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Injury assessment by using a whole-body pedestrian dummy is one of the ways to investigate pedestrian safety performance of vehicles. The authors’ group has improved the biofidelity of the lower limb and the pelvis of the mid-sized male pedestrian dummy (POLAR III) by modifying those components. This study aims to evaluate the biofidelity of the whole-body response of the modified dummy in full-scale impact tests.The pelvis, the thigh and the leg of POLAR III have been modified in a past study by optimizing their compliance by means of the installation of plastic and rubber parts, which were used for the tests. The generic buck developed for the assessment of pedestrian dummy whole-body impact response and specified in SAE J3093 was used for this study. The buck representing the geometry of a small family car is comprised of six parts: lower bumper, bumper, grille, hood edge, hood and windshield. Tests were performed by conforming to SAE J2782 that specifies test conditions to evaluate the performance of a mid-sized male pedestrian research dummy. The buck was made to collide with the pedestrian dummy on its right side at 40 km/h. The trajectory of the head, upper spine, mid-thorax and pelvis and the time history of the head velocity were measured and compared with the requirements specified in SAE J2782. In addition, the test results were quantitatively assessed using the ranking method proposed by a past study.The trajectories of the landmarks along with the time histories of the head velocity generally showed a good match with the requirements specified in SAE J2782, except the trajectory of the pelvis. The biofidelity ranking parameters were rated as “excellent” or “good” using the proposed thresholds. The trajectory of the pelvis was further analyzed from the viewpoints of the structure of the dummy and the generic buck.

In obstructive sleep apnea (OSA), the upper airway is obstructed during sleep due to obesity and/or posterior collapse of the tongue root. Maxillofacial morphological abnormalities increase the risk of OSA in the Asian population. This study sought to elucidate whether three-dimensional (3D) photogrammetry measurements correlate with the severity of OSA irrespective of sex and degree of obesity.A prospective pilot study was performed, in which 37 consecutive adult patients (M/F = 28/9) underwent polysomnography and 3D photogrammetry in the supine position for the diagnosis of OSA. Measurements obtained from 3D photogrammetry included mandibular width (Mw), mandibular length (Ml), mandibular depth (Md), mandibular width-length angle (Mwla), and mandibular area (Ma). The effects of sex and body mass index (BMI) on the measurements and their association with the apnea-hypopnea index (AHI) were statistically analyzed. The inter-rater reliability of the measurements was evaluated using intraclass correlation coefficients (ICC).Mwla (R = 0.73, p 0.01), Mw (R = 0.39, p 0.05), and Md (R = -0.34, p 0.05) were significantly correlated with the severity of OSA. On multivariate analysis, Mwla (p 0.01) and Md (p 0.05) remained independent factors for AHI after adjusting for sex, age, BMI, and neck circumference. In addition, diagnosability analysis revealed that Mwla was useful for identifying the presence of OSA (AHI ≥5) (cutoff: 78.6°, sensitivity: 0.938, specificity: 0.800, area under the curve: 0.931). The ICC was0.9, showing high reliability.This study suggests that Mwla measured using 3D photogrammetry can predict the presence of OSA and correlates with the severity of OSA, independent of obesity and sex.

The prevalence of sleep disordered breathing is high in patients with end-stage renal disease. Salt intake is related to the severity of obstructive sleep apnea in patients with resistant hypertension and hyperaldosteronism. We investigated the relationship between salt intake and sleep disordered breathing in patients on maintenance hemodialysis. We studied 128 dialysis outpatients (mean age 63 ± 11 years) who were followed at Kokura Daiichi Hospital. We estimated each patient's salt intake using an InBody S10 body composition analyzer and measured the 3% oxygen desaturation index (ODI) during sleep using a Pulsewatch: PMP-200 GplusX. The average estimated salt intake was 8.0 ± 2.6 g/day, and the median value of that was 7.5 g/day. Blood pressure (BP) before and after dialysis were 140 ± 18/78 ± 11 and 127 ± 13/72 ± 8 mmHg, respectively. The geometric average number of 3% ODI was 7.1, and sleep disordered breathing was detected in 30% of all subjects. The patients with ≥ 7.5 g/day salt intake were younger and more frequently male and had higher body mass index (BMI) and BP before dialysis compared to those with salt intakes

