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Objectives The authors sought to elucidate the prognostic value of cardiac sympathetic nerve dysfunction as evaluated using iodine-123-labeled metaiodobenzylguanidine (123I-MIBG) single-ph...

Background Extensive ablation in addition to pulmonary vein isolation (PVI) would be effective for modification of non-pulmonary vein (non-PV) substrates, whereas PVI might be sufficient for elimination of PV triggers. This study aimed to test the hypothesis that in patients with reproducible atrial fibrillation (AF) triggered by premature atrial contractions originating only from PVs, PVI alone can be sufficient to maintain sinus rhythm.Methods and Results:This study is a prespecified subanalysis of the EARNEST-PVI randomized controlled trial. This study investigated the efficacy of the PVI-alone strategy (PVI-alone) in comparison with the extensive strategy (PVI-plus) for persistent AF with a trigger-based mechanism vs. a substrate-based mechanism. Patients were stratified into 3 groups based on AF mechanisms: (1) Substrate group (N=236); (2) PV trigger group (N=236); and (3) non-PV trigger group (N=24). The hazard ratios for AF recurrence of the PVI-alone strategy with reference to the PVI-plus strategy were 1.456 (95% confidence interval [CI] [0.864-2.452]) in the substrate group, 1.648 (95% CI 0.969-2.801) in the PV trigger group, and 0.937 (95% CI 0.252-3.488) in the non-PV trigger group. No significant interaction between ablation strategy and AF mechanism was observed (P for interaction=0.748). Conclusions This study indicated that the efficacies of the PVI-alone strategy compared with the PVI-plus strategy were consistent across persistent AF with trigger-based and substrate-based mechanisms.

Recurrence rates of atrial fibrillation (AF) after pulmonary vein isolation (PVI) are higher in patients with a left atrial low‐voltage area (LVA) than those without. However, the efficacy of LVA guided ablation is still unknown. The purpose of this study—the Efficacy and Safety of Left Atrial Low‐voltage Area Guided Ablation for Recurrence Prevention Compared to Pulmonary Vein Isolation Alone in Patients with Persistent Atrial Fibrillation trial (SUPPRESS‐AF trial)—is to elucidate whether LVA guided ablation in addition to PVI is superior to PVI alone in patients with persistent AF. The Osaka Cardiovascular Conference will conduct a multicenter, randomized, open‐label trial aiming to examine whether LVA guided ablation in addition to PVI is superior to PVI alone in patients with persistent AF and LVAs. The primary outcome is the recurrence of AF documented by scheduled or symptom‐driven electrocardiography (ECG) during the 1 year follow‐up period after the index ablation. The key secondary endpoints include all‐cause death, symptomatic stroke, bleeding events, and other complications related to the procedure. A total of 340 patients with an LVA will be enrolled and followed up to 1 year. The SUPPRESS‐AF trial is a randomized controlled trial designed to assess whether LVA guided ablation in addition to PVI is superior to PVI alone for patients with persistent AF and LVAs detected while undergoing their first catheter ablation.

Introduction Corynebacterium jeikeium normally presents on human skin, and it is often judged as contamination when it is cultured from blood. C. jeikeium can cause infective endocarditis, especially, that associated with cardiac surgery and prosthetic valvular endocarditis. Case report A 66-year-old Japanese male patient was diagnosed with C. jeikeium-induced infective endocarditis (IE) and perivalvular abscess after a coronary artery bypass grafting and aortic valve replacement with bioprosthesis; pyogenic spondylodiscitis was also observed. Patch repair for aortic valve annulus and re-Bentall procedure with bioprosthesis was performed for IE and perivalvular abscess. The causative bacterium was confirmed as C. jeikeium on 16S ribosomal RNA sequencing of surgical sample and positive blood culture. The patient underwent six weeks of intravenous antibacterial treatment with vancomycin and an additional two weeks of oral treatment with linezolid, following which, his condition improved. Corynebacterium jeikeium can cause infective endocarditis and perivalvular abscess, which is a more severe condition than IE. Conclusion 16S ribosomal RNA sequencing is useful in diagnosing bacterial species that can cause contamination, such as Corynebacterium spp.

Syphilis has recently increased in prevalence in Japan. Neurosyphilis is a special pathological condition of syphilis well known to cause cerebral vasculitis and ischemic stroke. Neurosyphilis in the meningovascular stage rarely causes caliber irregularity of the cerebral blood vessels or cerebral hemorrhage. We describe the case of a 49-year-old Japanese man with neurosyphilis. Cerebral hemorrhage, multiple cerebral infarctions, and caliber irregularity of the cerebral blood vessels were observed, the patient underwent surgery for cerebral hemorrhage on the day of admission, all of which were suspected to be caused by syphilis. He was started on an antibacterial treatment of penicillin on the day of admission and was diagnosed with neurosyphilis the following week based on his serum and spinal fluid test results. His condition improved, and he was transferred to another hospital after 4 weeks of treatment consisting of 3 weeks of infusion treatment with benzylpenicillin followed by oral treatment with amoxicillin. To the best of our knowledge, this is a rare case of neurosyphilis in conjunction with cerebral hemorrhage and cerebral infarction. Clinicians should consider syphilis in the differential diagnosis of cerebral hemorrhage and cerebral infarction and test patients for sexually transmitted diseases, in addition to cerebrospinal fluid testing, when cerebral hemorrhage occurs with an unknown cause. This is especially pertinent when patients present with cerebral infarction or caliber irregularity of the cerebral blood vessels.

Multiple primary lung cancers (MPLCs) harbour various genetic profiles among the tumours, even from individuals with same non-intrinsic risk factors. Paired mutational analyses were performed to obtain a census of mutational events in MPLC and assess their relationship with non-intrinsic risk factors. Thirty-eight surgical specimens from 17 patients diagnosed as MPLC were used. Extracted DNAs were sequenced for somatic mutations in 409 cancer-associated genes from a comprehensive cancer panel. We statistically analysed the correlation between each driver mutation frequency and non-intrinsic risk factors using Fisher's exact test, and whether genetic mutations occurred concomitantly or randomly in MPLC using an exact test. Comprehensive genetic analyses suggested different mutation profiles in tumours within the same individuals, with some exceptions. EGFR, KRAS, TP53, or PARP1 mutations were concomitantly detected in some MPLC cases. EGFR mutations were significantly more frequent in never or light smokers and females. Concomitant EGFR or KRAS mutations in MPLCs were significantly more frequent than expected by chance (P = .0023 and .0049, respectively) suggesting a more prominent role of non-intrinsic risk factors in EGFR and KRAS mutations than other mutations, which occurred more randomly. Concomitant EGFR or KRAS mutations were particularly prominent in never or light smokers and males.

Aims Cardiohepatic interactions have been a focus of attention in heart failure (HF). The model for end‐stage liver disease excluding international normalized ratio (MELD‐XI) score has been shown to be useful for predicting poor outcomes in patients with acute decompensated HF (ADHF). Furthermore, the fibrosis‐4 (FIB‐4) index, a simple marker to assess liver fibrosis, predicts adverse prognoses in patients with HF as well. However, there is little information available on the prognostic significance of the combination of the MELD‐XI score and FIB‐4 index in patients with ADHF and its association with left ventricular ejection fraction (LVEF) subgroup. Methods and results We prospectively studied 466 consecutive patients who were admitted for ADHF [HF with reduced LVEF (LVEF

Aims Co‐morbidities are associated with poor clinical outcomes in patients with chronic heart failure, while cardiac iodine‐123 (I‐123) metaiodobenzylguanidine (MIBG) imaging provides prognostic information in such patients. We sought to prospectively investigate the incremental prognostic value of cardiac MIBG imaging over the co‐morbid burden, in patients admitted for acute decompensated heart failure (ADHF). Methods and results In 433 consecutive ADHF patients with survival to discharge, we measured the co‐morbidity using age‐adjusted Charlson co‐morbidity index (ACCI), commonly employed to evaluate a weighted and scored co‐morbid condition, adding additional points for age. In cardiac MIBG imaging, the cardiac MIBG heart‐to‐mediastinum ratio (late HMR) was measured on the delayed image. Over a follow‐up period of 2.9 ± 1.5 years, 160 patients had a cardiac event (a composite of cardiac death and unplanned hospitalization for worsening heart failure). Patients with high ACCI (≥6: median value) had a significantly greater risk of a cardiac event. In multivariate Cox analysis, the ACCI and late HMR were significantly and independently associated with a cardiac event. In both high and low ACCI subgroups (ACCI ≥ 6 and

