Tokai University Tokyo Hospital

Satisfactory results have not yet been obtained in therapy for secondary prevention in ischemic stroke patients with antiphospholipid syndrome (APS). We therefore compared single antiplatelet therapy and a combination of antiplatelet and anticoagulation therapy for secondary prevention in ischemic stroke patients with APS.The subjects were 20 ischemic stroke patients with antiphospholipid antibody, 13 with primary antiphospholipid syndrome and 7 with SLE-related antiphospholipid syndrome. Diagnosis of APS was based on the 2006 Sydney criteria. Eligible patients were randomly assigned to either single antiplatelet therapy (aspirin 100 mg) or a combination of antiplatelet and anticoagulation therapy (target INR: 2.0-3.0; mean 2.4+/-0.3) for the secondary prevention of stroke according to a double-blind protocol. There was no significant difference between the two groups in age, gender, NIH Stroke Scale on admission, mRS at discharge, or rate of hypertension, diabetes mellitus, hyperlipidemia, or cardiac disease. We obtained Kaplan-Meier survival curves for each treatment. The primary outcome was the occurrence of stroke. The mean follow-up time was 3.9+/-2.0 years. The cumulative incidence of stroke in patients with single antiplatelet treatment was statistically significantly higher than that in patients receiving the combination of antiplatelet and anticoagulation therapy (log-rank test, p-value=0.026). The incidence of hemorrhagic complications was similar in the two groups. The recent APASS study did not show any difference in effectiveness for secondary prevention between single antiplatelet (aspirin) and single anticoagulant (warfarin) therapy. Our results indicate that combination therapy may be more effective in APS-related ischemic stroke.

BACKGROUND: The modified Rankin scale (mRS) is commonly employed as a measure of functional outcome after stroke. The purpose of this study was to investigate the reliability of the mRS using an expanded guidance scheme and a corresponding questionnaire on an unprecedentedly large scale. METHODS: Neurologists interviewed patients with cerebral infarction on the basis of the questionnaire. These interviews were recorded on videotape. Raters (10 neurologists, 6 nurses and 4 physiotherapists) watched the videotapes of 30 patients interviewed and assessed the mRS according to the guidance scheme. RESULTS: The agreement between the raters, as estimated from the intraclass correlation coefficient, was found to be satisfactory with values of 0.947 for neurologists and 0.963 for nurses and physiotherapists. The reproducibility was also satisfactory with values of 0.865 and 0.871, respectively. CONCLUSION: The data obtained suggest that our guidance scheme and questionnaire are useful for ensuring the quality of assessments made with the mRS.

AIMS/INTRODUCTION: Elevation of the branched-chain amino acids (BCAAs), valine, leucine and isoleucine; and the aromatic amino acids, tyrosine and phenylalanine, has been observed in obesity-related insulin resistance. However, there have been few studies on Asians, who are generally less obese and less insulin-resistant than Caucasian or African-Americans. In the present study, we investigated the relationship between homeostasis model assessment of insulin resistance (HOMA-IR) and plasma amino acid concentration in non-diabetic Japanese participants. MATERIALS AND METHODS: A total of 94 healthy men and women were enrolled, and plasma amino acid concentration was measured by liquid chromatography/mass spectrometry after overnight fasting. The associations between HOMA-IR and 20 amino acid concentrations, and anthropometric and clinical parameters of lifestyle-related diseases were evaluated. RESULTS: The mean age and body mass index were 40.1 ± 9.6 years and 22.7 ± 3.9, respectively. Significantly positive correlations were observed between HOMA-IR and valine, isoleucine, leucine, tyrosine, phenylalanine and total BCAA concentration. Compared with the HOMA-IR ≤ 1.6 group, the HOMA-IR > 1.6 group showed significantly exacerbated anthropometric and clinical parameters, and significantly elevated levels of valine, isoleucine, leucine, tyrosine, phenylalanine and BCAA. CONCLUSIONS: The present study shows that the insulin resistance-related change in amino acid profile is also observed in non-diabetic Japanese subjects. These amino acids include BCAAs (valine, isoleucine and leucine) and aromatic amino acids (tyrosine and phenylalanine), in agreement with previous studies carried out using different ethnic groups with different degrees of obesity and insulin resistance.

