The 103,200-arm acceleration dataset in the UK Biobank revealed a landscape of human sleep phenotypes.

SignificanceHuman sleep phenotypes are diversified by genetic and environmental factors, and a quantitative classification of sleep phenotypes would lead to the advancement of biomedical mechanisms underlying human sleep diversity. To achieve that, a pipeline of data analysis, including a state-of-the-art sleep/wake classification algorithm, the uniform manifold approximation and projection (UMAP) dimension reduction method, and the density-based spatial clustering of applications with noise (DBSCAN) clustering method, was applied to the 100,000-arm acceleration dataset. This revealed 16 clusters, including seven different insomnia-like phenotypes. This kind of quantitative pipeline of sleep analysis is expected to promote data-based diagnosis of sleep disorders and psychiatric disorders that tend to be complicated by sleep disorders.

Omalizumab ameliorates extrarespiratory symptoms in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Omalizumab, an anti-IgE antibody, has clinical efficacy against respiratory symptoms of aspirin-exacerbated respiratory disease (AERD). However, some patients with AERD also present with extrarespiratory (chest, gastrointestinal, and/or cutaneous) symptoms, which are resistant to conventional treatment but can be alleviated by systemic corticosteroids. OBJECTIVE: We evaluated the efficacy of omalizumab on extrarespiratory symptoms related to AERD. METHODS: In study 1, a total of 27 consecutive patients with AERD initially prescribed omalizumab at Sagamihara National Hospital between July 2009 and March 2019 were retrospectively studied. Frequency of exacerbations of AERD-related extrarespiratory symptoms was compared before and after omalizumab treatment. In study 2, we reported 3 AERD cases with aspirin challenge-induced extrarespiratory symptoms among patients studied in our previous randomized trial (registration UMIN000018777), which evaluated the effects of omalizumab on hypersensitivity reactions during aspirin challenge to AERD patients. Extrarespiratory symptoms induced during the aspirin challenge were compared between placebo and omalizumab phases. RESULTS: In study 1, omalizumab treatment was associated with decrease in frequency of exacerbation of chest pain (no. [%] of patients with exacerbation frequency ≥1 time per year, 6 [22.2%] vs 0; P < .001), gastrointestinal symptoms (9 [33.3%] vs 2 [7.4%]; P = .016), and cutaneous symptoms (16 [59.3%] vs 2 [7.4%]; P < .001), even under conditions of treatment-related reduction in systemic corticosteroid dose. Omalizumab also attenuated all the extrarespiratory symptoms during aspirin challenge in study 2. CONCLUSION: Omalizumab ameliorated extrarespiratory symptoms at baseline (without aspirin exposure) and during aspirin challenge.

[STATE-OF-THE-ART OF GLOBAL START-UP INVESTMENT FOR ALLERGY AND IMMUNOLOGY 2022].

BACKGROUND: In 2022, the "New Capitalism Grand Design and Implementation Plan" was adopted in Japan, emphasizing the promotion and environmental development of startups. Given this context, an investigation into the startup and investment landscape in the allergy sector, both domestically and internationally, becomes imperative. METHODS: We analyzed 156 allergy-related startups from Japan, the US, and Europe from 2010 to 2021. Data on corporate information and investment trends were extracted from databases and VC websites. RESULTS: The total investment reached approximately 7.2 billion USD, with a ratio of 20:6:1 for the US, Europe, and Japan, respectively. The US showed a decline post its peak from 2016-2018, while Europe and Japan experienced growth. Notably, the US primarily invested in biopharmaceuticals for atopic dermatitis and food allergies, Europe in asthma-related apps, and Japan in healthcare apps and cross-border startups. DISCUSSION AND CONCLUSION: While Japan's investment environment in the allergy sector remains in its nascent stages and has room for development, the US and Europe are evidently ahead. Considering the rise of startups and funding limitations in Japan, external funding from regions like the US becomes a potential avenue. These findings are anticipated to contribute to the strategic activation of startups in allergy research and development.

Identification of asthma cases in Japan using health insurance claims data: Positive and negative predictive values of proposed discrimination criteria: A single-center study.