Physical inactivity is associated with comorbidities and mortality in chronic obstructive pulmonary disease (COPD) patients. Although non-exercise activity thermogenesis (NEAT) is important for evaluating the physical activity level (PAL) of patients with chronic diseases, it has not yet been assessed in COPD patients. This study included male patients with COPD (n = 28) and high risk for COPD (n = 8). Total energy expenditure (TEE) and basal metabolic rate (BMR) were measured using the doubly labeled water (DLW) method and indirect calorimetry, respectively. PAL was calculated as TEE/BMR, while the NEAT was obtained from a questionnaire. Physical activity was also assessed using an accelerometer. The total NEAT score was correlated with PAL (r = 0.534, P

Yellow nail syndrome (YNS) is a rare disease comprising the clinical triad of yellow nail discoloration, pleural effusion, and lower limb lymphedema. We encountered a difficult-to-treat case of YNS in which the diagnosis was finally made based on intranodal lymphangiography. An 84-year-old man was admitted to our hospital with pleural effusion and yellow-green discoloration of the nails, accompanied by onychomycosis and limb lymphedema. Intranodal lymphangiography revealed a slow contrast flow and narrowing of the thoracic duct, suggesting lymphatic duct dysplasia and leading to the diagnosis of YNS.

Background: The vertical P-wave axis on electrocardiography (ECG) is a useful criterion for screening patients with chronic obstructive pulmonary disease (COPD). This study aimed to investigate the clinical characteristics of patients with COPD with a vertical P-wave axis as they have not yet been elucidated. Methods: Keio University and its affiliated hospitals conducted an observational COPD cohort study over 3 years. We analyzed 201 patients using ECG and chest computed tomography. Results: The severity of airflow limitation was higher in patients with a P-wave axis >75° than in those with a P-wave axis ≤75°. Patients with a P-wave axis >75° exhibited significantly higher total COPD assessment test scores and increased St. George’s Respiratory Questionnaire total, activity, and impact scores than those with a P-wave axis ≤75°. The incidence of exacerbations over 1 and 3 years was significantly higher in patients with a P-wave axis >75° than in those with a P-wave axis ≤75°. The optimal cutoff for the P-wave axis for a percentage of the predicted forced expiratory volume in 1 s 75° than in those with a P-wave axis ≤75°. However, the ratio of the airway wall area did not differ between the 2 groups. Conclusions: Patients with COPD with a vertical P-wave axis exhibited severe airflow limitation and emphysema, a worse health status, and more frequent exacerbation than patients without a vertical P-wave. Detection of the vertical P-wave axis by ECG is beneficial for the management of patients with COPD.

Although an important cause of vocal cord dysfunction (VCD) is psychogenic reaction, VCD may be associated with severe asthma and must be distinguished from the disease. A 30-years-old woman was admitted to our hospital with dyspnea despite treatment for asthma. Inspiratory stridor and expiratory wheezes were noted, and neck and chest computed tomography showed normal airways and lungs. Fractional exhaled nitric oxide levels were also normal. Pulmonary function test with a flow-volume loop curve showed normal expiratory loop with flattening of the inspiratory loop after methacholine inhalation. During the attack, bronchoscopy revealed the vocal cord closing with stridor during the inspiratory phase. Therefore, the patient was diagnosed with VCD. The dyspnea improved with respiratory rehabilitation and pursed-lip breathing. VCD should be considered in the differential diagnosis of intractable severe asthma. In this case, bronchoscopy and bronchial inhalation challenge with methacholine helped in the diagnosis.

