Les troubles respiratoires du sommeil, notamment le syndrome d’apnée du sommeil, représentent un problème de santé publique. Ils contribuent aux symptômes diurnes comme la somnolence sévère et sont associés à des maladies chroniques.Depuis quelques années, une variété d’appareils de traitement ventilatoire a été développée pour traiter les troubles respiratoires du sommeil, principalement les maladies liées à l’obstruction de la voie aérienne supérieure (apnée obstructive) ou à la commande centrale (apnée centrale). Ces appareils fonctionnent suivant des principes différents, en raison de leurs propres algorithmes, qui sont souvent mal connus et protégés par les fabricants. Les évaluations des appareils de ventilation sont effectuées pendant les traitements cliniques chez des patients. Il est donc difficile de comparer ces différents appareils dans les mêmes conditions à cause des variabilités inter- et intra-patient. Un banc d’essai pourrait permettre de tester les réponses des appareils dans les conditions standardisées et reproductibles.Cette thèse a consisté à construire un banc d’essai qui permet de reproduire les signaux de patients et de respecter de la physiologie humaine. La réaction du banc d’essai prend aussi en compte la réaction de l’appareil à tester sur le système, i.e., ce modèle fonctionne en « boucle fermée ». Avec le banc d’essai construit, les différentes machines de pression positive continue (PPC) autopilotée disponibles sur le marché ont été évaluées pour leurs algorithmes ainsi pour leurs modes confort. De plus, trois machines de ventilation auto-asservie (ASV) ont été soumises aux différents événements respiratoires du sommeil créés par un autre modèle d’un principe similaire. Nous avons montré que les machines de PPC autopilotée ne sont pas équivalentes pour l’efficacité du traitement et la précision des données du rapport. Les modes confort pourraient éventuellement dégrader l’efficacité du traitement de PPC si la pression thérapeutique n’est pas ajustée lors de leur introduction au traitement. Pour les machines ASV, leurs réponses ne sont pas suffisantes pour normaliser la respiration et les réglages des machines peuvent influencer l’efficacité du traitement. Les résultats pourraient compléter les données cliniques et fournir une option complémentaire pour le processus futur de certification de ces dispositifs médicaux. / Sleep disordered breathing including sleep apnea is a major public health problem. It contributes to daytime sleepiness and is associated with chronic diseases. In recent years, a variety of ventilation devices have been developed with the objective of treating sleep disorders related to the upper airway obstruction (obstructive apnea) or the central command (central apnea). These devices operate with different algorithms, which are little known and protected by the device manufacturers. Since most devices are evaluated during patient treatment, it is difficult to compare them in the same conditions due to inter- and intra-patient variability. Bench test has been proposed to evaluate the device responses in standardized and reproducible conditions. This thesis was aimed to develop a respiratory bench model able to reproduce patients’ signals and also in concordance with human physiology. The bench model can take into account the pressure responses of tested devices and works in a “closed loop” setting.With this bench model, several commercially available auto-titrating continuous positive airway pressure devices were evaluated for their auto-titration algorithms as well as their pressure-relief modes. Also, three adaptive servo-ventilation devices were evaluated by subjecting various sleep disordered breathing events that were generated by another bench model of a similar principle. We demonstrated that eleven auto-titrating continuous positive airway pressure devices were not equivalent in terms of their treatment efficacy and the data accuracy in the device report. The pressure-relief modes may attenuate the efficacy if not adjusted at the time of their introduction. The responses of adaptive servo-ventilation devices were not sufficient to normalize the breathing flow and their efficacy depended on the initial settings.The current certification process of these ventilatory devices, which focus mainly on clinical aspects, may be completed by the results of our bench.