BACKGROUND: Asthma cases have been increasingly investigated using claims data. However, the validity of defining asthma cases using health insurance claims in Japan is unclear. This study aims to assess the positive and negative predictive values of our proposed discrimination criteria for asthma. METHODS: We developed discrimination criteria for asthma based on both the International Statistical Classification of Diseases and Related Health Problems (ICD)-10 disease codes for asthma and health insurance claims data for prescriptions and the treatment of asthma. Inclusion criteria were patients aged ≥16 years with at least one health insurance claim from April 2018 to March 2019 in all departments of our hospital. Physician-diagnosed asthma documented in the charts was used as the reference standard. Positive and negative predictive values of the discrimination criteria for physician-diagnosed asthma were estimated and compared with those estimated from discrimination criteria based solely on ICD-10 codes. RESULTS: The new discrimination criteria had a high positive predictive value (PPV) of 86.0%, which was significantly higher than the PPV for the criteria defined solely by the ICD-10 codes (61.5%) (P < 0.01). The negative predictive values for both criteria were 100%. Allergic rhinitis and chronic cough were frequently misclassified as asthma using the discrimination criteria based solely on ICD-10 codes but were more likely to be appropriately classified using our proposed criteria. CONCLUSIONS: Our proposed criteria adequately identified asthma subjects using health insurance claims data in Japan with a high PPV. Further studies are needed for external validation of these criteria.

Longitudinal changes in the prevalence of adult asthma: An epidemiological survey among Japanese salaried employees and their dependents using healthcare insurance claim from 1999 to 2019.

BACKGROUND: Information on changes in asthma prevalence and the treatment status for asthma is used as basic information for taking medical and administrative measures against asthma. However, this information among adults is relatively limited. METHODS: To elucidate changes in the prevalence of asthma and treatment status over time among Japanese adults, health insurance claim data from some health insurance societies covering salaried employees and their dependents were studied longitudinally. Claim data from FY1999 to 2007 were obtained from two health insurance societies, and data from FY 2011 to 2019 were obtained from three different health insurance societies, and changes in standardized asthma prevalence among subjects aged 20-59 years, proportion of asthma patients prescribed ICS, leukotriene receptor antagonist (LTRA), and LABA, and the mean number of acute asthma exacerbations per year were analyzed. RESULTS: The prevalence of asthma increased from 1.6% in 1999 to 3.0% in 2007 and 2.9% in 2011 to 4.6% in 2019. Increased trends in asthma prevalence from 2011 to 2019 were more noticeable in subjects in their 50s than those in their 20s for both sexes. The number of emergency visits related to asthma was 1.5 per year in 1999, which decreased to 0.8 per year in 2019. The proportion of people prescribed all anti-asthma medications (ICS, LTRA, and LABA) increased over time. CONCLUSIONS: The prevalence of adult asthma among Japanese salaried employees and their dependents has increased over the last 20 years, suggesting more attention should be paid to the prevention of this disease in adults.

Sleep Apnea and Abnormal Respiratory Patterns with Deep Sedation during Radiofrequency Catheter Ablation in Patients with Atrial Fibrillation.

Background: Abnormal respiration during radiofrequency catheter ablation (RFCA) with deep sedation in patients with atrial fibrillation (AF) can affect the procedure's success. However, the respiratory pattern during RFCA with deep sedation remains unclear. This study aimed to investigate abnormal respiration during RFCA and its relationship with sleep apnea in patients with AF. Methods: We included patients with AF who underwent RFCA with cardiorespiratory monitoring using a portable polygraph both at night and during RFCA with deep sedation. The patients were divided based on the administered sedative medicines. Results: We included 40 patients with AF. An overnight sleep study revealed that 27 patients had sleep apnea; among them, 9 showed central predominance. During RFCA with deep sedation, 15 patients showed an abnormal respiratory pattern, with 14 patients showing obstructive predominance. Further, 17 and 23 patients were administered with propofol alone and dexmedetomidine plus propofol, respectively. There was no significant between-group difference in the respiratory event index (REI) at night (7.9 vs. 9.3, p = 0.744). However, compared with the group that received dexmedetomidine plus propofol, the propofol-alone group showed a higher REI during RFCA (5.4 vs. 2.6, p = 0.048), more frequent use of the airway (47% vs. 13%, p = 0.030), and a higher dose of administered propofol (3.9 mg/h/kg vs. 1.2 mg/h/kg, p < 0.001). Multivariable analysis revealed that only the propofol amount was associated with REI during RFCA (p = 0.007). Conclusions: Our findings demonstrated that respiratory events during RFCA with deep sedation were mainly obstructive. Propofol should be administered with dexmedetomidine rather than alone to reduce the propofol amount and avoid respiratory instability.

Omalizumab for Aspirin Hypersensitivity and Leukotriene Overproduction in Aspirin-exacerbated Respiratory Disease. A Randomized Controlled Trial.