Background Physical inactivity due to cachexia and muscle wasting is well recognized as a sign of poor prognosis in chronic obstructive pulmonary disease (COPD). However, there have been no reports on the relationship between trunk muscle measurements and energy expenditure parameters, such as the total energy expenditure (TEE) and physical activity level (PAL), in COPD. In this study, we investigated the associations of computed tomography (CT)-derived muscle area and density measurements with clinical parameters, including TEE and PAL, in patients with or at risk for COPD, and examined whether these muscle measurements serve as an indicator of TEE and PAL. Methods The study population consisted of 36 male patients with (n = 28, stage 1–4) and at risk for (n = 8) COPD aged over 50 years. TEE was measured by the doubly labeled water method, and PAL was calculated as the TEE/basal metabolic rate estimated by the indirect method. The cross-sectional areas and densities of the pectoralis muscles, rectus abdominis muscles, and erector spinae muscles were measured. We evaluated the relationship between these muscle measurements and clinical outcomes, including body composition, lung function, muscle strength, TEE, and PAL. Results All the muscle areas were significantly associated with TEE, severity of emphysema, and body composition indices such as body mass index, fat-free mass, and trunk muscle mass. All trunk muscle densities were correlated with PAL. The product of the rectus abdominis muscle area and density showed the highest association with TEE (r = 0.732) and PAL (r = 0.578). Several trunk muscle measurements showed significant correlations with maximal inspiratory and expiratory pressures, indicating their roles in respiration. Conclusions CT-derived measurements for trunk muscles are helpful in evaluating physical status and function in patients with or at risk for COPD. Particularly, trunk muscle evaluation may be a useful marker reflecting TEE and PAL.

Although weight loss suggests poor prognosis of COPD, only a few studies have examined total energy expenditure (TEE) or physical activity level (PAL) using the doubly labelled water (DLW) method. We evaluated TEE and PAL using the DLW method together with a triaxial accelerometer to elucidate the relationships between TEE, PAL and clinical parameters leading to a practical means of monitoring COPD physical status. This study evaluated 50- to 79-year-old male patients with mild to very severe COPD (n=28) or at risk for COPD (n=8). TEE, activity energy expenditure for 2 weeks and basal metabolic rate were measured by DLW, an accelerometer and indirect calorimetry, respectively. All patients underwent pulmonary function, chest-computed tomography, 6-min walk test, body composition and grip strength tests. Relationships between indices of energy expenditure and clinical parameters were analysed. Bland–Altman analysis was used to examine the agreement of TEE and PAL between the DLW method and the accelerometer. TEE and PAL using DLW in the total population were 2273±445 kcal·day−1 and 1.80±0.20, respectively. TEE by DLW correlated well with that from the accelerometer and grip strength (p, Although total energy expenditure and physical activity level in COPD patients were underestimated by an accelerometer, they can be predicted using indices of the accelerometer and clinical parameters such as the 6-min walk distance and grip strength. https://bit.ly/2OYbuaI

Emphysema is a major pathological change in chronic obstructive pulmonary disease (COPD). However, the annual changes in the progression of emphysematous have not been investigated. We aimed to determine possible baseline predicting factors of the change in emphysematous progression in a subgroup of COPD patients who demonstrated rapid progression. In this observational study, we analyzed patients with COPD who were followed up by computed tomography (CT) at least two times over a 3-year period (n = 217). We divided the annual change in the low attenuation area percentage (LAA%) into quartiles and defined a rapid progression group (n = 54) and a non-progression group (n = 163). Predictors of future changes in emphysematous progression differed from predictors of high LAA% at baseline. On multivariate logistic regression analysis, low blood eosinophilic count (odds ratio [OR], 3.22; P = 0.04) and having osteoporosis (OR, 2.13; P = 0.03) were related to rapid changes in emphysematous progression. There was no difference in baseline nutritional parameters, but nutritional parameters deteriorated in parallel with changes in emphysematous progression. Herein, we clarified the predictors of changes in emphysematous progression and concomitant deterioration of nutritional status in COPD patients.