Abstract International Headache Society published the International Classification of Headache Disorders 2nd Edition (ICHD‐II) in 2004. In response to this development, the “Clinical Practice Guideline for Chronic Headache” was compiled in Japan by the Study Group for Chronic Headache Clinical Practice Guideline Development. In 2006, the book entitled “The Clinical Practice Guideline for Chronic Headache (edited by Japanese Headache Society)” was published as the first edition. As triptans have become widely used, clinical practice for chronic headache has also been changed in Japan and there was a need to revise the first edition. Essentially based on the first edition, the new guideline has added the latest information and presented the concept of international standards of chronic headache care. This guideline included eight chapters and appendix: I. headache: general considerations, II. migraine, III. tension‐type headache, IV. trigeminal autonomic cephalalgias, V. other primary headache disorders, VI. medication‐overuse headache, VII. headaches in children, and VIII. genetics. We have published the second version in Japanese in 2013, but 1 month after we published the original guideline, the International Classification of Headache Disorders 3rd Edition beta version (ICHD‐3beta) was published. We changed this guideline to the new version in English based on ICHD‐3beta. This guideline is the final product of the Committee's efforts in 2015, which was opened in the home page of the Japanese Headache Society. This manuscript was written to show the main part of this guideline as Recommendation of each CQ. Among 121 CQs, only five CQ was selected to present full sentences including not only Recommendation but also other parts.

BACKGROUND: The Cilostazol Stroke Prevention Study 2 (CSPS 2) showed that cilostazol significantly reduced the risk of stroke by 25.7% relative to aspirin, with significantly fewer hemorrhagic events, in patients with prior ischemic stroke, excluding cardioembolic stroke. However, whether the benefit of cilostazol is sustained in patients with a high risk of bleeding has not been examined. METHODS: We conducted a subanalysis of CSPS 2 to examine whether known risk factors for hemorrhagic stroke, such as stroke subtype and systolic blood pressure (SBP), influence the efficacy of the study drugs on hemorrhagic stroke. The relative risk reduction of hemorrhagic stroke was determined from the incidences calculated by the person-year method. The cumulative incidence rates of ischemic stroke and hemorrhagic stroke were estimated and plotted using the Kaplan-Meier method. Incidences of serious hemorrhage and hemorrhage requiring hospital admission were also evaluated in the two treatment groups. Hazard ratios (HR) and 95% confidence intervals (95% CI) calculated by the Cox proportion hazard model for cilostazol versus aspirin were assessed, and a log-rank test was used for the comparison between treatments. RESULTS: The incidence of hemorrhagic stroke was significantly lower in the cilostazol group than in the aspirin group among patients with prior lacunar stroke (0.36 vs. 1.20% in person-year, HR 0.35, 95% CI 0.18-0.70, p < 0.01), but not among those with prior atherothrombotic stroke (0.31 vs. 0.59% in person-year, HR 0.53, 95% CI 0.14-2.0, p = 0.34). The incidence of hemorrhagic stroke was significantly lower in the cilostazol group than in the aspirin group throughout all SBP categories (Poisson regression model including time-dependent covariates, p < 0.01) including SBP above 140 mm Hg (cilostazol 0.45% vs. aspirin 1.44% in person-year; Poisson regression model including time-dependent covariates, p = 0.02). Cilostazol, compared with aspirin, significantly reduced the incidence of cerebral hemorrhage (HR 0.36, 95% CI 0.19-0.70, p < 0.01), overall hemorrhage requiring hospital admission (HR 0.53, 95% CI 0.29-0.97, p = 0.04), and gastrointestinal (GI) bleeding requiring hospital admission (HR 0.44, 95% CI 0.21-0.90, p = 0.03). CONCLUSIONS: Hemorrhagic stroke was less frequent in the cilostazol group than in the aspirin group among patients with lacunar stroke as well as those with increased blood pressure levels. As for extracranial hemorrhage requiring hospitalization, GI bleeding was also less frequent in the cilostazol than in the aspirin group. Cilostazol is supposed to be a therapeutic option to replace aspirin for secondary stroke prevention, especially in these subgroups with high risks for hemorrhagic events.