Invasive aspergillosis is a significant cause of mortality in patients with hematological malignancy. Early diagnosis of invasive pulmonary aspergillosis (IPA) by bronchoscopy is recommended but is often difficult to perform because of small lesion size and bleeding risk due to thrombocytopenia. A 71-year-old woman had received initial induction therapy for acute myeloid leukemia. On day 22 of chemotherapy, she had a high fever, and the chest computed tomography scan revealed a 20-mm-sized nodule with a halo sign. Bronchoscopy assisted by virtual bronchoscopic navigation (VBN) and endobronchial ultrasonography with a guide sheath (EBUS-GS) was performed, and Aspergillus terreus was identified from the culture of obtained specimens. A. terreus is often resistant to amphotericin B; thus, voriconazole is usually recommended for treatment. However, the obtained A. terreus isolate showed minimal inhibitory concentrations of 2 µg/mL for voriconazole and 0.5 µg/mL for amphotericin B. Therefore, the patient was successfully treated with liposomal amphotericin B. For patients suspected of having IPA, early diagnosis and drug susceptibility testing are very important. This case suggests that bronchoscopy using VBN and EBUS-GS is helpful for accurate diagnosis and successful treatment even if the lesion is small and the patient has a bleeding risk.

Background Congenital bronchial atresia is a rare pulmonary abnormality characterized by the disrupted communication between the central and the peripheral bronchus and is typically asymptomatic. Although it can be symptomatic especially when infections occur in the involved areas, fungal infections are rare complications in patients with bronchial atresia. We report a case of congenital bronchial atresia complicated by a fungal infection. Case presentation A 30-year-old man with no previous history of immune dysfunction was brought to a nearby hospital and diagnosed with a left lung abscess. Although antimicrobial treatment was administered, it was ineffective, and he was transferred to our hospital. Since diagnostic imaging findings and bronchoscopy suggested congenital bronchial atresia and a fungal infection, he was treated with voriconazole and surgical resection was subsequently performed. A tissue culture detected Aspergillus fumigatus and histopathological findings were compatible with bronchial atresia. After discharge, he remained well and voriconazole was discontinued 5 months after the initiation of therapy. Conclusion Bronchial atresia is a rare disease that is seldom complicated by a fungal infection, which is also a rare complication; however, physicians should consider fungal infections in patients with bronchial atresia who present with infections resistant to antimicrobial treatment.

Aims Previous studies could not demonstrate any benefit of more intensive ablation in addition to pulmonary vein isolation (PVI) including complex fractionated atrial electrogram (CFAE) and linear ablation for recurrence in the initial catheter ablation of persistent atrial fibrillation (AF). This study aimed to establish the non-inferiority of PVI alone to PVI plus these additional ablation strategies. Methods and results Patients with persistent AF who underwent an initial catheter ablation (n = 512, long-standing persistent AF; 128 cases) were randomly assigned in a 1:1 ratio to either PVI alone (PVI-alone group) or PVI plus CFAE and/or linear ablation (PVI-plus group). After excluding 15 cases who did not receive procedures, we analysed 249 and 248 patients, respectively. The primary endpoint was recurrence of AF, atrial flutter, and/or atrial tachycardia, and the non-inferior margin was set at a hazard ratio of 1.43. In the PVI-plus group, 85.1% of patients had linear ablation and 15.3% CFAE ablation. After 12 months, freedom from the primary endpoint occurred in 71.3% of patients in the PVI-alone group and in 78.3% in the PVI-plus group [hazard ratio = 1.56 (95% confidence interval: 1.10–2.24), non-inferior P = 0.3062]. The procedure-related complication rates were 2.0% in the PVI-alone group and 3.6% in the PVI-plus group (P = 0.199). Conclusion This randomized trial did not establish the non-inferiority of PVI alone to PVI plus linear ablation or CFAE ablation in patients with persistent AF, but implied that the PVI plus strategy was promising to improve the clinical efficacy (NCT03514693).

Background: Anticoagulation for patients with atrial fibrillation (AF) complicated by left atrial thrombi (LAT) is a frequent cause of bleeding complications, but risk factors remain unknown. Methods and Results: Of 3,139 AF patients who underwent transesophageal echocardiography, 82 with LAT under anticoagulation were included in this study. Patients treated with combination antiplatelet and anticoagulant therapy (n=31) were compared with those receiving anticoagulant monotherapy (n=51) to investigate the effects of antiplatelet agents during anticoagulation on bleeding complications. Over a mean (±SD) follow-up of 878±486 days, bleeding events occurred more frequently in the combination therapy than monotherapy group (58% vs. 20%; P

BACKGROUND: Differences in carcinogenesis and therapeutic efficacy according to ethnicity have been reported for lung cancer, and understanding differences in genetic mutation profiles among ethnicities is important for interpreting the results of clinical trials, preventing carcinogenesis, and individualizing treatment. However, no studies have focused on differences in mutation profiles among different ethnicities using large-scale genomic analysis data with detailed information on smoking history, the main cause of lung cancer. METHODS: To clarify the differences in genetic mutation profiles between Caucasian and Japanese subjects, we compared data from The Cancer Genome Atlas, which mainly included Caucasians, with results from the Japan Molecular Epidemiology for lung cancer study, which is an epidemiological study only involving Japanese subjects. We divided the participants into four groups according to smoking status and performed comparative analysis by tissue type (lung adenocarcinoma and squamous cell lung cancer). RESULTS: In patients with lung adenocarcinoma, the frequency of EGFR mutations was lower in Caucasian subjects than in Japanese subjects (14.6% vs. 51.1%), whereas the frequencies of mutations in other genes, namely KRAS (32.9% vs. 9.3%), TP53 (45.2% vs. 20.7%), BRAF (9.6% vs. 1.3%), PIK3CA (5.9% vs. 2.6%), KEAP1 (17.8% vs. 0.5%), NF1 (10.9% vs. 0.5%), STK11 (17.8% vs. 0.7%), RBM10 (8.7% vs. 0.1%), and MET (7.8% vs. 0.1%), were higher in Caucasian subjects. Among patients with squamous cell carcinoma, TP53 (81.2% vs. 49.1%), PIK3CA (14.5% vs. 6.8%), KEAP1 (12.7% vs. 0.9%), and NFE2L2 mutations (15.8% vs. 13.6%) were more common in Caucasian subjects. CONCLUSIONS: Ethnicity is an important and complex characteristic that must be recognized and considered, even in the era of precision medicine. We should collaborate to share data for different ethnicities and incorporate them into clinical practice and the design of global clinical studies. Carefully designed molecular epidemiological studies focusing on ethnic differences are warranted.

Background Atrial fibrillation (AF) may cause cerebral and systemic embolism. An increased D-dimer level indicates hyperactivation of secondary fibrinolysis, resulting in predilection for thrombosis. To clarify the differential effects of anticoagulation therapy, we compared the D-dimer levels in peripheral and left atrial (LA) blood of atrial fibrillation patients scheduled for ablation. Methods We analyzed 141 patients with non-valvular AF (dabigatran, n = 30; apixaban, n = 47; edoxaban, n = 64; mean age: 68 years, male: 60%). Peripheral venous blood and LA blood was collected before pulmonary vein isolation. We examined the laboratory and echocardiographic parameters. Results After adjusting for baseline characteristics, D-dimer level in the LA was significantly higher in patients treated with edoxaban than that in those on apixaban (0.77 ± 0.05 vs. 0.60 ± 0.05 μg/mL, P = 0.047), although there were no significant differences in peripheral D-dimer levels. We classified the D-dimer value of the LA into a normal group (P = 0.008) and left ventricular ejection fraction (LVEF) (OR, 0.947; 95% CI, 0.910–0.986; P = 0.008) were potential predictors of high LA D-dimer levels. Conclusions In apixaban-treated patients, the D-dimer level in the left atrium was lower than in edoxaban-treated patients on the day of ablation, suggesting that the anticoagulant effect of apixaban on the left atrium is better than that of edoxaban in patients with AF.