Shingo Nakayama,1 Shotaro Chubachi,1 Kaori Sakurai,1 Hidehiro Irie,1 Akihiro Tsutsumi,1 Mizuha Hashiguchi,2 Yuji Itabashi,3 Mitsushige Murata,4 Hidetoshi Nakamura,5 Koichiro Asano,6 Koichi Fukunaga1 1Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan; 2Division of Pulmonary Medicine, Keiyu Hospital, Yokohama, Kanagawa 220-0012, Japan; 3Department of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan; 4Center for Preventive Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan; 5Division of Pulmonary Medicine, Saitama Medical University Hospital, Saitama 350-0495, Japan; 6Division of Pulmonary Medicine, Department of Medicine, Tokai University School of Medicine, Isehara-Shi, Kanagawa 259-1193, JapanCorrespondence: Shotaro ChubachiDivision of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo 160-8582, JapanTel +81-3-5363-3406Fax +81-3-3353-2502Email bachibachi472000@live.jpBackground: Pulmonary hypertension (PH) is a major comorbidity of chronic obstructive pulmonary disease (COPD). However, the association of PH detected by echocardiography and COPD-related outcome in longitudinal follow-up has not been elucidated. In this study, we aimed to investigate the relationship between clinical characteristics of COPD patients with PH detected by echocardiography and various outcome parameters such as COPD exacerbation and health status over a three-year observation period.Methods: In this observational study, we analyzed patients with COPD who underwent chest computed tomography and echocardiography at baseline (n = 183).Results: The prevalence of PH was 21.9% (40 patients). The median estimated systolic pulmonary artery pressure in patients with PH was 38.8 mmHg. COPD patients with PH were older, had a lower body mass index, scored worse in the COPD Assessment Test and St. George’s Respiratory Questionnaire, and exhibited a lower diffusing capacity of the lung for carbon monoxide in comparison to patients without PH. In computed tomography images, the percentages of low-attenuation areas (LAA%) and interstitial abnormalities were higher in COPD patients with PH than in those without PH. Higher values for LAA% (LAA ≥ 30%) and interstitial abnormalities independently increased the risk of PH. The ratio of main pulmonary diameter to aortic artery diameter was significantly correlated with estimated systolic pulmonary artery pressure. In the follow-up analysis, the frequency of exacerbations in three years was significantly higher in patients with PH compared to patients without PH.Conclusion: In this study, we identified the clinical characteristics of COPD patients with PH detected by echocardiography. The presence of PH assessed by echocardiography was related to future COPD exacerbations and closely related to radiographical emphysema.Keywords: comorbidity, COPD, echocardiography, pulmonary hypertension

Background and objectiveWeight loss and reduced fat-free mass are independent risk factors for mortality among patients with chronic obstructive pulmonary disease (COPD). These factors are important for determining diet therapy and examining the validity of assessment for energy intake (EI). We assessed the agreement of EI between a brief-type self-administered diet history questionnaire (BDHQ) and the doubly labelled water (DLW) method among male patients with stable/at risk for COPD.MethodIn this cross-sectional observational study, data for 33 male patients were analysed. At the first visit, EI was estimated using a BDHQ (EIBDHQ). Total energy expenditure (TEE) was measured during 13–15 days by the DLW method, while corrected EI was calculated using the TEE and weight change during the DLW period (EIDLW). The difference between EIBDHQ and EIDLW was evaluated by the Bland-Altman method. Multiple regression analysis was used to determine the proportion of variance in the difference between EIBDHQ and EIDLW, as determined by the patient’s characteristics.ResultsEIBDHQ was 2100 (95% CI: 1905 to 2295) kcal/day in the total population. A fixed bias was observed between EIBDHQ and EIDLW as −186 (95% CI: −422 to 50) kcal/day, while a proportional bias was not detected by the Bland-Altman analysis. Age, weight, anxiety and interleukin 6 were responsible for 61.7% of the variance in the difference between both EIs in a multiple regression model.ConclusionsThe BDHQ underestimated EI among male patients with stable/at risk for COPD, but this estimation error was within an acceptable range compared with previous studies. EIBDHQ precision might be improved by considering common COPD traits, including inflammatory condition and mental state.