Rationale: Aspirin-exacerbated respiratory disease is characterized by severe asthma, nonsteroidal antiinflammatory drug hypersensitivity, nasal polyposis, and leukotriene overproduction. Systemic corticosteroid therapy does not completely suppress lifelong aspirin hypersensitivity. Omalizumab efficacy against aspirin-exacerbated respiratory disease has not been investigated in a randomized manner.Objectives: To evaluate omalizumab efficacy against aspirin hypersensitivity, leukotriene E4 overproduction, and symptoms during an oral aspirin challenge in patients with aspirin-exacerbated respiratory disease using a randomized design.Methods: We performed a double-blind, randomized, crossover, placebo-controlled, single-center study at Sagamihara National Hospital between August 2015 and December 2016. Atopic patients (20-79 yr old) with aspirin-exacerbated respiratory disease diagnosed by systemic aspirin challenge were randomized (1:1) to a 3-month treatment with omalizumab or placebo, followed by a >18-week washout period (crossover design). The primary endpoint was the difference in area under logarithm level of urinary leukotriene E4 concentration versus time curve in the intent-to-treat population during an oral aspirin challenge.Measurements and Main Results: Sixteen patients completed the study and were included in the analysis. The area under the logarithm level of urinary leukotriene E4 concentration versus time curve during an oral aspirin challenge was significantly lower in the omalizumab phase (median [interquartile range], 51.1 [44.5-59.8]) than in the placebo phase (80.8 [interquartile range, 65.4-87.8]) (P < 0.001). Ten of 16 patients (62.5%) developed oral aspirin tolerance up to cumulative doses of 930 mg in the omalizumab phase (P < 0.001).Conclusions: Omalizumab treatment inhibited urinary leukotriene E4 overproduction and upper/lower respiratory tract symptoms during an oral aspirin challenge, resulting in aspirin tolerance in 62.5% of the patients with aspirin-exacerbated respiratory disease.

Relationship between cardio-ankle vascular index and obstructive sleep apnea.

Patients with obstructive sleep apnea (OSA) are susceptible to developing atherosclerosis. Consequently, such patients are at a high risk of developing cardiovascular diseases, leading to poor prognosis. Many physiological parameters have been previously used to predict the development of atherosclerosis. One such parameter, the cardio-ankle vascular index (CAVI), a measure of arterial stiffness, has garnered much attention as it can also predict the degree of atherosclerosis. The CAVI can be calculated based on noninvasive measurements, and is less susceptible to blood pressure variations at the time of measurement. Therefore, the CAVI can assess changes in arterial stiffness and the risk of developing atherosclerosis independent of blood pressure changes. Continuous positive airway pressure (CPAP) is a standard therapy for OSA and can suppress the issue significantly. Several studies have shown that CPAP treatment for OSA could also reduce the CAVI. In this review, we discuss the relationship between OSA and arterial stiffness, primarily focusing on the CAVI. Furthermore, we propose future perspectives for the CAVI and OSA.

Relationship between sleep disordered breathing and heart rate turbulence in non-obese subjects.

Heart rate turbulence (HRT) is regarded as a parameter of cardiac autonomic dysfunction. Several studies have suggested that patients with sleep disordered breathing (SDB) have an impaired HRT, which play a role in the relationship between SDB and risk of cardiovascular morbidity and mortality. However, the impact of SDB on HRT independent from obesity is still debatable. Data of eligible subjects who underwent sleep test and 24 h Holter electrocardiogram (ECG) recording from 2009-2012 were analyzed. HRT parameters, turbulence onset (TO), and turbulence slope (TS) in the 24 h recording, while awakening, and sleeping (TO-24 h, TO-awake, TO-sleep, TS-24 h, TS-awake, and TS-sleep, respectively) were compared across subjects with no-to-mild, moderate, and severe SDB. Univariable and multivariable regression analyses including TO or TS as a dependent variable were performed. Data from 41 subjects were evaluated. Compared with the no-to-mild and moderate SDB groups, in the severe SDB group, the TO-24 h and TO-awake were significantly greater, and the TS-24 h, TS-awake, and TS-sleep were significantly lower. In multivariable analyses, the apnea-hypopnea index (AHI) was correlated directly with TO-24 h (coefficient, 0.36; P = 0.03) and TO-awake (coefficient, 0.40; P = 0.01). SDB severity, as represented by AHI, is related to HRT impairments in non-obese subjects. SDB, independent from obesity, may affect cardiac autonomic dysfunction.

Obesity, but not metabolic syndrome, as a risk factor for late-onset asthma in Japanese women.