ObjectivesThe severity of diastolic dysfunction is assessed using a combination of several indices of left atrial (LA) volume overload and LA pressure overload. We aimed to clarify which overload is more associated with the prognosis in patients with heart failure and preserved ejection fraction (HFpEF).SettingA prospective, multicenter observational registry of collaborating hospitals in Osaka, Japan.ParticipantsWe enrolled hospitalised patients with HFpEF showing sinus rhythm (men, 79; women, 113). Blood tests and transthoracic echocardiography were performed before discharge. The ratio of diastolic elastance (Ed) to arterial elastance (Ea) was used as a relative index of LA pressure overload.Primary outcome measuresAll-cause mortality and admission for heart failure were evaluated at >1 year after discharge.ResultsIn the multivariable Cox regression analysis, Ed/Ea, but not LA volume index, was significantly associated with all-cause mortality or admission for heart failure (HR 2.034, 95% CI 1.059 to 3.907, p=0.032), independent of age, sex, and the serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level. In patients with a higher NT-proBNP level, the effect of higher Ed/Ea on prognosis was prominent (p=0.015).ConclusionsEd/Ea, an index of LA pressure overload, was significantly associated with the prognosis in elderly patients with HFpEF showing sinus rhythm.Trial registration numberUMIN000021831.

研究グループは、大豆発酵製品であるイムバランスが喘息による気道炎症を抑制する効果があることを動物モデルで明らかにしました。気管支喘息は慢性的な気道炎症により喘鳴や呼吸困難などの症状が現れますが、根本的な治療方法がなく、新たな予防・治療法の確立が望まれています。大豆の摂取とアレルギー疾患との関連は過去にも疫学的に報告されており、大豆の成分に何らかの抗アレルギー作用がある可能性が示唆されています。そこで、本研究グループは、喘息モデルマウスにイムバランスを添加した飼料を与えて気道炎症に及ぼす影響を調査しました。その結果、イムバランス投与群では、BALF(気管支肺胞洗浄液)中の好酸球数が有意に減少し、気管支周囲の炎症や粘液産生が抑制されていることを発見しました。また、好酸球性炎症を誘導するBALF中のTh2サイトカインや血清IgEの発現も有意に抑制されていました。この発見により、今後イムバランスが気管支喘息における治療方法の新規候補として期待されます。, The fermented soy product ImmuBalance contains many active ingredients and its beneficial effects on some allergic diseases have been reported. We hypothesized that ImmuBalance could have potential effects on airway inflammation in a murine model of asthma. Mice sensitized and challenged with ovalbumin developed airway inflammation. Bronchoalveolar lavage fluid was assessed for inflammatory cell counts and levels of cytokines. Lung tissues were examined for cell infiltration and mucus hypersecretion. Oral administration of ImmuBalance significantly inhibited ovalbumin-induced eosinophilic inflammation and decreased Th2 cytokine levels in bronchoalveolar lavage fluid (p < 0.05). In addition, lung histological analysis showed that ImmuBalance inhibited inflammatory cell infiltration and airway mucus production. Our findings suggest that supplementation with ImmuBalance may provide a novel strategy for the prevention or treatment of allergic airway inflammation.

Aims Cardiac 123I-metaiodobenzylguanidine (123I-MIBG) imaging provides prognostic information in patients with chronic heart failure (HF). However, there is little information available on the prognostic role of cardiac 123I-MIBG imaging in patients admitted for acute decompensated heart failure (ADHF), especially relating to reduced ejection fraction [HFrEF; left ventricular ejection fraction (LVEF) < 40%], mid-range ejection fraction (HFmrEF; 40% ≤ LVEF < 50%) and preserved ejection fraction (HFpEF; LVEF ≥ 50%). Methods and results We studied 349 patients admitted for ADHF and discharged with survival. Cardiac 123I-MIBG imaging, echocardiography, and venous blood sampling were performed just before discharge. The cardiac 123I-MIBG heart-to-mediastinum ratio (late H/M) was measured on the chest anterior view images obtained at 200 min after the isotope injection. The endpoint was cardiac events defined as unplanned HF hospitalization and cardiac death. During a follow-up period of 2.1 ± 1.4 years, 128 patients had cardiac events (45/127 in HFrEF, 28/78 in HFmrEF, and 55/144 in HFpEF). On multivariable Cox analysis, late H/M was significantly associated with cardiac events in overall cohort (P = 0.0038), and in subgroup analysis of each LVEF subgroup (P = 0.0235 in HFrEF, P = 0.0119 in HFmEF and P = 0.0311 in HFpEF). Kaplan–Meier analysis showed that patients with low late H/M (defined by median) had significantly greater risk of cardiac events in overall cohort (49% vs. 25% P < 0.0001) and in each LVEF subgroup (HFrEF: 48% vs. 23% P = 0.0061, HFmrEF: 51% vs. 21% P = 0.0068 and HFpEF: 50% vs. 26% P = 0.0026). Conclusion Cardiac sympathetic nerve dysfunction was associated with poor outcome in ADHF patients irrespective of HFrEF, HFmrEF, or HFpEF.

Mucormycosis is a deep-seated fungal infection that mainly develops in patients with severe immunodeficiencies such as those with malignant hematological diseases. Despite poor prognosis, there is no reliable and minimally invasive diagnostic method—such as serodiagnosis—for making a clinical decision regarding the condition. As early diagnosis and early treatment improve the prognosis of mucormycosis, the development of a sensitive early diagnostic method is important. We had previously identified a Rhizopus-specific antigen (RSA) by signal sequence trapping and retrovirus-mediated expression (SST-REX), and evaluated its utility as a diagnostic antigen by constructing a sandwich enzyme-linked immunosorbent assay (ELISA) system to detect serum RSA levels in inoculated mice. In this study, we used the RSA-specific rabbit monoclonal antibodies generated by novel hybridoma technology to improve the sensitivity of the ELISA system. We observed an increase in serum and bronchoalveolar lavage fluid (BALF) levels of RSA in mouse model 1 day after inoculation, suggesting that this newly developed monoclonal antibody-based ELISA system may be useful for the diagnosis of mucormycosis in the early stages of infection. In addition, we measured RSA levels in human serum and BALF, and found that serum RSA level was higher in mucormycosis patients (15.1 ng/ml) than that in invasive pulmonary aspergillosis patients (0.53 ng/ml) and the negative control (0.49 ng/ml). Our results suggest that RSA may be a powerful tool for the diagnosis of pulmonary mucormycosis, and its differentiation from other deep-seated mycoses such as aspergillosis.

Background Oxidative stress is one of the important mechanisms underlying the pathogenesis of chronic obstructive pulmonary disease (COPD). Irisin is a type of myokine secreted from the muscle during exercise and acts against oxidative stress via nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor with antioxidant properties. Here, we examined the emphysema suppressive effects of the exercise-irisin-Nrf2 axis in mice. Methods Mice were divided into three groups, namely, the control, smoking, and exercise + smoking groups. All mice from the smoking and exercise + smoking groups were exposed to cigarette smoke once a day. The mice from the exercise + smoking group were adapted to a treadmill once a day. To investigate the Nrf2 cascade, after 12 weeks, serum irisin concentration and Nrf2 and heme oxygenase-1 (HO-1) expression in the lung homogenate were determined. To evaluate cigarette smoke-induced COPD, the number of inflammatory cells in bronchoalveolar lavage fluid (BALF), mean linear intercept (MLI), and destructive index in the lung tissue were examined. Results Serum irisin concentration and the expression levels of Nrf2 and HO-1 in the lung homogenate were significantly higher in mice from the exercise + smoking group than in those from the control and smoking groups. The proportion of neutrophils in the BALF was significantly lower in the exercise + smoking group than in the smoking group. The MLI and destructive index were also significantly smaller in mice from the exercise + smoking group than mice from the smoking group. Conclusion Irisin secreted from the muscle during exercise may exert protective effects against oxidative stress via Nrf2 and HO-1, and ameliorate emphysema of cigarette smoke-induced COPD. The exercise-irisin-Nrf2 axis may serve as a novel target for COPD treatment.