Aim To evaluate the association between periodontal disease and pneumonia mortality in haemodialysis patients. Materials and methods This prospective cohort study included 211 patients (mean age, 64.4 years) undergoing haemodialysis at a single medical centre. The patients underwent a baseline clinical dental examination in 2008 and were then followed up until July 2015. Periodontal disease was defined as the presence of clinical attachment loss of ≥4 mm in ≥30% of the probed sites. The primary endpoint, that is death from pneumonia, was determined by reviewing death certificates and was analysed using the competing-risks regression model. Results At baseline, 92 patients (43.6%) had periodontal disease. The median follow-up period was 84 months (interquartile range, 36-86 months). Of the 68 deaths that occurred, 21 were from pneumonia. The multivariable competing-risks regression model showed that periodontal disease was significantly associated with death from pneumonia (adjusted subhazard ratio, 3.49; 95% confidence interval, 1.14-10.64), after adjusting for other baseline health characteristics. Conclusions The results of this study suggest that periodontal disease is independently associated with pneumonia mortality in haemodialysis patients. Future studies evaluating the potential effect of oral interventions for periodontal health improvement on pneumonia in haemodialysis patients would be of great interest.

Background The chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) is a subjective measure of quality of life. The aim of this study was to examine the characteristics of COPD patients with increasing CAT scores within 3 years. Methods Keio University and its affiliate hospitals conducted an observational COPD cohort study over 3 years. St. George's Respiratory Questionnaire (SGRQ) and CAT were completed at baseline and annually thereafter. Patients who had at least 3 CAT scores were included (n = 315). The ΔCAT score/year and ΔSGRQ score/year were calculated by the slope between each of the measures and the date of measurement. Results The median ΔCAT score/year was 0.4, and ΔCAT score/year was significantly correlated with ΔSGRQ total score/year. Using an annual cut-off CAT score of +2 points, patients who deteriorated (n = 79) were older, had lower %FEV 1 , and more severe emphysema on computed tomography scan at baseline than patients who did not deteriorate. The baseline value was not a determinant of subsequent changes in the CAT score. Longitudinal changes in the CAT score were positively correlated with those in the SGRQ score. Conclusions Old age and severe COPD, not the CAT score at one time point, predicted worsening quality of life.

Shotaro Chubachi,1 Saeko Takahashi,1 Akihiro Tsutsumi,1 Naofumi Kameyama,1 Mamoru Sasaki,1 Katsuhiko Naoki,1 Kenzo Soejima,1 Hidetoshi Nakamura,2 Koichiro Asano,3 Tomoko Betsuyaku1 On behalf of the Keio COPD Comorbidity Research Group 1Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, 2Department of Respiratory Medicine, Saitama Medical University, Irima-gun, Saitama, 3Division of Pulmonary Medicine, Department of Medicine, Tokai University School of Medicine, Isehara-shi, Kanagawa, Japan Background: Only a few studies have evaluated the radiologic features of pre-existing structural abnormalities where lung cancer may develop. This study aimed to analyze the computed tomography (CT) images of lung areas where new cancer developed in chronic obstructive pulmonary disease (COPD) patients. Patients and methods: We conducted a multicenter, longitudinal cohort study, called the Keio COPD Comorbidity Research, to assess the incidence of lung cancer. Emphysema and interstitial abnormalities were evaluated in 240 COPD patients who had baseline CT scans applicable for further digital analyses. For patients who developed lung cancer during the 3-year follow-up period, the local spherical lung density of the precancerous area was individually quantified. Results: Lung cancer was newly diagnosed in 21 participants (2.3% per year). The percentage of low attenuation area in patients who developed lung cancer was higher than that of the other patients (20.0% vs 10.4%, P=0.014). The presence of emphysema (odds ratio [OR] 4.2, 95% confidence interval [CI] 1.0–29.0, P=0.049) or interstitial lung abnormalities (OR 15.6, 95% CI 4.4–65.4, P