INTRODUCTION: Research has consistently shown that sleep apnea is strongly associated with atrial fibrillation, with several lines of evidence demonstrating that this relationship is bidirectional and that each condition predisposes to and/or exacerbates the other. Many studies have suggested potential pathophysiologic mechanisms underlying this relationship, and that sleep apnea and atrial fibrillation share many of the same cardiovascular risk factors further implies that multiple pathways are likely involved in the mechanistic link between the two. Although the sleep apnea-atrial fibrillation relationship is quite established, numerous aspects of this association still require further study, such as the role of gender and the potential impact of positive airway pressure therapy. A deeper understanding of how these individual factors may be involved in the interrelationship between sleep apnea and atrial fibrillation has important clinical implications, such as for risk stratification and screening of patients. Thus, this study aims to further understand the different aspects and modulating factors of the sleep apnea-atrial fibrillation link, focusing on central sleep apnea as less is known about the central sleep apnea-atrial fibrillation relationship. METHODS: A total of 153 patients, originally seen at the cardiac electrophysiology clinic at Beth Israel Deaconess Medical Center and subsequently offered home sleep apnea testing, were included in this study. Several databases – home sleep apnea testing results, polysomnography reports, electrocardiogram reports and patient management systems – were used to obtain a variety of data on sleep pathology, high loop gain status, left ventricular ejection fraction and positive airway pressure therapy efficacy and compliance. Patients were considered to have central sleep apnea if home testing results demonstrated a central apnea-hypopnea index of 5 or greater and/or if the patient was documented as having high loop gain on polysomnography. Data were analyzed using the Statistical Package for Social Sciences software in order to examine how factors such as gender and therapy use may affect the sleep apnea-atrial fibrillation relationship, in a patient population with sleep pathology of at least moderate severity. RESULTS: Statistical analysis revealed significant sleep disturbances in the central sleep apnea patients compared to the non-central sleep apnea patients. Gender was found to be significantly associated with central sleep apnea, but not obstructive sleep apnea. When postmenopausal (age≥51) women were analyzed, very few patients met the study criteria for central sleep apnea, yet the majority were documented as having atrial fibrillation. As expected, positive airway pressure therapy was found to be beneficial for all users, but the common pattern of declining compliance to therapy was seen as adherence decreased over the course of three months. Of the select central sleep apnea patients who had sufficient data available, comparison of positive airway pressure therapy and cardiac data revealed possible benefits to cardiac health with compliant use of positive airway pressure therapy. CONCLUSION: Through examining different aspects of the sleep apnea-atrial fibrillation relationship, this study found promising evidence showing that gender and positive airway pressure therapy play important roles. Further studies, with larger sample sizes, need to be conducted in order to fully understand the specific impact of factors such as gender, gender and age and positive airway pressure therapy on the risks and outcomes in patients with sleep apnea and/or atrial fibrillation, and how these factors may change depending on the type of sleep apnea. Finally, these results further highlight the growing need for an effective collaborative care model between cardiologists and sleep medicine clinicians, as the management of patients with sleep apnea and atrial fibrillation requires an interdisciplinary approach in order to deliver the most optimal patient care.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18450号 / 医博第3905号 / 新制||医||1004(附属図書館) / 31328 / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊達 洋至, 教授 稲垣 暢也, 教授 森田 智視 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The consequences of sleep disordered breathing (SDB) in women are fatigue, morning headaches, insomnia, depression, low functional status, daytime sleepiness, mood disturbances, and poor neuro-behavioural performance. Women appear to be more symptomatic at lower disease severity than men. When CPAP is prescribed, women use it less than men, they reduce their usage within the first week of treatment, and they discontinue it more than men. There is a need to understand the factors influencing CPAP therapy uptake and usage in women to meaningfully address their needs. The purpose of this qualitative evidence synthesis was to identify and synthesize the factors influencing the uptake and use of CPAP in women by conducting a qualitative evidence synthesis guided by the Bargaining and Balancing Life with CPAP theory for content, and the Theoretical Domains Framework for data analysis. Twenty-one studies were included. Barrier domains were Skills, Emotions, Social/Professional Role and Identity, and Beliefs about Capabilities, while facilitator domains were Reinforcement, Social Influences, Goals, and Optimism. Seven themes emerged : 1) Expectations about CPAP, 2) Learning to use my CPAP machine, 3) The burden of the technology, 4) Improvement of SDB symptoms, 5) Not feeling (or looking) like myself, 6) Receiving support, and 7) Choosing my attitude. To ensure appropriate and meaningful SDB care for women, practices must be based on knowledge relevant to women with SDB. Findings from this thesis can inform the design and development of interventions to support women with CPAP therapy uptake and usage. Research on this topic is urgently needed because there was no study eligible with a sample comprised of women only.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25193号 / 医博第5079号 / 新制||医||1072(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 山本 洋介, 教授 中山 健夫, 教授 江木 盛時 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

