P-CAB) can rapidly block acid secretion. However, whether this P-CAB can relieve GORD symptoms quickly and adequately soon after starting treatment is unknown. AIM: To determine how rapidly vonoprazan and lansoprazole provide heartburn relief. METHODS: Patients (n = 32) with endoscopically confirmed erosive oesophagitis who experienced heartburn at least once a week were randomised in a double-blind manner to receive either daily vonoprazan (20 mg) or lansoprazole (30 mg) before breakfast for 14 days. Day time and night time heartburn were assessed daily throughout the study using a five-point Likert scale. The primary endpoint was the first day of complete day and night heartburn relief for at least seven consecutive days. The ethics committees of the participating institutions approved the study protocol. RESULTS: Heartburn was relieved sooner with vonoprazan than with lansoprazole (P < 0.05, log-rank test). Heartburn was completely relieved in 31.3% and 12.5% of patients on day 1 with vonoprazan and lansoprazole, respectively. Significantly more patients achieved complete nocturnal heartburn relief with vonoprazan than lansoprazole (P < 0.01). Both regimens were well tolerated. CONCLUSIONS: Complete sustained heartburn relief was achieved sooner with vonoprazan than with lansoprazole during the first week of therapy. (UMIN000018776).

Analysis of risk factors for colonic diverticular bleeding and recurrence.

The increase in incidence of colonic diverticular bleeding is relative to an age-related rise in the incidence of colonic diverticulosis and use of antithrombotic medication. However, risk factors related to the onset, recurrence, and prophylaxis have not been established. Therefore, we aimed to determine risk factors for the onset and recurrence of colonic diverticular bleeding.An age- and sex-matched case-control study was performed to assess the risk factors for the onset of colonic diverticular bleeding. The distribution of diverticulosis, comorbidity, and medication were evaluated from medical records. We also assigned patients with a first-time bleeding into groups with and without rebleeding during follow-up to determine risk factors for recurrence.Bilateral colonic diverticulosis, nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin (LDA), and anticoagulants were significant risk factors for the onset of colonic diverticular bleeding on multivariate analysis. In contrast, the use of selective cyclooxygenase-2 (COX-2) inhibitor was not a risk factor for the onset. The incidence of bleeding in direct oral anticoagulant and warfarin users was not different between the 2 groups. The cumulative recurrence rate at 1 year was 15%. Recurrence rate was significantly higher in patients with a prior history of colonic diverticular bleeding than those without. Steroid use was associated with recurrence.Extensive distribution of diverticulosis and use of nonselective NSAIDs, LDA, and anticoagulants are regarded as risk factors for the onset of colonic diverticular bleeding. In addition, a prior history of colonic diverticular bleeding is related to the recurrence.

Successful Treatment with Alectinib for Choroidal Metastasis in Anaplastic Lymphoma Kinase Rearranged Non-small Cell Lung Cancer.

Choroidal metastasis is rare in cancer patients and it may cause visual disturbances that reduce their quality of life. In non-small cell lung cancer (NSCLC), targeted therapy against actionable driver mutations has gradually replaced radiotherapy as the treatment of choice for choroidal metastasis. Recently, there have been several case reports of choroidal metastasis in patients with anaplastic lymphoma kinase (ALK)-rearranged NSCLC. We herein report the case of a 40-year-old Japanese woman diagnosed with choroidal metastasis of an ALK-rearranged NSCLC who received alectinib as the first-line chemotherapy. Alectinib may be the best treatment for choroidal metastasis in patients harboring an ALK translocation because of its favorable side effect profile involving visual disturbances.

Interstitial Lung Disease as an Initial Manifestation of Giant Cell Arteritis.