An 80-year-old woman presented with general fatigue and leg edema for several months. Ultrasonography and contrast-enhanced computed tomographic angiography revealed inferior vena cava thrombosis, ilio-iliac arteriovenous fistula (AVF), and iliac artery pseudoaneurysm. Furthermore, malignant cells were observed in the aspirated thrombus. Although thrombus aspiration and anticoagulant therapy were unsuccessful in reducing the thrombotic mass and alleviating her symptoms, endovascular therapy for AVF and pseudoaneurysm improved her leg edema without recurrence or any endoleak. These findings highlight that endovascular therapy can be effective in older adults with cancer because of its low invasiveness.

Background: In superficial femoral artery (SFA) stenosis, stenosis resistance may increase, but the relationship between stenosis resistance and stenotic severity remains to be seen. This study aimed to investigate the physiological response, through a hyperemic condition, and the pathophysiological significance of Doppler flow and stenosis resistance in SFA. Methods: Twenty-four limbs with focal stenosis of the SFA were analyzed. We assessed the fractional flow reserve (FFR), hyperemic stenosis resistance (h-SR), and vascular flow reserve (VFR) of the SFA with a pressure/Doppler flow sensor-tipped combination guidewire before and after endovascular therapy (EVT). Results: FFR, h-SR, and VFR changed significantly after EVT. h-SR was more strongly correlated with % area stenosis, measured by intravascular ultrasound than FFR (FFR: r=−0.716, h-SR: r=0.741, p0.36 mmHg·sec/cm, and FFR 75% area stenosis with area under curves of 0.883 and 0.828, respectively. Conclusion: h-SR can indicate stenotic severity in an SFA focal lesion more prominently than FFR and may be a new physiological index to determine indication for EVT. VFR was not feasible for assessment in SFA focal stenosis.

Mikulicz's disease is one of the IgG4-related diseases (IgG4-RDs) that involves the cardiovascular system; however, small-sized vasculitis is rare in IgG4-related diseases. A 64-year-old man presented with distal occlusive disease and developed left cerebrovascular infarction with occlusion of the middle cerebral artery and diseased temporal artery branches. He underwent superficial temporal artery-middle cerebral artery anastomosis surgery. Histology of the temporal artery biopsy showed smooth muscle cell proliferation with many IgG4-positive plasma cells. He then developed salivary gland inflammation, and Mikulicz's disease was diagnosed. Small-sized occlusive vasculitis was observed in this IgG4-RD. Low-dose corticosteroid therapy is effective in preventing progressive occlusive disease. Keywords: Cerebral infarction, Endovascular therapy, IgG4-related disease, Mikulicz’s disease, Small-sized vasculitis

We retrospectively investigated the impact of the tumor microenvironment (TME) on the efficacy of epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) as first‐line treatment in 70 patients with advanced EGFR‐mutant non‐small cell lung cancer and who were seen at Osaka City University Hospital (Osaka, Japan) between August 2013 and December 2017. Using immunohistochemical staining with 28‐8 and D7U8C Abs, the tumor proportion score was assessed for programmed cell death‐1 ligand‐1 (PD‐L1), as high (50% or more) or low (less than 50%), and ligand‐2 (PD‐L2) expression, respectively. The extent of CD8+ tumor‐infiltrating lymphocytes was evaluated on a scale of 0‐3, with 0‐1 as low and 2‐3 as high. The TME of the 52 evaluable pretreatment specimens was categorized into 4 subtypes, according to the respective PD‐L1 tumor proportion and CD8+ scores, as follows: (a) high/high (13.5%, n = 7); (b) low/low (42.3%, n = 22); (c) high/low (17.3%, n = 9); and (d) low/high (26.9%, n = 14). Expression of PD‐L2 was significantly the highest in type 1 (57.1% vs 4.5% vs 11.1% vs 7.1%, respectively; P = .0090). Response rate was significantly the lowest in type 1 (14.3% vs 81.8% vs 66.7% vs 78.6%, respectively; P = .0085). Progression‐free survival was the shortest in type 1 and the longest in type 4 (median, 2.4 vs 11.3 vs 8.4 vs 17.5 months, respectively; P = .00000077). The efficacy of EGFR‐TKIs differed according to the TME, and the phenotype with high PD‐L1 and CD8+ expression might be the subset that would poorly benefit from such treatment.

BACKGROUND: The authors sought to quantify the results of clinical and radiological analyses of extreme lateral interbody fusion (XLIF) plus percutaneous pedicle screw (PPS) fixation for patients with lumbar spinal stenosis (LSS) by focusing on the distinct mechanism of indirect decompression. METHODS: Data obtained from a total of 37 patients with 47 surgical sites were retrospectively analyzed. Clinical outcomes for all patients were evaluated using the Japanese Orthopaedic Association (JOA) score and the improvement rate of the JOA score. Preoperative and postoperative magnetic resonance images were used to measure the transverse areas of both the dural sac (DS area) and ligamentous flavum (LF area) in the axial sections and the length of the intervertebral disc bulge (DB length) in sagittal sections. Then, the rate of change (RC) of the DS area (RC-DS), the RC of the LF area (RC-LF), and the RC of the DB length (RC-DB) from the preoperative period to the postoperative period were calculated. Furthermore, we divided all surgical sites into the small expansion group (SE group; RC-DS

BACKGROUND: Ultrasound (US)-guided percutaneous needle biopsy is a useful diagnostic technique with short examination time and real-time monitoring at the bedside. However, there are only a few studies that report on thoracic lesions, whereas the computed tomography (CT)-guided biopsy is well established. There is also limited data comparing US- and CT-guided biopsy. We aimed to clarify the efficacy and safety of US-guided biopsy for thoracic lesions adjacent to the chest wall. METHODS: We retrospectively enrolled consecutive patients who underwent US- or CT-guided percutaneous biopsies for thoracic lesions adjacent to the chest wall between April 2012 and December 2017. Clinical characteristics, lesion size, lesion-pleura contact arc length (LPCAL), diagnostic rate, and complications were compared between the 2 groups. RESULTS: This study enrolled 61 US-guided and 70 CT-guided biopsies. No significant difference was found in age or sex. The lesion size and LPCAL in the US-guided group were significantly larger than those in the CT-guided group (P40 mm was significantly higher in the US-guided group than in the CT-guided group (P=0.009). Complication rates were significantly lower in the US-guided group (3.3%) than in the CT-guided group (24.3%) (P

Background The relationship between the timing of the first early recurrence and late recurrence after a single catheter ablation procedure for atrial fibrillation is controversial. Methods The Efficacy of Short-Term Use of Antiarrhythmic Drugs After Catheter Ablation for Atrial Fibrillation trial followed 2038 patients who underwent radiofrequency catheter ablation for atrial fibrillation. Results Of the patients, 907 (45%) had early recurrences within 90 days after the initial ablation. We divided these patients into two groups according to the timing of the first early recurrence episode, namely the ER1 group (early recurrence during the early phase; 0–30 days, n = 814) and ER2 group (early recurrence during the late phase; 31–90 days, n = 93). Three years after ablation, patients with early recurrences had a significantly lower event-free rate from late recurrences after a 90-day blanking period than patients without early recurrences (36.2% and 74.2%, respectively; log-rank, P Conclusion Early recurrences were strongly associated with late recurrences, especially in patients with the first recurrence episode at >1 month within the blanking period after a single ablation procedure. Therefore, these patients should undergo close observation during follow-up, when they had especially with non-paroxysmal atrial fibrillation.