Sleep-disordered breathing and insomnia are common sleep disorders and associated with an increased risk of morbidity. The aim of this thesis was to study the contribution of a behavioural sleep medicine perspective on sleep-disordered breathing and insomnia. More specific, factors considered important for changing eating behaviour and the impact of physical activity were studied. Methods: In study I, semi-structured interviews of participants with obstructive sleep apnoea and obesity (n = 15) were analysed using a qualitative content analysis. A population-based female cohort was followed prospectively over ten years in study II and III using a postal questionnaire on two occasions (n = 4,851 and n = 5062, respectively). In study IV, a series of five experimental single-case studies was conducted testing how an aerobic exercise intervention affected selected typical snores, following an A1B1A2B2A3 design over nine days and nights (n = 5). Results:  Facilitators and barriers towards eating behaviour change were identified. A low level of self-reported leisure-time physical activity was a risk factor among women for future habitual snoring complaints, independent of weight, weight gain alcohol dependence or smoking. Maintaining higher levels or increasing levels of leisure-time physical activity over the ten-year period partly protected from snoring complaints (study II). Further, a low level of self-reported leisure-time physical activity is a risk factor for future insomnia among women. Maintaining higher levels or increasing levels of leisure-time physical activity over the ten-year period partly protect against self-reported insomnia, independent of psychological distress, age, change in body mass index, smoking, alcohol dependence, snoring status or level of education (study III). Single bouts of aerobic exercise did not produce an acute effect on snoring the following nights in the studied individuals. A pronounced night-to-night variation in snoring was identified (study IV). Conclusion: Women with sleep disorders would benefit from a behavioural sleep medicine perspective targeting their physical activity in the prevention and management of snoring and insomnia. This is motivated by the protective effects of physical activity confirmed by this thesis. Knowledge was added about facilitators and barriers for future eating behaviour change interventions.

Obstructive sleep apnoea/hypopnoea syndrome (OSAHS) is characterised by repeated cycles of upper airway obstruction during sleep, leading to diurnal symptoms. Individuals with Down syndrome (DS) are predisposed to this as the DS phenotype overlaps with OSAHS risk factors. Around 2-4% of the general adult population and 55% of children with DS have OSAHS but, to date, no large-scale study has assessed OSAHS prevalence or efficacy of treatment in DS adults. This study aimed to: 1) Systematically assess subjective and objective OSAHS prevalence; 2) Assess the effectiveness of continuous positive airway pressure (CPAP) in an adult DS population. Standard questionnaires including pictorial Epworth Sleepiness Scale (pESS) and Developmental Behaviour Checklist for Adults (DBC-A) were sent to UK adults aged ≥16yr with DS and their caregivers. All questionnaire responders were invited to undergo home polygraphy. Symptomatic adults with DS with ≥10 apnoeas/hypopnoeas per hour in bed (AH) on home polygraphy were invited to participate in a prospective randomised controlled trial (RCT) of CPAP v. lifestyle advice, with review at 1, 3, 6 and 12m. Participants in the lifestyle arm were offered CPAP at 1m. Standard measurements of sleepiness, behaviour, cognitive function and general health were undertaken. Standard statistical analyses were conducted, with significance set at p < 0.001 to control for multiple testing. Of 5270 questionnaires sent, 1105 responses were valid (21%). Responders (55% males) were overweight/obese young adults: mean BMI 29.0±6.8kg/m2; mean age 28±9 years. Women had a higher BMI (p < 0.0001), but collar size was greater in men (p < 0.0001). Mean pESS scores were broadly within the normal range (7±5/24). No significant gender differences in OSAHS symptoms were noted. Individuals with probable OSAHS had higher pESS and DBC-A scores, and significantly more symptoms of OSAHS. Subjective OSAHS prevalence was estimated at 35%. Of the 790 individuals invited, 149 underwent polygraphy, with 134 valid studies obtained: mean AH 21.8(10.9-42.7); mean oximetry desaturation index (ODI) 6.6(2.3-20.0). No significant gender differences were observed. Forty-two percent of participants met standard clinical diagnostic criteria for OSAHS. Twenty-eight eligible adults with DS (19 male) were randomised: age 28±9yr; BMI 31.5±7.9kg/m2; AH 28.6(14.8-47.9); ODI 7.3(1.8-21.9); pESS 11±6/24. Groups did not differ significantly at baseline. By 12m, 4 participants had withdrawn (all remaining participants on CPAP). The pESS (p=0.001), DBC-A Disruptive (p < 0.0001) and Kaufmann Brief Intelligence Test verbal subscale (p=0.001) scores improved significantly. This first large study of OSAHS prevalence in the adult DS population estimates a prevalence of 35-42% - around 10 times higher than in the general adult population. Sustained, significant improvements in sleepiness, cognitive function and behavioural/emotional outcomes with CPAP use over a 12m period were demonstrated during this first RCT of CPAP in adults with DS. A larger trial of CPAP in this population is warranted.