BACKGROUND: Several cross-sectional studies have suggested an association between obesity and asthma. However, few studies have investigated this relationship longitudinally, especially in middle-aged subjects. Although metabolic syndrome is a well-known risk factor for many non-communicable diseases, its contribution to asthma remains controversial. METHODS: From 2008, specific health checkups for metabolic syndrome have been conducted throughout Japan. To seek relationships of obesity and metabolic syndrome with late-onset asthma in Japan, we analyzed data collected from health insurance claims and specific health checkups for metabolic syndrome at three large health insurance societies. Among subjects aged 40-64 years (n = 9888), multivariate logistic regression analyses were performed to investigate the relationships of obesity and metabolic syndrome in fiscal year 2012 (from April 2012 to March 2013) with the incidence of late-onset asthma in the following two years (from April 2013 to March 2015). RESULTS: In women, BMI 25-29.9 kg/m2 or ≥30 kg/m2, waist circumference ≥90 cm, and waist-to-height ratio ≥0.5 were shown to be significant risk factors for asthma, with adjusted odds ratios (95% CI) of 1.92 (1.35-2.75), 2.24 (1.23-4.09), 1.89 (1.30-2.75), and 1.53 (1.15-2.03), respectively. Significance was retained even after adjustment for metabolic syndrome, and there were no significant relationships between metabolic syndrome itself and the incidence of asthma in men or women. CONCLUSIONS: Only the obesity measures, not metabolic syndrome, were shown to be significant risk factors for the incidence of late-onset asthma but only in middle-aged Japanese women, and not in men.

THE FRACTION OF EXHALED NITRIC OXIDE (FENO) AND FORCED OSCILLATION TECHNIQUE (FOT) CAN PREDICT BRONCHIAL HYPERRESPONSIVENESS AGAINST ACETYLCHOLINE IN TREATED ASTHMATICS.

BACKGROUND: The bronchial hyperresponsiveness (BHR) test is useful to diagnose or evaluate effect of therapy in asthmatics, but invasive. On the other hands, the fraction of exhaled nitric oxide (FENO) is a useful noninvasive marker of eosinophilic airway inflammation in asthmatics. And also, the forced oscillation technique (FOT) is a noninvasive method that is used to measure respiratory mechanics, including respiratory resistance and reactance at multiple frequencies. AIM: To evaluate the complementary roles of FENO and FOT to predict bronchial hyperresponsiveness in adult stable asthmatic patients taking inhaled corticosteroids. METHODS: From our outpatient clinic, we recruited 115 stable asthmatics that were being treated with inhaled corticosteroids at the time of the study. For each subject, we measured FENO by using an offline methods (CEIS' method); and we measured resistance at 5Hz (R5), resistance at 20Hz (R20), R5-R20, reactance at 5Hz (X5), frequency of resonance (Fres), and low-frequency reactance area (ALX), by using a MostGraph FOT machine. We also used spirometry to test BHR to acetylcholine (PC20Ach). RESULTS: LogPC20Ach was significantly correlated with FENO, R5, R20, R5-R20 and %FEV1. The ROC curve decided that the cutoff point of FENO was 37.8ppb (AUC=0.647, sensitivity 83.3%, specificity 55.6%, p=0.007) and that of R5 was 3.03cmH2O/L/S (AUC=0.684, sensitivity 72.2%, specificity 52.8%, p=0.001) and that of R20 was 2.77cmH2O/L/S (AUC=0.684, sensitivity 74.5%, specificity 59.4%, p=0.001). When R5 was >3.03 and FENO was >37.8ppb, 25 of 38 subjects (65.7%) had bronchial hyperresponsiveness. If R5 was <3.03 and FENO was <37.8 ppb, only 5 of 29 (17.2%) subjects had. When R20 was >2.77 and FENO was >37.8ppb, 29 of 43 subjects (67.4%) had bronchial hyperresponsiveness. If R20 was <3.03 and FENO was <37.8ppb, only 2 of 18 (11.1%) subjects had. CONCLUSION: Combining R5 or R20 and FENO can predict the level of bronchial hyperresponsiveness in adult stable asthmatics.

DIFFERENCES IN FRACTION OF EXHALED NITRIC OXIDE VALUES MEASURED BY TWO HAND-HELDED ANALYZERS (NObreath® AND NIOX Vero®).

BACKGROUND: The fraction of exhaled nitric oxide (FENO) is a useful marker of asthma control. The FENO measurement with two hand-helded analyzers (NObreath® and NIOX Vero®) may be more affordable, no studies have examined the differences in FENO values measured with those methods in adult. METHODS: The study population comprised 44 subjects at our outpatient clinic. FeNO values (FENOb and FENOv) were measured by two methods (NObreath® and NIOX Vero®). RESULTS: FENOb values were significantly correlated with FENOv (r = 0.911, p < 0.001). However, FENOv values were high compared with FENOb (FENOv = 1.40 × FENOb). CONCLUSION: Differences exist in the values of FENO measured by two hand-helded analyzers: conversion equations are needed to compare the FENO values between these methods.