Background: Empagliflozin reduces the risk of hospitalization for heart failure in patients with type 2 diabetes and cardiovascular disease. We sought to elucidate the effect of empagliflozin as an add-on therapy on decongestion and renal function in patients with type 2 diabetes admitted for acute decompensated heart failure. Methods: The study was terminated early due to COVID-19 pandemic. We enrolled 59 consecutive patients with type 2 diabetes admitted for acute decompensated heart failure. Patients were randomly assigned to receive either empagliflozin add-on (n=30) or conventional glucose-lowering therapy (n=29). We performed laboratory tests at baseline and 1, 2, 3, and 7 days after randomization. Percent change in plasma volume between admission and subsequent time points was calculated using the Strauss formula. Results: There were no significant baseline differences in left ventricular ejection fraction and serum NT-proBNP (N-terminal pro-B-type natriuretic peptide), hematocrit, or serum creatinine levels between the 2 groups. Seven days after randomization, NT-proBNP level was significantly lower in the empagliflozin group than in the conventional group ( P =0.040), and hemoconcentration (≥3% absolute increase in hematocrit) was more frequently observed in the empagliflozin group than in the conventional group ( P =0.020). The decrease in percent change in plasma volume between baseline and subsequent time points was significantly larger in the empagliflozin group than in the conventional group 7 days after randomization ( P =0.017). The incidence of worsening renal function (an increase in serum creatinine ≥0.3 mg/dL) did not significantly differ between the 2 groups. Conclusions: In this exploratory analysis, empagliflozin achieved effective decongestion without an increased risk of worsening renal function as an add-on therapy in patients with type 2 diabetes with acute decompensated heart failure. Registration: URL: https://www.umin.ac.jp/ctr/index.htm ; Unique identifier: UMIN000026315.

Introduction: Atrial fibrillation causes cerebral infarction and systemic embolism. Increased D-dimer level indicates the hyperactivation of secondary fibrinolysis, showing thrombosis tendency in the vessel. Hypothesis: To clarify the effects of anticoagulation therapy, we planned to compare the D-dimer levels of peripheral and left atrial (LA) blood in patients scheduled for atrial fibrillation ablation during administration of dabigatran (D), apixaban (A) and edoxaban (E). Methods and Results: We analyzed 141 patients with non-valvular atrial fibrillation (D, n=30; A, n= 47; E, n=64; median age: 68[38-84] years, male: 60%) after exclusion of patients on dialysis. Peripheral venous blood was collected immediately before ablation and LA blood was collected immediately after the Brockenbrough method. We examined laboratory and echocardiographic parameters such as D-dimer and protein C levels, and LA diameter. Anticoagulation therapy was discontinued on the day of ablation. There were no significant differences in ejection fraction, LA diameter and peripheral C-reactive protein levels among the three groups treated with D, A and E. After adjusting for baseline characteristics, D-dimer level in the left atrium treated with E was significantly higher among the three groups (D, 0.550±0.078 vs. A, 0.603±0.052 vs. E, 0.774±0.046), although there were no significant differences in peripheral D-dimer levels (Table). Protein C levels of peripheral blood in group E were significantly suppressed among the three groups (D, 130.17±4.84 vs. A, 102.13±3.59 vs. E, 91.92±2.11, p Conclusions: In the edoxaban group, the D-dimer level in the left atrium was higher than that in the apixaban group, suggesting that the anticoagulatory effect of left atrium is better in apixaban as compared to edoxaban in patient with non-valvular atrial fibrillation.

Background: Diuretic resistance is associated with poor clinical outcome in patients with acute decompensated heart failure (ADHF). However, little information is available on the prognostic significance of diuretic resistance in ADHF patients, relating to reduced, mid-range, or preserved left ventricular ejection fraction (LVEF). Methods: We studied 400 consecutive patients who were admitted for ADHF and survived to discharge. Diuretic resistance (DR) was defined by furosemide dose per body weight (BW) at discharge. Patients were classified by DR, and high dose group (higher DR) was defined by furosemide dose of > median value of DR (0.580). The endpoint was a composite of all-cause mortality and unplanned hospitalization for worsening heart failure. Results: There were 139 patients with heart failure with reduced LVEF (HFrEF, LVEF Conclusions: In this study, higher DR was shown to be associated with poor clinical outcome in HFpEF patients admitted with ADHF.

Backgrounds: Although B-type natriuretic peptide (BNP) and N-terminal pro B-type natriuretic peptide (NT-proBNP ) are interrelated parameters in assessment heart failure severity and prognosis, the ratio of NT-proBNP to BNP (NT-proBNP/BNP) are affected by various clinical factors, such as renal function. However, little is known about the influence of inflammation on NT-proBNP/BNP in patients with heart failure and preserved ejection fraction (HFpEF). Methods and Results: Patients data were extracted from PURSUIT-HFpEF registry, which is a multicenter prospective observational study including patients hospitalized for acute heart failure with left ventricular ejection fraction of >50%. Of 871 patients, data of BNP and NT-proBNP was available in 654 patients. The median baseline concentration of BNP was 474 pg/ml (299-720), NT-proBNP was 3310 pg/ml (1740-6840), and NT-proBNP/BNP was 7.6 (5.0-11.8). In multivariable linear regression analyses, older age [odds ratio (OR); 1.05, 95% confidence interval (CI); 1.02-1.09, p=0.001], higher creatinine [OR; 2.63, 95% CI; 1.66-4.16, pmedian value of 7.6). However, other factors expected to affect NT-proBNP/BNP, such as atrial fibrillation and body mass index, were not associated with a higher NT-proBNP/BNP in this study. Patients in the highest CRP quartile had significantly higher NT-proBNP/BNP than those with other quartiles. Conclusion: In HFpEF patients, concomitant inflammation was associated with high NT-proBNP/BNP, which indicated that we need a careful interpretation on these two natriuretic peptides of patients with HFpEF and inflammatory status, such as infection.

Backgrounds: Controlled heart rate (HR) and increased pulse pressure (PP) are related to better outcomes in stable heart failure. Hemodynamic response to stress evaluated by an acute hemodynamics index (AHI), the product of HR and PP, has been reported to be associated with poor outcomes in patients admitted for acute decompensated heart failure (ADHF). However, there is no information available on the long-term prognostic value of the serial change of AHI during hospitalization in patients admitted for ADHF. Methods and Results: We studied 259 patients admitted for ADHF and discharged with survival. We measured AHI (HR x PP/1000) at admission and discharge. AHI significantly decreased from admission to discharge (6.98±3.04 to 3.81±1.21 bpm·mmHg, p Conclusions: Cardiac death was frequently observed in ADHF patients who had less degree of the decrease in AHI during hospitalization. The change of AHI during hospitalization would be a simple and useful marker for risk stratification in patients admitted for ADHF.

Backgrounds: The Get with The Guidelines (GWTG) heart failure (HF) risk score was developed in the GWTG inpatient HF registry to predict in-hospital mortality and has been recently reported to be associated with post-discharge long-term outcomes. Malnutrition is associated with poor outcome in ADHF patients. However, there is no information available on the long-term prognostic significance of the combination of GWTG-HF risk score and malnutrition in patients admitted for ADHF, relating to reduced left ventricular ejection fraction (LVEF). Methods: We studied 303 ADHF patients discharged with survival (HFrEF(LVEF Results: During a follow-up period of 4.2±3.3 yrs, 86 patients had CVR. At multivariate Cox analysis, GWTG-HF risk score and GNRI were significantly and independently associated with CVR, in both HFrEF and HFpEF groups. The patients with both greater GWTG-HF score (>median value=35) and malnutrition had a significantly increased risk of CVR than those with either and none of them ([HFrEF] 60% vs 32% vs 16%, p Conclusion: Malnutrition assessed by GNRI would provide the additional long-term prognostic information to GWTG-HF risk score in patients admitted for ADHF, irrespective of the presence of reduced LV function.