BACKGROUND: Although there is evidence about the beneficial effects of probiotics, their effects on aspirin-induced small bowel injuries have not been well examined. We evaluated the effects of the probiotic Lactobacillus gasseri OLL2716 (LG) on aspirin-induced small intestinal lesions, such as ulcers, erosions, reddened lesions, and bleeding. SUMMARY: This study enrolled 64 patients who received aspirin for more than 1 month and provided written informed consent to be part of the study. The patients received 112 ml of yogurt containing LG or placebo twice daily for 6 weeks. Small bowel injuries were evaluated by capsule endoscopy before and after consuming the yogurt. The effect of LG on patient symptoms was also assessed using the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (FSSG) and Gastrointestinal Symptom Rating Scale (GSRS) questionnaires before and after 6 weeks of treatment. There was no significant difference in any baseline characteristics and the number of small bowel mucosal breaks between the 2 groups. In contrast with the placebo group, the LG group had significantly fewer small bowel mucosal breaks and reddened lesions after 6 weeks (p < 0.01). The FSSG and GSRS scores were also significantly improved in the LG group but not in the placebo group. Key Messages: This double-blind, placebo-controlled study found that LG may be useful in reducing aspirin-induced small bowel injuries and in mitigating gastrointestinal symptoms.

Importance: The clinical characteristics and outcomes of women and men with atrial fibrillation (AF) are reported to be different. However, whether sex-related differences extend to patients' symptom burden and perceived quality of life (QOL) or the management pattern of AF has been rarely studied, particularly in Asian countries. Objective: To assess the differences in symptoms, treatment, and QOL between Japanese female and male patients with AF. Design, Setting, and Participants: Retrospective cohort study using data from the multicenter outpatient registry Keio Interhospital Cardiovascular Studies-Atrial Fibrillation (KiCS-AF), which collects information regarding health status and the treatment of patients with newly diagnosed or referred AF. One-year follow-up data were available for 1534 patients at 11 referral centers in the Tokyo, Japan, area who were enrolled between September 2012 and December 2015. All data available up to the 1-year follow-up examination through July 31, 2017, were included. Main Outcomes and Measures: Sex, symptoms, AF treatment, and QOL as determined by Atrial Fibrillation Effect on Quality of Life (AFEQT) questionnaires at their initial visit and 1 year later. Results: Of 1534 patients, 1076 (70.1%) were men. Compared with men, women were more likely to be older (median age, 73 years [interquartile range {IQR}, 65-78 years] vs 65 years [IQR, 57-73 years], P < .001) and have higher median brain-type natriuretic peptide levels (102.8 pg/mL [IQR, 47.3-235.5 pg/mL] vs 74.1 pg/mL [IQR, 28.5-150.5 pg/mL], P < .001). Women also had lower median AFEQT overall summary scores than men (75 [IQR, 61-85] vs 80 [IQR, 69-90]; P < .001) but similar treatment satisfaction at baseline. During follow-up, women were less likely to be treated with a rhythm control strategy (48.1% [n = 214] vs 58.0% [n = 621], P < .001), including catheter ablation of AF (adjusted hazard ratio, 0.77 [95% CI, 0.62-0.95]; P = .02). At 1-year follow-up, women and men had improved QOL scores, regardless of their baseline characteristics (eg, age or brain-type natriuretic peptide levels) or treatment strategies, yet the sex gap persisted and grew (adjusted change in AFEQT overall summary score during 12 months, 5.89 [95% CI, 2.24-9.54] in women vs 8.94 [95% CI, 5.59-12.30] in men; P = .02). Conclusions and Relevance: In contemporary Japanese clinical practice among unselected patients with AF, women were initially seen with greater QOL impairment, and the sex gap grew 1 year after presentation. The present study underscores the need for focused efforts to better understand and close this observed sex gap over the initial year of treatment for patients with AF.