A CASE OF BRONCHIAL ASTHMA WITH HYPEREOSINOPHILIA WITH EFFECTIVE SAIBOKUTOU THERAPY.

A 42 year old woman visited on our hospital because of cough, sputum, pruritus and erythema. She showed peripheral blood eosinophilia, high level of FENO, bronchial hyperresponsiveness. Diagnosis of bronchial asthma and atopic dermatitis was made, but she rejected therapy except for Saibokutou, a Kampo herbal medicine. After 1 year, her symptoms and her laboratory data were improved.

Altered breathing syndrome in heart failure: newer insights and treatment options.

In patients with heart failure (HF), altered breathing patterns, including periodic breathing, Cheyne-Stokes breathing, and oscillatory ventilation, are seen in several situations. Since all forms of altered breathing cause similar detrimental effects on clinical outcomes, they may be considered collectively as an "altered breathing syndrome." Altered breathing syndrome should be recognized as a comorbid condition of HF and as a potential therapeutic target. In this review, we discuss mechanisms and therapeutic options of altered breathing while sleeping, while awake at rest, and during exercise.

The Correlation between the Severity of Obstructive Sleep Apnea and Insulin Resistance in a Japanese Population.

Background: Repetitive episodes of apnea and hypopnea during sleep in patients with obstructive sleep apnea (OSA) are known to increase the risk of atherosclerosis. Underlying obesity and related disorders, such as insulin resistance, are indirectly related to the development of atherosclerosis. In addition, OSA is independently associated with insulin resistance; however, data regarding this relationship are scarce in Japanese populations. Methods: This study aimed to examine the relationship between the severity of OSA and insulin resistance in a Japanese population. We analyzed the data of consecutive patients who were referred for polysomnography under clinical suspicion of developing OSA and who did not have diabetes mellitus or any cardiovascular disease. Multiple regression analyses were performed to determine the relationship between the severity of OSA and insulin resistance. Results: The data from a total of 483 consecutive patients were analyzed. The median apnea-hypopnea index (AHI) was 40.9/h (interquartile range: 26.5, 59.1) and the median homeostasis model assessment for insulin resistance (HOMA-IR) was 2.00 (interquartile range: 1.25, 3.50). Multiple regression analyses revealed that the AHI, the lowest oxyhemoglobin saturation (SO2), and the percentage of time spent on SO2 < 90% were independently correlated with HOMA-IR (an adjusted R-squared value of 0.01278821, p = 0.014; an adjusted R-squared value of -0.01481952, p = 0.009; and an adjusted R-squared value of 0.018456581, p = 0.003, respectively). Conclusions: The severity of OSA is associated with insulin resistance assessed by HOMA-IR in a Japanese population.

Clinical outcomes of chronic heart failure patients with unsuppressed sleep apnea by positive airway pressure therapy.

Introduction: Heart failure (HF) is an advanced stage of cardiac disease and is associated with a high rate of mortality. Previous studies have shown that sleep apnea (SA) is associated with a poor prognosis in HF patients. Beneficial effects of PAP therapy that is effective on reducing SA on cardiovascular events, were not yet established. However, a large-scale clinical trial reported that patients with central SA (CSA) which was not effectively suppressed by continuous positive airway pressure (CPAP) revealed poor prognosis. We hypothesize that unsuppressed SA by CPAP is associated with negative consequences in patients with HF and SA, including either obstructive SA (OSA) or CSA. Methods: This was a retrospective observational study. Patients with stable HF, defined as left ventricular ejection fraction of ≤50%; New York Heart Association class ≥ II; and SA [apnea-hypopnea index (AHI) of ≥15/h on overnight polysomnography], treated with CPAP therapy for 1 month and performed sleep study with CPAP were enrolled. The patients were classified into two groups according to AHI on CPAP (suppressed group: residual AHI ≥ 15/h; and unsuppressed group: residual AHI < 15/h). The primary endpoint was a composite of all-cause death and hospitalization for HF. Results: Overall, data of 111 patients including 27 patients with unsuppressed SA, were analyzed. The cumulative event-free survival rates were lower in the unsuppressed group during a period of 36.6 months. A multivariate Cox proportional hazard model showed that the unsuppressed group was associated with an increased risk for clinical outcomes (hazard ratio 2.30, 95% confidence interval 1.21-4.38, p = 0.011). Conclusion: Our study suggested that in patients with HF and SA including either OSA or CSA, presence of unsuppressed SA even on CPAP was associated with worse prognosis as compared to those with suppressed SA by CPAP.