Background: Cardiac MIBG imaging provides prognostic information in patients with chronic heart failure (CHF). Recent studies showed that the highest occurrence of severe arrhythmic events (SAE) was seen in CHF patients with an intermediate decrease in MIBG uptake rather than the lowest values. On the other hand, non-sustained ventricular tachycardia (NSVT) has been shown to be associated with SAE in CHF patients. However, there is little information available on long-term prognostic value of intermediate decrease in MIBG up take and NSVT for the prediction of severe ventricular tachyarrhythmias in implantable cardioverter defibrillator (ICD) patients. Methods and Results: We prospectively enrolled 201 consecutive outpatients with ICD (age: 64±14 years, male: 81%, NYHA class:1.7±0.7, LVEF: 49±17%). At entry, all patients underwent cardiac MIBG imaging and 24-hour Holter electrocardiogram monitoring. An intermediate decrease in heart-to-mediastinum ratio on delayed planar image (H/M) was defined as 1.40-1.89. NSVT was defined as consecutive 3 or more beats and more than 100 bpm. During a follow-up period of 4.0±2.5 years, 59 patients had appropriate ICD discharge for severe ventricular tachyarrhythmias. At multivariate Cox regression analysis, intermediate decrease in H/M and NSVT were significantly and independently associated with appropriate ICD discharge after adjustment with age, sex and low left ventricular ejection fraction (≤35%). Appropriate ICD discharge was significantly more frequently observed in patients with both intermediate decrease in H/M and NSVT and with either intermediate decrease in H/M or NSVT than with none of them (47% vs 36% vs 14%, p Conclusions: Combination of cardiac MIBG imaging and NSVT would be more strongly associated with an increased risk for severe ventricular tachyarrhythmias in ICD patients.

Background: Cardiohepatic interactions have been a focus of attention in heart failure(HF), and the model for end-stage liver disease excluding INR (MELD-XI) has been shown to be useful for prediction of poor outcome in patients (pts) with acute decompensated heart failure (ADHF). Furthermore, it has been reported that liver stiffness predicts adverse prognosis in pts with HF. Liver fibrosis is assessed by non-invasive fibrosis markers such as Fibrosis-4 (FIB4) index, non-alcoholic fatty liver disease fibrosis score (NFS) and aminotransferase to platelet ratio index (APRI). Recently, a new group of HF pts with mid-range ejection fraction (HFmrEF) has been defined, separated from reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). However, there is little information available on the comparison of prognostic significance of MELD-XI and liver fibrosis scores in ADHF pts, relating to LVEF. Methods: We prospectively studied 466 consecutive ADHF pts (HFrEF (LVEF≦40%): n=164, HFmrEF (40 Results: During a follow-up period of 2.8±1.5 years, 143 pts had ACD. At multivariate Cox analysis, MELD-XI and FIB4 index was independently associated with ACD irrespective of LVEF. The pts with both greater MELD-XI ([HFrEF]≥25.8, [HFmrEF]≥33.2, [HFpEF]≥30.1) and greater FIB4 index ([HFrEF]≥2.58, [HFmrEF]≥2.58, [HFpEF]≥2.22) had a significantly increased risk of ACD than those with either and none of them in all three groups. Conclusions: The combination of MELD-XI and FIB4 index might be useful for stratifying pts at risk for ACD in ADHF pts with irrespective of LVEF.

Backgrounds: Cardiohepatic interactions have been a focus of attention among heart failure (HF). It was reported that liver stiffness assessed by non-invasive fibrosis marker such as Fibrosis-4(FIB4) index provide prognostic information in HF patients. Furthermore, the albumin-bilirubin (ALBI) score has recently been proposed as a validated index of liver dysfunction. We sought to investigate the long-term prognostic values of the combination of FIB4 index and ALBI score in patients admitted for acute decompensated heart failure (ADHF). Methods and Results: We studied 299 ADHF pts with survival discharge. FIB4 index was calculated by the formula: age(yrs) х AST[U/L]/(platelets [10 3 /μL] х (ALT[U/L]) 1/2 ). The ALBI was calculated using the formula: log 10 (total bilirubin) х 0.66 + albuminх-0.085. During a follow-up period of 4.3±3.3 yrs, 94 patients died. At multivariate Cox analysis, FIB4 index and ALBI score were significantly associated with total mortality, independently of prior HF hospitalization and body mass index after adjustment with systolic blood pressure, left ventricular end-diastolic dimension and left atrial dimension indexes. Patients with both greater FIB4 index (>3.608: top tertile) and ALBI score (>-2.076:top tertile) had a significantly higher risk of total mortality than those with either or none of them (46% vs 34% vs 25%, respectively, p=0.002). Conclusion: The combination of FIB4 index and ALBI score might identify higher risk subset for total mortality in ADHF patients.

Background: A four-parameter risk model including cardiac iodine-123 metaiodobenzylguanidine (MIBG) imaging and readily available clinical parameters has been recently developed for the prediction of 2-year cardiac mortality risk in patients with chronic heart failure (CHF) using a Japanese CHF database consisting of 1322 patients. However, there is no information available on the usefulness of 2-year MIBG-based cardiac mortality risk score for the prediction of post-discharge prognosis in patients with heart failure with preserved LVEF (HFpEF) who are admitted with acute decompensated heart failure (ADHF). Methods and Results: Patients' data were extracted from The Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with Preserved Ejection Fraction (PURSUIT-HFpEF) study, which is a prospective multicenter observational registry for ADHF patients with LVEF ≥50% in Osaka. We studied 239 patients who survived to discharge. Cardiac MIBG imaging was performed just before discharge. The 2-year cardiac mortality risk score was calculated using four parameters, including age, LVEF, NYHA functional class, and the cardiac MIBG heart-to-mediastinum ratio on delayed image. The patients were stratified into three groups based on the 2-year cardiac mortality risk score: low- (12%) groups. The endpoint was all-cause death. During a follow-up period of 1.6±0.8 years, 33 patients had all-cause death. Multivariate Cox analysis showed that 2-year MIBG-based cardiac mortality risk score was an independent predictor of all-cause death (p=0.0009). There was significant difference in the rate of all-cause death among the three groups stratified by 2-year cardiac mortality risk score (Figure). Conclusions: In this multicenter study, the 2-year MIBG-based cardiac mortality risk score was shown to be useful for the prediction of post-discharge clinical outcome in HFpEF patients admitted for ADHF.

研究グループは、病後や術後の食欲不振に処方される漢方薬「人参養栄湯」がCOPD(慢性閉塞性肺疾患)の骨格筋合併症に効果があることを明らかにしました。加齢や疾患により筋力が衰え、疲れやすくなり家に閉じこもりがちになるなど、健常から要介護へ移行する中間の段階である衰え全般を「フレイル」と呼び、健康寿命増進のための課題として注目されています。COPDは主にタバコ煙を吸入することにより肺胞が破壊されたり気管支が傷害されたりして生じる肺疾患であり、咳や痰、息切れの他にしばしばフレイルの中核である筋萎縮や筋力低下といった「サルコペニア(筋肉減少症)」を合併します。フレイル・サルコペニアはCOPDの予後を悪化させる因子として知られており、COPDによる死亡者数増加の一端を担っていると考えられます。そのため、COPDの骨格筋合併症に対する治療は喫緊の課題ですが、運動療法以外に単独の効果が確立されたものがないのが現状です。本研究では、人参養栄湯投与により骨格筋組織においてPGC-1α発現が亢進し、COPDモデルマウスの骨格筋合併症が改善されることが示されました。COPD患者においても人参養栄湯を摂取することでサルコペニア・フレイルの悪循環を断ち切ることができる可能性が示され、今まで克服が困難であったCOPDの骨格筋合併症の新たな治療戦略として注目されます。, Purpose: Sarcopenia, the loss of skeletal muscle mass and strength, is a common systemic consequence of chronic obstructive pulmonary disease (COPD) and is correlated with higher mortality. Ninjin’yoeito (NYT) is a Japanese herbal medicine used to treat athrepsia and anorexia and is reported to ameliorate weight loss and muscular dysfunction. Recent studies have shown that its crude components upregulate the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)-related pathway, which is involved in skeletal muscle functions. Here, we examined whether NYT improves skeletal muscle complications by upregulating PGC-1α in COPD model mice. / Materials and Methods: Mice were divided into four groups: control, NYT, smoking, and smoking + NYT. The smoking and smoking + NYT groups were exposed to cigarette smoke for 60 min once daily....