Exercise stress testing has been widely undertaken for the diagnosis of heart diseases. The accurate assessment of clinical conditions can be conducted by comparing the findings obtained from the results of stress echocardiography with the changes in the blood/heart rate and electrocardiograms. Numerous overseas studies have reported the utility of stress echocardiography in diagnosing myocardial ischemia; in Japan, the use of this modality for this purpose was included in the national health insurance reimbursable list in 2012. Nevertheless, stress echocardiography is far from being a widespread practice in Japan. This might be due to insufficient equipment (e.g., ergometers, space for test implementation) at each medical institution, shortage of technicians and sonographers who are well experienced and who are responsible for obtaining images during stress testing. The other possible reasons include the limited evidence available in Japan and the lack of a standardized testing protocol. Further dissemination of the practice of exercise stress echocardiography in this country is deemed necessary to establish satisfactory evidence for the use of stress echocardiography in the Japanese population. To this end, efforts are underway to develop a standardized protocol and report format to be adopted throughout Japan. We here present a guideline created by the Guideline Development Committee of the Japanese Society of Echocardiography that describes safe and effective stress echocardiography protocols and report formats. The readers are encouraged to perform exercise stress echocardiography using the proposed template for consensus document and report attached to this guideline.

BACKGROUND: Many studies have investigated the prognosis of nonalcoholic fatty liver disease (NAFLD); however, most studies had a relatively short follow-up. To elucidate the long-term outcome of NAFLD, we conducted a retrospective cohort study of patients with biopsy-proven NAFLD. METHODS: We re-evaluated 6080 patients who underwent liver biopsy from 1975 to 2012 and identified NAFLD patients without other etiologies. With follow-up these patients, we evaluated the outcome-associated factors. RESULTS: A total of 223 patients were enrolled, 167 (74.9%) was non-alcoholic steatohepatitis (NASH). The median follow-up was 19.5 (0.5-41.0) years and 4248.3 person-years. The risk of type 2 diabetes mellitus (T2DM) and hypertension was 11.7 (95% confidence interval [CI] 8.70-15.6) and 7.99 (95% CI 6.09-10.5) times higher, respectively, in NAFLD patients than in the general population. Twenty-three patients died, 22 of whom had NASH. Major causes of death were extrahepatic malignancy and cardiovascular disease (21.7%) followed by liver-related mortality (13.0%). All-cause mortality was significantly higher in NASH patients than in nonalcoholic fatty liver patients (P = 0.041). In multivariate analysis, older age (hazard ratio [HR] 1.09 [95% CI 1.05-1.14], P<0.001) and T2DM (HR 2.87 [95% CI 1.12-7.04], P = 0.021) were significantly associated with all-cause mortality. The factors significantly associated with liver-related events were older age, T2DM, milder hepatic steatosis, and advanced liver fibrosis. Body mass index wasn't associated with either mortality or liver-related events. CONCLUSIONS: T2DM was highly prevalent in NAFLD patients and was significantly associated with both all-cause mortality and liver-related events. The lean patients' prognosis wasn't necessarily better than that of overweight patients.

BACKGROUND: In vitro drug screening studies have indicated that camostat mesilate (FOY-305) may prevent SARS-CoV-2 infection into human airway epithelial cells. This study was conducted to investigate whether camostat mesilate is an effective treatment for SARS-CoV-2 infection (COVID-19). METHODS: This was a multicenter, double-blind, randomized, parallel-group, placebo-controlled study. Patients were enrolled if they were admitted to a hospital within 5 days of onset of COVID-19 symptoms or within 5 days of a positive test for asymptomatic patients. Severe cases (e.g., those requiring oxygenation/ventilation) were excluded. Patients were enrolled, randomized, and allocated to each group using an interactive web response system. Randomization was performed using a minimization method with the factors medical institution, age, and underlying diseases (chronic respiratory disease, chronic kidney disease, diabetes mellitus, hypertension, cardiovascular diseases, and obesity). The patients, investigators/subinvestigators, study coordinators, and other study personnel were blinded throughout the study. Patients were administered camostat mesilate (600 mg qid; four to eight times higher than the clinical doses in Japan) or placebo for up to 14 days. The primary efficacy endpoint was the time to the first two consecutive negative tests for SARS-CoV-2. RESULTS: One-hundred fifty-five patients were randomized to receive camostat mesilate (n = 78) or placebo (n = 77). The median time to the first test was 11.0 days (95% confidence interval [CI]: 9.0-12.0) in the camostat mesilate group and 11.0 days (95% CI: 10.0-13.0) in the placebo group. Conversion to negative viral status by day 14 was observed in 45 of 74 patients (60.8%) in the camostat mesilate group and 47 of 74 patients (63.5%) in the placebo group. The primary (Bayesian) and secondary (frequentist) analyses found no significant differences in the primary endpoint between the two groups. No additional safety concerns beyond those already known for camostat mesilate were identified. CONCLUSIONS: Camostat mesilate did not substantially reduce the time to viral clearance, based on upper airway viral loads, compared with placebo for treating patients with mild to moderate SARS-CoV-2 infection with or without symptoms. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04657497. Japan Registry for Clinical Trials, jRCT2031200198.