Introdução: A obesidade é um problema de saúde pública em crescimento, sendo o principal fator de risco para os transtornos respiratórios durante o sono (TRS), como a apneia obstrutiva do sono (AOS) e a hipoventilação noturna. A cirurgia bariátrica se consolidou como possibilidade terapêutica para a obesidade significativa. A identificação precoce dos TRS na fase pré-operatória é essencial, pois acarretam um risco aumentado de complicações perioperatórias. Diversas propostas de triagem dos TRS com abordagens mais simplificadas em relação à polissonografia (PSG) têm surgido na literatura nos últimos anos, nem todas avaliadas em uma população de pacientes obesos. Objetivo: Determinar os padrões ventilatórios em obesos candidatos à cirurgia bariátrica e avaliar três estratégias de rastreamento de TRS nessa população. Métodos: Os critérios de inclusão foram pacientes com idade ≥18 anos com obesidade graus III [índice de massa corporal (IMC) ≥40 kg/m2] ou II (IMC ≥35 kg/m2) com comorbidades relacionadas à obesidade encaminhados para avaliação para cirurgia bariátrica. Foram excluídos pacientes com cardiopatia e/ou pneumopatia graves ou descompensadas. Foram avaliados 91 pacientes através de três estratégias: (1) Clínica [Escala de Sonolência de Epworth e questionários STOP-Bang, Berlim e Sleep Apnea Clinical Score (SACS), acrescidos de gasometria arterial (GA)]; (2) Oximetria (holter de oximetria durante o sono e GA) e (3) Portátil [monitorização portátil (MP) durante o sono e capnografia)]. Todos os testes realizados foram comparados com o teste padrão, a PSG, para o diagnóstico de AOS. Resultados: A amostra estudada foi composta por 77 mulheres (84,6%) com média de idade de 44,7 ± 11,5 anos e de IMC de 50,1 ± 8,2 kg/m2. Os padrões ventilatórios identificados foram ronco, hipoxemia isolada durante o sono, AOS e hipoventilação noturna em associação com AOS. Os dados polissonográficos evidenciaram AOS em 67 de 87 pacientes (77%), sendo 26 com transtorno leve, 19 moderado e 22 grave. Vinte pacientes (23%) tiveram diagnóstico de ronco e dois deles também apresentaram hipoxemia isolada durante o sono sem AOS ou hipoventilação concomitantes. Hipoventilação noturna associada com AOS foi identificada por capnografia em um paciente. Na Estratégia Clínica, o melhor resultado alcançado foi com o escore STOP-Bang ≥6 em pacientes com índice de apneia hipopneia (IAH) ≥30 (acurácia total de 82,8%). Na Estratégia Oximetria, os pontos de corte com maior sensibilidade e especificidade para IAH ≥5, ≥10, ≥15 e ≥30 foram tempo total de registro com saturação periférica de oxigênio (SpO2) <90% por, pelo menos, 5 minutos; índice de dessaturação (ID)3% ≥22 dessaturações/hora de registro e ID4% ≥10 e ≥15 dessaturações/hora de registro. Todas as áreas sobre a curva (ASC) situaram-se acima de 0,850. Para um IAH ≥5, o ID4% ≥10 apresentou sensibilidade de 97%, especificidade de 73,7%, valor preditivo positivo de 92,8% e negativo de 87,5% e acurácia total de 91,8%. Na Estratégia Portátil, o índice de distúrbios respiratórios (IDR) foi um bom preditor de AOS nos variados pontos de corte de IAH (ASC de 0,952 a 0,995). As melhores sensibilidades e especificidades foram alcançadas em pontos de corte semelhantes de IDR e IAH, especialmente nos extratos de IAH ≥10 e ≥30. A acurácia total máxima foi de 93,9% para IDR ≥5, ≥10 e ≥30 nos seus correspondentes IAH. Baseados nesses resultados, foram testadas estratégias combinadas compostas pelo questionário STOP-Bang ≥6 com ID4% ≥10 ou ≥15. O melhor equilíbrio entre sensibilidade e especificidade e a maior acurácia foram obtidos com a estratégia STOP-Bang ≥6 com ID4% ≥15 em AOS grave. Conclusões: A frequência de ocorrência de TRS nos obesos em avaliação para cirurgia bariátrica foi alta, sendo a AOS o transtorno mais encontrado. Os questionários disponíveis até o momento, isoladamente, parecem ser insuficientes para o rastreamento de AOS nessa