Background Good’s syndrome (GS) is characterized by immunodeficiency, and can lead to severe infection, which is the most significant complication. Although Mycobacterium rarely causes infection in patients with GS, disseminated nontuberculous mycobacterial (NTM) infection frequently occurs in GS patients that are also positive for the human immunodeficiency virus (HIV) or anti-interferon (IFN)-γ autoantibodies. Here, we report a rare case of GS with NTM without HIV or IFN-γ autoantibodies. Case presentation A 57-year-old Japanese male with GS and myasthenia gravis (treated with prednisolone and tacrolimus) was diagnosed with disseminated NTM infection caused by Mycobacterium abscessus subsp. massiliense. He presented with fever and back pain. Blood, lumbar tissue, urine, stool, and sputum cultures tested positive for M. abscessus. Bacteremia, spondylitis, intestinal lumber abscess, and lung infection were confirmed by bacteriological examination and diagnostic imaging; urinary and intestinal tract infections were suspected by bacteriological examination but not confirmed by imaging. Despite multidrug combination therapy, including azithromycin, imipenem/cilastatin, levofloxacin, minocycline, linezolid, and sitafloxacin, the patient ultimately died of the infection. The patient tested negative for HIV and anti-IFN-γ autoantibodies. Conclusions Since myasthenia gravis symptoms interfere with therapy, patients with GS and their physicians should carefully consider the antibacterial treatment options against disseminated NTM.

Immune checkpoint inhibitors (ICIs) have improved the overall survival of many patients with advanced cancers. However, unlike cytotoxic and targeted drugs, ICIs may cause various immune-related adverse events (irAEs). Among these irAEs, autoimmune meningitis is very rare. Here, we report a case of early-onset, atezolizumab-induced meningitis after administration of one dose of atezolizumab. A 56-year-old man with lung adenocarcinoma had received seventh-line treatment with atezolizumab when he experienced dysarthria. Blood examinations, including the measurement of electrolytes, glucose, and organ functions, were unremarkable, but enhanced head magnetic resonance imaging T1-weighted images showed meningeal enhancement. Although cerebral spinal fluid (CSF) examinations revealed elevated lymphocyte and protein levels, no cancer cells were detected in the CSF. CSF cultures and serological tests, including polymerase chain reaction for herpes simplex virus, were negative. The patient was therefore diagnosed with atezolizumab-triggered autoimmune meningitis. With steroid treatment, the patient's clinical and neurological state improved immediately and he recovered to baseline conditions. Prompt diagnosis and therapeutic intervention are essential for the effective treatment of autoimmune meningitis.

The effect of antimicrobial stewardship (AS) on anaerobic bacteremia is uncertain. This study aimed to assess the effect of interventions by the AS team (AST) on clinical and microbiological outcomes and antimicrobial use. An AS program was introduced at Osaka City University Hospital in January 2014; an interdisciplinary AST was established. We enrolled patients with anaerobic bacteremia between January 2009 and December 2018. Patients were classified into the pre-intervention group (from January 2009 to December 2013) and the post-intervention group (from January 2014 to December 2018). A significant decrease in definitive carbapenem use (P = 0.0242) and an increase in empiric tazobactam/piperacillin use (P = 0.0262) were observed in the post-intervention group. The de-escalation rate increased significantly from 9.38% to 32.7% (P = 0.0316) in the post-intervention group. The susceptibility of Bacteroides species and 30-day mortality did not worsen in the post-intervention group. These results showed that interventions by an AST can reduce carbapenem use and increase the de-escalation rate without worsening patient outcomes.

Background Atrial fibrillation (AF) and ventricular arrhythmias (VAs) are associated with increased morbidity and mortality. However, data are lacking concerning the association of AF and VAs. This study aimed to clarify the association between AF and VAs and to investigate the effect of amiodarone on the incidence of VAs in patients with implantable cardioverter defibrillators (ICDs). Methods and results We enrolled 612 patients who had ICDs or who underwent cardiac resynchronization therapy with a defibrillator (CRT-D) and classified them into two groups (sinus rhythm [SR] group, n = 427; AF group, n = 185) according to their basal rhythm at enrollment. Patients with paroxysmal AF were grouped into the AF group. The incidence of VAs, i.e., ventricular tachycardia (VT) and ventricular fibrillation (VF), was significantly lower in the AF group than in the SR group (0.54 vs 0.95 episodes/person/year, P = 0.032). Furthermore, amiodarone use was significantly higher in the AF group than in the SR group (P = 0.003). Non-use of amiodarone was associated with a significant increase in the occurrence of VT/VF in the two groups. This beneficial suppressive effect of amiodarone on the incidence of VT/VF was present in the AF group regardless of left ventricular ejection fraction (LVEF). However, this effect of amiodarone was present only in patients with LVEF ≥ 40% in the SR group. Conclusions Amiodarone was negatively associated with VT/VF occurrence and was frequently used in ICD/CRT-D patients with AF. VT/VF was controlled by amiodarone in all cases in the AF group but only in patients with an LVEF ≥ 40% in the SR group.

A 47-year-old female patient was admitted with a complaint of severe chest pain on effort. She had a history of effort angina treated using coronary artery bypass with left internal thoracic arterial bypass to the left ascending coronary artery. She also had left subclavian and vertebral arterial stenoses, which were treated with balloon-expandable stents. Exercise stress myocardial perfusion imaging revealed anterior to apex left ventricular myocardial ischemia. Cardiac ischemia due to left subclavian stenosis was diagnosed. We treated the left subclavian arterial stenosis with endovascular therapy. We observed that the vertebral Palmaz stent protruded from the ostium and the jailed subclavian artery on high-resolution angioscopy (Zemporshe with a 0.48-megapixel equivalent resolution; Taisho Biomed Instruments, Osaka, Japan) and optical frequency domain imaging (OFDI). A guide wire was successfully crossed through the Palmaz stent strut, which was confirmed using three-dimensional OFDI. The stent strut was dilated using balloon angioplasty. New imaging technologies are promising tools for improving the efficacy and safety of craniocervical intervention.

Background Clinically amyopathic dermatomyositis with anti-Melanoma Differentiation-Associated gene 5 (MDA5) antibody often presents with severe interstitial lung disease. Although serum ferritin level is known to reflect interstitial lung disease activity, there are few case reports describing this association. Case presentation A 58-year-old man was referred to our outpatient clinic with a 3-week history of cough and respiratory distress. He had erythema over the V area of the neck and a Gottron’s sign. Chest computed tomography revealed diffuse ground-glass opacities and reticular shadows in both lungs. Test for anti-MDA5 antibody was positive. After admission, he received triple combination therapy (methylprednisolone pulse therapy, tacrolimus, and cyclophosphamide). However, his respiratory condition worsened as the serum ferritin level increased. Despite no apparent deterioration on chest radiography, he ultimately died due to respiratory failure. Conclusions In this case, triple combination therapy was not effective for the patient’s respiratory condition. The serum ferritin level was correlated with disease activity and was more useful than chest radiography for monitoring clinical status.