Legumes are low-carbohydrate food and are abundant in dietary fiber. In order to provide a functional staple food that does not cause a rapid increase in postprandial blood glucose levels, four kinds of legumes were focused on as ingredients. Noodles made from dehulled yellow pea, unshelled yellow pea, chickpea, and lentil were prepared and evaluated as functional staple foods for controlling blood glucose via an in vitro digestion method. We also measured breaking stress and breaking strain using a creep meter, as well as sensory tests on a 9-point hedonic scale. The noodles made from yellow pea had high values for both breaking stress and breaking strain, and was highly regarded in the sensory tests. Therefore, the noodles made from yellow pea on postprandial glucose and insulin response were measured in a randomized double-blind study (n = 12). The results show that noodles made from yellow pea have a low glycemic index (50.4), and have potential as a functional staple food.

Echocardiography plays a pivotal role as an imaging modality in the modern cardiology practice. Information derived from echocardiography is definitely helpful for a patient care. The Japanese Society of Echocardiography has promoted echocardiography for a routine clinical and research use. One of the missions of the Society is to provide information that is useful for high-quality examinations. To ensure it, we believe equipment in good conditions and a comfortable environment are important for both a patient and an examiner. Thus, the Committee for Guideline Writing, the Japanese Society of Echocardiography published brief guidance for the routine use of echocardiography equipment in 2015. Recently, the importance of international standardization has been emphasized in the medical laboratories. Accordingly, the committee has revised and updated our guidance for the routine use of echocardiography equipment.

BACKGROUND: The predictive value of asymptomatic intracranial artery stenosis for future stroke remains uncertain. The aim of this study is to assess the stroke risk of asymptomatic intracranial artery stenosis and to compare it with that of extracranial artery disease. METHODS: The study subjects were 2,924 participants (mean age 55 years) without any history of stroke. We examined the relation between intra- or extracranial large-artery disease and subsequent cerebrovascular events (mean follow-up 63 months). RESULTS: The incidence rate of total cerebrovascular events in persons with intracranial artery stenosis was 1.3% per year. In the group without plaque in the extracranial carotid arteries, the annual rate of total cerebrovascular events was only 0.6%, but in the group with plaque, the rate was 3.6%. Kaplan-Meier analysis of total events showed a significant difference between the 2 groups (p = 0.002). CONCLUSIONS: The stroke risk in subjects with asymptomatic extracranial artery disease is markedly increased if intracranial artery stenosis is also present.

To investigate the relationships between sensitivity loss in various subfields of the central 10° of the binocular integrated visual field (IVF) and vision-related quality of life (VRQoL) in 172 patients with advanced glaucoma. Using the Random Forest algorithm, which controls for inter-correlations among various subfields of the IVF, we analysed the relationships among the Rasch analysis-derived person ability index (RADPAI), age, best-corrected visual acuity (BCVA), mean total deviations (mTDs) of eight quadrant subfields in the IVF measured with the Humphrey Field Analyzer (HFA) 10-2 program (10-2 IVF), and mTDs of the upper/lower hemifields in the IVF measured with the HFA 24-2 program (24-2 IVF). Significant contributors to RADPAIs were as follows: the inner and outer lower-right quadrants of the 10-2 IVF contributed to the dining and total tasks; the lower-left quadrant of the 10-2 IVF contributed to the walking, going out and total tasks; the lower hemifield of the 24-2 IVF contributed to the walking, going out, dining, miscellaneous and total tasks; and BCVA contributed more to the letter, sentence, dressing and miscellaneous tasks than to others. The impact of damage in different 10-2 IVF subfields differed significantly across daily tasks in patients with advanced glaucoma.