população, à exceção do STOP-Bang ≥6 em pacientes com AOS grave. O uso de uma medida fisiológica objetiva expressa pelo holter de oximetria foi útil para rastrear AOS em pacientes obesos. A MP apresentou acurácia aumentada, especialmente nos extremos de valores de IAH, com resultados comparáveis aos da PSG. A PSG poderia ser reservada apenas para confirmação diagnóstica em casos selecionados. / Introduction: Obesity is a growing public health problem and the main risk factor for sleep-disordered breathing (SDB), including obstructive sleep apnea (OSA) and nocturnal hypoventilation. Bariatric surgery has become an option for the treatment of significant obesity. Early detection of SDB preoperatively is essential, since these disorders are associated with an increased risk of perioperative complications. Several screening tools for SDB, with a more simplified approach than polysomnography (PSG), have been proposed in recent years, but not all of them have been evaluated in a population of obese patients. Objective: To determine ventilatory patterns in obese candidates for bariatric surgery and evaluate three SDB screening strategies in this population. Methods: Eligible participants were all patients aged ≥18 years with grade III (body mass index [BMI] ≥ 40kg/m2) or grade II (BMI ≥35 kg/m2) obesity and obesity-related comorbidities who were referred for evaluation for bariatric surgery. Exclusion criteria were heart disease and/or severe or decompensated pulmonary disease. Ninety-one patients were evaluated by three strategies: (1) Clinical (Epworth Sleepiness Scale and STOP-Bang questionnaire, Berlin questionnaire and Sleep Apnea Clinical Score [SACS] plus blood gas analysis [BGA]); (2) Oximetry (overnight Holter-oximeter monitoring and BGA); and (3) Portable (overnight portable monitoring and capnography). All tests were compared with the gold standard, PSG, for the diagnosis of OSA. Results: The sample consisted of 77 women (84.6%) with a mean (SD) age of 44.7 (11.5) years and BMI of 50.1 (8.2) kg/m2. The ventilatory patterns identified were snoring, isolated nocturnal hypoxemia, OSA, and nocturnal hypoventilation associated with OSA. Polysomnographic data showed OSA in 67 of 87 patients (77%), 26 with mild, 19 with moderate and 22 with severe disorder. Twenty patients (23%) had a diagnosis of snoring, and two of them also had isolated nocturnal hypoxemia without concomitant OSA or hypoventilation. Nocturnal hypoventilation associated with OSA was detected by capnography in one patient. In the Clinical Strategy, the best result was obtained with the STOP-Bang score ≥6 in patients with an apnea-hypopnea index (AHI) ≥30 (overall accuracy of 82.8%). In the Oximetry Strategy, the cutoff values with the highest sensitivity and specificity for AHI ≥5, ≥10, ≥15, and ≥30 were total recording time with peripheral oxygen saturation (SpO2)< 90% for at least 5 minutes, 3% oxygen desaturation index (ODI) ≥22 desaturations/hour of recording, and 4%ODI ≥10 and ≥15 desaturations/hour of recording. All areas under the curve (AUC) were above 0.850. For AHI ≥5, 4%ODI ≥10 had a sensitivity of 97%, specificity of 73.7%, positive predictive value of 92.8%, negative predictive value of 87.5%, and overall accuracy of 91.8%. In the Portable Strategy, the respiratory disturbance index (RDI) was a good predictor of OSA in various cutoff values of AHI (AUC of 0.952 to 0.995). The highest sensitivity and specificity were obtained at similar cutoff values for RDI and AHI, especially for AHI ≥10 and ≥30. The maximum overall accuracy was 93.9% for RDI ≥5, ≥10, and ≥30 in their corresponding AHI. Based on these results, combined strategies were tested consisting of the STOP-Bang score ≥6 combined with 4%ODI ≥10 or ≥15. The best balance between sensibility and specificity and the maximum accuracy were achieved with the strategy composed by STOP-Bang ≥6 and 4%ODI ≥15 in patients with severe