Yukari Sugiyama, Kazuhisa Asai, Kazuhiro Yamada, Yuko Kureya, Naoki Ijiri, Tetsuya Watanabe, Hiroshi Kanazawa, Kazuto Hirata Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan Background: Cigarette smoking-induced oxidant–antioxidant imbalance is a factor that contributes to the pathogenesis of COPD through epithelial cell apoptosis. Irisin is a skeletal muscle cell-derived myokine associated with physical activity. Irisin is also known to decrease oxidant-induced apoptosis in patients with diabetes mellitus. However, the correlation between irisin and emphysema in COPD and its role in epithelial cell apoptosis remains unknown. Subjects and methods: Forty patients with COPD were enrolled in this study. Pulmonary function tests and measurements of the percentage of low-attenuation area on high-resolution computed tomography images were performed, and the results were evaluated for correlation with serum irisin levels. The effect of irisin on cigarette-smoke extract-induced A549 cell apoptosis and the expression of Nrf2, a transcription factor for antioxidants, was also examined in vitro. Results: Serum irisin levels were significantly correlated with lung diffusing capacity for carbon monoxide divided by alveolar volume (r=0.56, P

The index for a target that can lead to improved prognoses and more reliable therapy in each heterogeneous patient with heart failure with preserved ejection fraction (HFpEF) remains to be defined. We examined the heterogeneity in the cardiac performance of patients with HFpEF by clarifying the relationship between the indices of left atrial (LA) volume (LAV) overload and pressure overload with echocardiography. We enrolled patients with HFpEF (N = 105) who underwent transthoracic echocardiography during stable sinus rhythm. Relative LAV overload was evaluated using the LAV index or stroke volume (SV)/LAV ratio. Relative LA pressure overload was estimated using E/e’ or the afterload-integrated index of left ventricular (LV) diastolic function: diastolic elastance (Ed)/arterial elastance (Ea) ratio = (E/e’)/(0.9 × systolic blood pressure). The logarithmic value of the N-terminal pro-brain natriuretic peptide was associated with SV/LAV (r = −0.214, p = 0.033). The pulmonary capillary wedge pressure was positively correlated to Ed/Ea (r = 0.403, p = 0.005). SV/LAV was negatively correlated to Ed/Ea (r = −0.292, p = 0.002), with no observed between-sex differences. The correlations between the LAV index and E/e’ and Ed/Ea and between SV/LAV and E/e’ were less prominent than the abovementioned relationships. SV/LAV and Ed/Ea, showing relative LAV and LA pressure respectively, were significantly but modestly correlated in patients with HFpEF. There may be considerable scatter in the relationships between these indices, which could possibly affect the selection of medications or efforts to improve the prognoses of patients with HFpEF.

Background: Chronic Obstructive Pulmonary Disease (COPD) is a pulmonary disease caused by long-term inhalation exposure of harmful substances, mainly cigarette smoke. Oxidative stress is considered as one of the important mechanisms of COPD. Irisin is a kind of myokine secreted from muscle by exercise. Recent studies have shown that irisin acts defensively against oxidative stress via Nrf2, a transcription factor responsible for antioxidant capacity. In this study, we examined emphysema suppression effect of exercise in mice. Methods: Mice were divided into three groups: control, smoking, and exercise+smoking. All mice in smoking and exercise+smoking groups were exposed to cigarette smoking for 60 minutes per session once a day. All mice in exercise+smoking group were adapted to treadmill for 30 minutes per session once a day. After 12 weeks intervention, serum irisin concentration, expression of Nrf2 mRNA and protein in lung homogenate, number of inflammatory cells in bronchoalveolar lavage fluid (BALF), and Mean Liner Intercept (MLI) in lung tissue were examined. Results: Serum irisin concentration and expression of Nrf2 (mRNA and protein) in lung homogenate were significantly elevated in exercise+smoking group compared to control group and smoking group. Proportion of neutrophils in BALF was significantly lower in exercise+smoking group than that in smoking group. MLI was significantly smaller in exercise+smoking group than that in smoking group. Conclusions: Our results suggested that irisin secreted from muscle by exercise might act defensively against oxidative stress via Nrf2, and ameliorate emphysema in lung. Exercise-irisin axis might be a novel target for COPD treatment.

概要：抗酸化物質で大豆などに含まれるイソフラボンがCOPD(慢性閉塞性肺疾患)の予防効果を有することを明らかにしました。COPDは日本では約500万人以上が罹患しており、進行すると咳や痰、息切れを自覚し、在宅酸素療法を必要とする患者さんもいます。COPDによる死亡者数は年々増加しており、WHO(世界保健機関)の報告ではCOPDは世界の死因第3位の疾患で、COPD患者の肺では、マクロファージや好中球などの炎症細胞の増加、肺胞壁の破壊による肺気腫が見られます。現時点では破壊された肺を元に戻す有効な治療法はなく、予防が肝要とされています。これまで疫学研究では大豆摂取によるCOPD発症リスク低減が報告されていましたが、そのメカニズムは解明されていませんでした。そこで、喫煙曝露によりCOPDを発症するマウスにイソフラボンを投与したところ、炎症細胞の減少や肺気腫の抑制効果を認めました。また、肺組織中の炎症形成に関わるサイトカイン等の上昇を抑制することも確認しました。本研究は、イソフラボンが抗炎症作用によりCOPD予防を果たすことを実験的に明らかにしたもので、今後のCOPD治療確立に向けて重要な知見であるといえます。, Chronic obstructive pulmonary disease (COPD), a lung disease caused by chronic exposure to cigarette smoke, increases the number of inflammatory cells such as macrophages and neutrophils and emphysema. Isoflavone is a polyphenolic compound that exists in soybeans. Daidzein and genistein, two types of isoflavones, have been reported to have anti-inflammatory effects in various organs. We hypothesized that the daidzein-rich soy isoflavone aglycones (DRIAs) attenuate cigarette smoke-induced emphysema in mice. Mice were divided into four groups: the (i) control group, (ii) isoflavone group, (iii) smoking group, and (iv) isoflavone + smoking group. The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) and the airspace enlargement using the mean linear intercept (MLI) were determined 12 weeks after smoking exposure. Expressions of neutrophilic inflammatory cytokines and chemokines were also examined. In the isoflavone + smoking group, the number of neutrophils in BALF and MLI was significantly less than that in the smoking group. Furthermore, the gene-expressions of TNF-α and CXCL2 (MIP-2) in the isoflavone + smoking group were significantly less than those in the smoking group. Supplementation of the COPD murine model with DRIAs significantly attenuates pathological changes of COPD via suppression of neutrophilic inflammation.

Objectives Low-frequency epidermal growth factor receptor (EGFR) T790M mutation could be detected by ultrasensitive methods in EGFR tyrosine kinase inhibitor (TKI)-naive non-small cell lung cancer (NSCLC). However, the impact of pretreatment T790M (preT790M) on the efficacy of EGFR-TKIs and on resistance remains unclear. Materials and methods Two independent cohorts consisting of advanced EGFR-mutated NSCLC patients treated with first-line EGFR-TKIs, a derivation cohort that started treatment between August 2013 and July 2016 (cohort A, n = 44) and a validation cohort between August 2016 and December 2017 (cohort B, n = 22), were examined in this study. Among these, 28 patients underwent re-biopsy at disease progression. DNAs from pretreatment tumor biopsy samples and re-biopsy samples were assessed to detect T790M by the Cobas EGFR Mutation Test v2 (Cobas) and for quantitating T790M by droplet digital polymerase chain reaction (ddPCR). Results Detection rates of preT790M were 40.9% (18/44) in cohort A and 45.5% (10/22) in cohort B by ddPCR, and none by Cobas. A cutoff value of 0.3% for dividing into high- vs. low-preT790M allele frequency was determined by receiver operating characteristic curve analysis in cohort A. Progression-free survival (PFS) was significantly shorter in the high- preT790M group (n = 12) than in the low-preT790M (n = 6) and negative (n = 26) groups (combined low-preT790M) (median: 6.9 vs. 13.8 months, P = 0.00073). These observations were validated in cohort B [median: 6.2 (n = 5) vs. 15.3 months (n = 17), P = 0.0029]. In 28 paired biopsies, Cobas detected post-progression T790M in 60% (3/5) of the high-preT790M, in 57% (4/7) of the low-preT790M, and in 56% (9/16) of the negative-preT790M groups. Conclusion EGFR-mutated NSCLC with high preT790M had significantly shorter PFS on EGFR-TKIs. However, preT790M abundance may not necessarily confer post-TKI T790M resistance.