CONCLUSION: We performed therapeutically successful intracordal injection of autologous fat harvested from the buccal fat pad. OBJECTIVE: Autologous fat has been used increasingly for intracordal injection as vocal rehabilitation in patients with deficient glottal closure. Adipose tissues used have been harvested mostly from the lower abdomen. However, patients differ considerably in the amount of fat available from the lower abdomen, and it is often difficult to obtain sufficient fat in patients with a low body mass index (BMI). Moreover, the scar visible after harvesting can be cosmetically undesirable. As an alternative, we evaluated harvesting of the buccal fat pad, as in plastic surgery. PATIENTS AND METHODS: From January to December 2005, intracordal buccal fat injection was performed for 10 patients, who were subsequently followed up for over 6 months. Buccal mucosa was incised under general anesthesia to expose and harvest the buccal fat pad. This fat was cut into small pieces and injected into the vocal cord. Maximum phonation time and glottal aerodynamics were evaluated pre- and postoperatively. Glottal closure and mucosal vibration were examined stroboscopically. RESULTS: Except in one patient, no postoperative complications such as swelling or infection followed either harvesting or injection. After injection, phonation showed notable improvement that was maintained throughout follow-up.

Purpose Besides the high rates of morbidity and mortality, atrial fibrillation (AF) is also associated with impairment of quality-of-life (QOL). However, reports covering non-selected AF population within Asian countries remain scarce. The objective of the Keio interhospital Cardiovascular Studies-atrial fibrillation (KiCS-AF) registry is to clarify the baseline and QOL profiles of the AF patients at the time of initial referral to identify areas for improvement and country-specific gaps. Participants The KiCS-AF registry is a multicentre, prospective cohort study designed to specifically recruit AF patients newly referred to the 11 network hospitals within the Kanto area of Japan. The registry completed its enrolment in June 2018. All patients were requested to answer the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire both at baseline and 1 year, with planned clinical follow-up for 5 years. The registry also assessed individual treatment strategies including rate and rhythm control, stroke prophylaxis, and their impacts on patient-reported QOL. Findings to date As of December 2016, 2464 AF patients were registered; their mean age was 67.1 years (SD, 11.7), majority (69.7%; n=1717) were men and 49.2% presented with paroxysmal AF. The mean CHA 2 DS 2 -VASc (cardiac failure or dysfunction, hypertension, age ≥75 years, diabetes, stroke including vascular disease, age 65-74 years, and sex category [female]) score was 2.3 (SD, 1.6) and oral anticoagulant therapy was used for 88.6% of patients with CHA 2 DS 2 -VASc scores ≥2. The median AFEQT-overall summary score was 79.1 (IQR, 66.6–89.1). Roughly 50% had significantly impaired QOL (ie, AFEQT &lt;80) at baseline. Currently, 2307 eligible patients (93.6%) have completed the 1-year follow-up, of which 2072 patients (89.8%) answered the second AFEQT questionnaire. Future plans The KiCS-AF allowed for extensive investigation of AF-related QOL in a non-selected population with long-term follow-up using a rigorously validated QOL assessment tool. Almost half of patients had impaired QOL at baseline. Further investigations aimed at providing care and improving patient-reported QOL are required.

Recent advances in imaging analysis have enabled evaluation of ventilation and perfusion in specific regions by chest computed tomography (CT) and magnetic resonance imaging (MRI), in addition to modalities including dynamic chest radiography, scintigraphy, positron emission tomography (PET), ultrasound, and electrical impedance tomography (EIT). In this review, an overview of current functional imaging techniques is provided for each modality. Advances in chest CT have allowed for the analysis of local volume changes and small airway disease in addition to emphysema, using the Jacobian determinant and parametric response mapping with inspiratory and expiratory images. Airway analysis can reveal characteristics of airway lesions in chronic obstructive pulmonary disease (COPD) and bronchial asthma, and the contribution of dysanapsis to obstructive diseases. Chest CT is also employed to measure pulmonary blood vessels, interstitial lung abnormalities, and mediastinal and chest wall components including skeletal muscle and bone. Dynamic CT can visualize lung deformation in respective portions. Pulmonary MRI has been developed for the estimation of lung ventilation and perfusion, mainly using hyperpolarized 129Xe. Oxygen-enhanced and proton-based MRI, without a polarizer, has potential clinical applications. Dynamic chest radiography is gaining traction in Japan for ventilation and perfusion analysis. Single photon emission CT can be used to assess ventilation-perfusion (V˙/Q˙) mismatch in pulmonary vascular diseases and COPD. PET/CT V˙/Q˙ imaging has also been demonstrated using “Galligas”. Both ultrasound and EIT can detect pulmonary edema caused by acute respiratory distress syndrome. Familiarity with these functional imaging techniques will enable clinicians to utilize these systems in clinical practice.