Interstitial lung disease (ILD) has rarely been reported as a manifestation of giant cell arteritis (GCA). We herein report a unique case of GCA in a 76-year-old woman who presented with ILD as an initial manifestation of GCA. Ten years before admission, she had been diagnosed with granulomatous ILD of unknown etiology. Corticosteroid therapy induced remission. One year after the cessation of corticosteroid therapy, she was admitted with a persistent fever. After admission, she developed left oculomotor paralysis. Positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography (18F-FDG PET/CT) proved extremely useful in establishing the diagnosis. Our case promotes awareness of GCA as a possible diagnosis for granulomatous ILD with unknown etiology.

Varicella Reinfection with Unilateral Varicella Pneumonia.

Varicella zoster virus (VZV) infection does not always provide lifelong immunity. A reinfection with VZV occurs more commonly than previously thought. Varicella infection spreads through the blood-stream, causing pneumonia. Varicella pneumonia results in bilateral pulmonary nodular infiltrations. We herein report a case of varicella reinfection with unilateral varicella pneumonia in which a reduced pulmonary blood flow due to radiation damage was considered to be the cause of unilateral pneumonia. In patients with an asymmetric pulmonary blood flow, careful interpretation of unilateral infiltration is therefore considered to be important with making a differential diagnosis.

Diffuse thyroid enlargement following metastasis of lung adenocarcinoma.

A 55-year-old man presented with a rapidly enlarging thyroid. He had been diagnosed with lung adenocarcinoma nine months earlier. Computed tomography (CT) and ultrasound (US) detected reticular cord-like structures, but no nodules, in the thyroid. A fine-needle aspiration biopsy (FNAB) of the thyroid revealed thyroglobulin-negative adenocarcinoma cells, thus establishing the diagnosis of diffuse thyroid metastases of lung cancer. Moreover, the fluid demonstrated milky chyliform effusion. This case suggests that the presence of reticular cord-like structures on US and CT may be a key imaging finding for the clinical diagnosis of diffuse thyroid metastases and that chyliform effusion may contribute to rapid goiter formation.

Pulmonary Sarcoidosis Presenting with Miliary Opacities.

Lung lesions often appear in patients with sarcoidosis; however, miliary opacities are rare. We herein report the case of a 40-year-old woman with pulmonary sarcoidosis who presented with dyspnea on exertion. Subsequent computed tomography showed miliary opacities, and the presence of granulomas was confirmed by a transbronchial lung biopsy. Glucocorticoid therapy was initiated and the symptoms and miliary opacities rapidly improved. Although miliary sarcoidosis is uncommon, physicians should consider sarcoidosis in addition to tuberculosis, malignancy, and pneumoconiosis when presented with miliary opacities.

Diagnosis of small intramucosal signet ring cell carcinoma of the stomach by non-magnifying narrow-band imaging: A pilot study.

AIM: To examine the efficacy of non-magnifying narrow-band imaging (NM-NBI) imaging for small signet ring cell carcinoma (SRC). METHODS: We retrospectively analyzed 14 consecutive small intramucosal SRCs that had been treated with endoscopic submucosal dissection (ESD) and 14 randomly selected whitish gastric ulcer scars (control). The strength and shape of the SRCs and whitish scars by NM-NBI and white-light imaging (WLI) were assessed with Image J (NIH, Bethesda). RESULTS: NM-NBI findings of SRC showed a clearly isolated whitish area amid the brown color of the surrounding normal mucosa. The NBI index, which indicates the potency of NBI for visualizing SRC, was significantly higher than the WLI index (P = 0.001), indicating SRC was more clearly identified by NM-NBI. Although the NBI index was not significantly different between SRCs and controls, the circle (C)-index, as an index of circularity of tumor shape, was significantly higher in SRCs (P = 0.001). According to the receiver-operating characteristic analysis, the resulting cut-off value of the circularity index (C-index) for SRC was 0.60 (85.7% sensitivity, 85.7% specificity). Thus a lesion with a C-index ≥ 0.6 was significantly more likely to be an SRC than a gastric ulcer scar (OR = 36.0; 95%CI: 4.33-299.09; P = 0.0009). CONCLUSION: Small isolated whitish round area by NM-NBI endoscopy is a useful finding of SRCs which is the indication for ESD.