OSA. Conclusions: The frequency of occurrence of SDB in obese individuals undergoing evaluation for bariatric surgery was high, and OSA was the most frequent occurrence. Currently available questionnaires were insufficient to screen for OSA in this population, with the exception for the STOP-Bang score ≥6 in patients with severe OSA. The use of an objective physiological measure, such as Holter-oximetry monitoring, was useful as a screening tool for OSA in obese patients. Portable monitoring showed increased accuracy, especially in extreme AHI values, with results comparable to those obtained with PSG. The PSG could be reserved only for certain cases where diagnostic confirmation is necessary.

The overall aim of this thesis was to describe the prevalence of depressive symptoms, sleep disordered breathing (SDB) and sleep complaints, as well as to investigate the prognostic value of health-related quality of life (Hr-QoL) and depressive symptoms on mortality in an elderly community living population with a focus on those with impaired systolic function/heart failure (HF). Descriptive, prognostic and explorative study designs were used to examine if a single question about global perceived health (GPH) is associated with the domains of Hr-QoL as assessed by the SF-36 (I), as well as to evaluate whether GPH provided prognostic information concerning cardiovascular mortality (II). The aim was also to evaluate if depressive symptoms are associated with mortality (III), and to describe the prevalence of SDB and its relationship to impaired systolic function, different insomnia symptoms, as well as excessive daytime sleepiness (IV). In primary care elderly patients with HF, GPH correlated to the physical and mental aspects of Hr-QoL. Patients who rated poor GPH also scored worse physical and mental Hr-QoL compared to patients with good GPH, but the mental aspect of Hr-QoL was however not significant (p&lt;0.07) (I). Moreover, GPH also had an independent association with cardiovascular mortality during a ten-year follow-up. Compared to patients with good GPH, those who scored poor GPH had a four times increased risk for cardiovascular mortality (II). A total of 24% of the patients with HF suffered from depressive symptoms, not significantly different compared to 19% among those without HF. Depressive symptoms were a poor prognostic sign during the six-year follow-up and HF patients with depressive symptoms had the highest risk for cardiovascular mortality compared to HF patients without depressive symptoms (III). SDB is common among elderly people living in the community, almost one quarter (23%) had moderate or severe SDB. However, people with moderate impaired systolic function had a median apnea hypopnea index that was more than twice as high compared to those with normal systolic function (10.9 vs. 5.0, p&lt;0.001). No obvious associations between SDB and excessive daytime sleepiness or the insomnia symptoms; difficulties maintaining sleep; non-restorative sleep; or early morning awakenings were detected. Difficulties initiating sleep were however more common in those with moderate or severe SDB (IV). GPH can be used as a simple tool in clinical routine practice as an aid in identifying patients in need of additional management. SDB is a common phenomenon among elderly people and associated with impaired systolic function, but with a limited impact on subjective sleep complaints. Depressive symptoms were shown to be a poor prognostic sign and may amplify the patient’s experience of suffering. Screening for depressive symptoms could therefore be an important action in the management of patients with HF.

名古屋大学博士学位論文 学位の種類:博士（医療技術学）（課程） 学位授与年月日:平成19年3月23日 / "Daytime polysomnography and portable recording device for diagnosis and CPAP therapy in patients with obstructive sleep apnea syndrome" Sleep and Breathing, v.11, n.2 (2007) pp.109-115 を、博士論文として提出したもの。