Potential conflict of interest: Nothing to report. Osteoporosis is a major complication in patients with primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH). Denosumab, a fully human monoclonal antibody against the receptor activator of nuclear factor‐dB ligand (RANKL), increases bone mineral density (BMD) by inhibiting development and activity of osteoclasts and decreasing bone resorption. We have already reported the efficacy and safety of short‐term (1‐year) denosumab therapy for osteoporosis in patients with PBC or AIH,1 but the effect of long‐term administration remains unknown. In this study, we aimed to clarify the efficacy and safety of long‐term denosumab therapy for osteoporosis in patients with PBC or AIH. Case Series We enrolled 10 consecutive PBC (n = 6, 5; stage I or II, 1; stage IV) or AIH (n = 4) patients with osteoporosis who received subcutaneous denosumab treatment at a dose of 60 mg every 6 months for 36 months or more between November 2014 and September 2018, whose BMD at the lumbar spine by dual‐energy X‐ray absorptiometry was less than 2.5 SD below the mean of young adult population (expressed as a T score). All patients were postmenopausal women with a median age of 68.5 (range: 59‐79) years who had not received bone resorption inhibitors. The PBC and AIH patients had been treated for more than 6 months with ursodeoxycholic acid (600 mg/day) and small doses of prednisolone (3 or 5 mg/day), respectively, without any signs of cholestasis or liver failure. All patients received supplementation with oral calcium (305 mg/day) and vitamin D (200 IU/day) in addition to these drugs. The BMD (T score) gradually and significantly improved with denosumab treatment over 36 months (Fig. 1A). Serum tartrate‐resistant acid phosphatase 5b (TRACP‐5b) and alkaline phosphatase 3 (ALP3, bone‐related isozyme) levels were significantly reduced (Fig. 1B,C). In this study period, fresh vertebral fractures and denosumab‐related adverse events including hypocalcemia, atypical femoral fractures, and osteonecrosis of the jaw were not observed (Fig. 1D).Figure 1: Changes in (A) BMD (T score), (B) serum TRACP‐5b, (C) ALP 3, and (D) calcium (Ca) levels before and 12, 24, and 36 months (M) after denosumab treatment. Data are presented as box‐and‐whisker plots and are expressed as a median with the interquartile range and maximum and minimum values. Dots represent outliers defined as values exceeding the 75th percentile plus 1.5 times the interquartile range. *P < 0.01 (Wilcoxon signed‐rank test).Discussion This report shows the efficacy and safety of long‐term denosumab therapy for osteoporosis in patients with autoimmune liver diseases. The BMD significantly increased after denosumab treatment compared with the baseline. The decline in serum level of TRACP‐5b, a bone resorption marker, and ALP3 suggests the decrease in bone turnover by denosumab treatment. PBC and AIH are refractory autoimmune liver diseases that predominantly occur in middle‐aged women. PBC is associated with the development of osteoporosis—a relative risk of 2.79 for osteoporosis and an odds ratio of 1.86 for the development of bone fractures compared with non‐PBC populations. The suggested mechanisms of increased risk of osteoporosis in PBC include impaired conversion to 25‐OH vitamin D, releasing cytokines and deficiency of insulin‐like growth factor‐1.2 Glucocorticoid induces RANKL expression, which leads to inappropriate bone remodeling with increase in osteoclastogenesis and decrease in osteoblastogenesis. Hence, the patients with AIH on maintenance corticosteroid therapy have a higher risk of osteoporosis and bone fractures.3 Bisphosphonates are effective in preventing osteoporosis in patients with PBC or induced by glucocorticoid.3 Denosumab has different mechanisms of action and can be used as a first‐line treatment or as an alternative to bisphosphonates. In postmenopausal women with osteoporosis previously treated with oral bisphosphonates, denosumab was well‐tolerated and increased BMD at all measured skeletal sites and inhibited bone remodeling more effectively compared with once‐yearly intravenous bisphosphonate therapy with zoledronic acid.5 Furthermore, denosumab does not require dose adjustment according to the renal function, indicating superiority of denosumab to bisphosphonates. In this pilot study, we showed that long‐term denosumab therapy significantly increased BMD without any adverse effects in patients with autoimmune liver diseases. These results warrant a large‐scale prospective study.