Numerous strains of Aspergillus oryzae are industrially used for Japanese traditional fermentation and for the production of enzymes and heterologous proteins. In A. oryzae, deletion of the ku70 or ligD genes involved in non-homologous end joining (NHEJ) has allowed high gene targeting efficiency. However, this strategy has been mainly applied under the genetic background of the A. oryzae wild strain RIB40, and it would be laborious to delete the NHEJ genes in many A. oryzae industrial strains, probably due to their low gene targeting efficiency. In the present study, we generated ligD mutants from the A. oryzae industrial strains by employing the CRISPR/Cas9 system, which we previously developed as a genome editing method. Uridine/uracil auxotrophic strains were generated by deletion of the pyrG gene, which was subsequently used as a selective marker. We examined the gene targeting efficiency with the ecdR gene, of which deletion was reported to induce sclerotia formation under the genetic background of the strain RIB40. As expected, the deletion efficiencies were high, around 60~80%, in the ligD mutants of industrial strains. Intriguingly, the effects of the ecdR deletion on sclerotia formation varied depending on the strains, and we found sclerotia-like structures under the background of the industrial strains, which have never been reported to form sclerotia. The present study demonstrates that introducing ligD mutation by genome editing is an effective method allowing high gene targeting efficiency in A. oryzae industrial strains.

Filamentous fungi are used for food fermentation and industrial production of recombinant proteins. They also serve as a source of secondary metabolites and are recently expected as hosts for heterologous production of useful secondary metabolites. Multiple-step genetic engineering is required to enhance industrial production involving these fungi, but traditional sequential modification of multiple genes using a limited number of selection markers is laborious. Moreover, efficient genetic engineering techniques for industrial strains have not yet been established. We have previously developed a clustered regulatory interspaced short palindromic repeats (CRISPR)/Cas9-based mutagenesis technique for the industrial filamentous fungus Aspergillus oryzae, enabling mutation efficiency of 10 to 20%. Here, we improved the CRISPR/Cas9 approach by including an AMA1-based autonomously replicating plasmid harboring the drug resistance marker ptrA By using the improved mutagenesis technique, we successfully modified A. oryzae wild and industrial strains, with a mutation efficiency of 50 to 100%. Conditional expression of the Aoace2 gene from the AMA1-based plasmid severely inhibited fungal growth. This enabled forced recycling of the plasmid, allowing repeated genome editing. Further, double mutant strains were successfully obtained with high efficiency by expressing two guide RNA molecules from the genome-editing plasmid. Cotransformation of fungal cells with the genome-editing plasmid together with a circular donor DNA enabled marker-free multiplex gene deletion/integration in A. oryzae The presented repeatable marker-free genetic engineering approach for mutagenesis and gene deletion/integration will allow for efficient modification of multiple genes in industrial fungal strains, increasing their applicability.IMPORTANCE Multiple gene modifications of specific fungal strains are required for achieving industrial-scale production of enzymes and secondary metabolites. In the present study, we developed an efficient multiple genetic engineering technique for the filamentous fungus Aspergillus oryzae The approach is based on a clustered regulatory interspaced short palindromic repeats (CRISPR)/Cas9 system and recycling of an AMA1-based autonomous replicating plasmid. Because the plasmid harbors a drug resistance marker (ptrA), the approach does not require the construction of auxotrophic industrial strains prior to genome editing and allows for forced recycling of the gene-editing plasmid. The established plasmid-recycling technique involves an Aoace2-conditional expression cassette, whose induction severely impairs fungal growth. We used the developed genetic engineering techniques for highly efficient marker-free multiple gene deletion/integration in A. oryzae The genome-editing approaches established in the present study, which enable unlimited repeatable genetic engineering, will facilitate multiple gene modification of industrially important fungal strains.

Periodontitis is common among dialysis patients. The current cross-sectional study aimed to explore associations between periodontitis and health-related quality of life (HRQoL) among hemodialysis patients. Data from 188 dentate patients undergoing hemodialysis between May and July 2008 at a medical center in Kitakyushu city, Japan, were analyzed while applying modified Centers for Disease Control and Prevention/American Academy of Periodontology periodontitis case definitions to categorize the participants into the following three groups: severe, moderate, and no/mild periodontitis, respectively. HRQoL was assessed by the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) where a higher score indicates better health status. Associations between periodontitis groups and the eight health domains of SF-36 were evaluated using general linear models that were adjusted for age, sex, underlying cause of dialysis, duration of dialysis, comorbidities, serum biomarkers, body mass index, smoking status, and alcohol use. Among the 188 participants, 18 (9.6%) had severe periodontitis, 100 (53.2%) had moderate periodontitis, and the remaining 70 (37.2%) had no/mild periodontitis. Compared with the participants with no/mild periodontitis, those with severe periodontitis had worse scores in the following five of eight SF-36 health scales: physical functioning, role physical, vitality, social functioning, and mental health (P

Background and objectives Patients with chronic obstructive pulmonary disease (COPD) frequently suffer from various comorbidities. Recently, cluster analysis has been proposed to examine the phenotypic heterogeneity in COPD. In order to comprehensively understand the comorbidities of COPD in Japan, we conducted multicenter, longitudinal cohort study, called the Keio COPD Comorbidity Research (K-CCR). In this cohort, comorbid diagnoses were established by both objective examination and review of clinical records, in addition to self-report. We aimed to investigate the clustering of nineteen clinically relevant comorbidities and the meaningful outcomes of the clusters over a two-year follow-up period. Material and Methods The present study analyzed data from COPD patients whose data of comorbidities were completed (n = 311). Cluster analysis was performed using Ward's minimum-variance method. Results Five comorbidity clusters were identified: less comorbidity; malignancy; metabolic and cardiovascular; gastroesophageal reflux disease (GERD) and psychological; and underweight and anemic. FEV 1 did not differ among the clusters. GERD and psychological cluster had worse COPD assessment test (CAT) and Saint George's respiratory questionnaire (SGRQ) at baseline compared to the other clusters (CAT: p = 0.0003 and SGRQ: p = 0.00046). The rate of change in these scores did not differ within 2 years. The underweight and anemic cluster included subjects with lower baseline ratio of predicted diffusing capacity (D L co/V A ) compared to the malignancy cluster (p = 0.036). Conclusions Five clusters of comorbidities were identified in Japanese COPD patients. The clinical characteristics and health-related quality of life were different among these clusters during a follow-up of two years.

The serine-threonine kinase Rim15p is a master regulator of stress signaling and is required for stress tolerance and sexual sporulation in the yeast Saccharomyces cerevisiae. However, in filamentous fungi that reproduce asexually via conidiation, the physiological function of Rim15p homologs has not been extensively analyzed. Here, we functionally characterized the protein homolog of Rim15p in the filamentous fungus Aspergillus oryzae, by deleting and overexpressing the corresponding Aorim15 gene and examining the role of this protein in stress tolerance and development. Deletion of Aorim15 resulted in an increase in the sensitivity of conidia to oxidative and heat stresses, whereas conidia of the Aorim15 overexpressing strain were more resistant to these stresses. These results indicated that AoRim15 functions in stress tolerance, similar to S. cerevisiae Rim15p. Phenotypic analysis revealed that conidiation was markedly reduced by overexpression of Aorim15 in A. oryzae, and was completely abolished in the deletion strain. In addition, the formation of sclerotia, which is another type of developmental structure in filamentous fungi, was decreased by the deletion of Aorim15, whereas Aorim15 overexpression increased the number of sclerotia. These results indicated that AoRim15 is a positive regulator of sclerotia formation and that overexpression of AoRim15 shifts the developmental balance from conidiation towards sclerotia formation. Collectively, we demonstrated that AoRim15 is involved in the stress tolerance of conidia and differentially regulates between the two developmental fates of conidiation and sclerotia formation.