Chronic intermittent hypoxia (IH) induces activation of the sympathoadrenal system, which plays a pivotal role in attenuating hypoxic pulmonary vasoconstriction (HPV) via central β1-adrenergic receptors (AR) (brain) and peripheral β2AR (pulmonary arteries). Prolonged hypercatecholemia has been shown to upregulate β3AR. However, the relationship between IH and β3AR in the modification of HPV is unknown. It has been observed that chronic stimulation of β3AR upregulates inducible nitric oxide synthase (iNOS) in cardiomyocytes and that IH exposure causes expression of iNOS in RAW264.7 macrophages. iNOS has been shown to have the ability to dilate pulmonary vessels. Hence, we hypothesized that chronic IH activates β3AR/iNOS signaling in pulmonary macrophages, leading to the promotion of NO secretion and attenuated HPV. Sprague-Dawley rats were exposed to IH (3-min periods of 4-21% O2) for 8 h/d for 6 weeks. The urinary catecholamine concentrations of IH rats were high compared with those of controls, indicating activation of the sympathoadrenal system following chronic IH. Interestingly, chronic IH induced the migration of circulating monocytes into the lungs and the predominant increase in the number of pro-inflammatory pulmonary macrophages. In these macrophages, both β3AR and iNOS were upregulated and stimulation of the β3AR/iNOS pathway in vitro caused them to promote NO secretion. Furthermore, in vivo synchrotron radiation microangiography showed that HPV was significantly attenuated in IH rats and the attenuated HPV was fully restored by blockade of β3AR/iNOS pathway or depletion of pulmonary macrophages. These results suggest that circulating monocyte-derived pulmonary macrophages attenuate HPV via activation of β3AR/iNOS signaling in chronic IH.

Purpose: Patients with chronic obstructive pulmonary disease (COPD) have decreased physical activity (PA) compared with healthy adults. As lower PA is associated with increased mortality, improving PA is an important objective for COPD management. This large-scale, multicenter, non-interventional, cross-sectional study examined the activity status of COPD patients in Japan and explored factors related to PA. Patients and Methods: Outpatients aged ≥40 years with confirmed COPD diagnosis and pulmonary function test data were enrolled. Primary study outcomes were measurement of daily steps (over 14 consecutive days, using an activity monitor), assessment of activity time by activity intensity (using metabolic equivalents [METs]), and evaluation of correlation between PA and patient characteristics. Secondary outcomes included further investigation of the influence of patient characteristics on PA. Results: Data from 417 patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I (29.5%), II (43.9%), III (23.5%), and IV (3.1%) were evaluated. Median (Q1, Q3) daily step count was 3440.8 (1831.3, 5709.3). Median (Q1, Q3) durations of PA at ≥3 (moderate-to-vigorous) and ≥2 METs (light-to-vigorous) were 18.7 (6.5, 41.3) and 186.9 (126.9, 259.2) minutes, respectively. For >30% of patients, time spent in ≥3 METs activity was ≤10 minutes. Unemployment was significantly correlated with reduced activity time (≥3 and ≥2 METs) and step count. Severe GOLD stage was significantly correlated with reduced activity time (≥3 and ≥2 METs). High modified Medical Research Council (mMRC) dyspnea score was significantly correlated with reduced activity time (≥3 METs) and step count. Patients tended to overestimate the time spent in activities requiring ≥2 METs in their subjective reports compared with activity monitor measurements. Conclusion: Reduced PA was observed in the Japanese COPD patients with the majority of them being GOLD stage I/II. Employment status, GOLD stage, and mMRC dyspnea score could help identify patients at risk of reduced PA. Clinical Trial Registration: NCT03642613 (ClinicalTrials.gov); UMIN000032962 (UMIN-CTR, umin.ac.jp).