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Jiaqi Pu,1,&ast; Qun Yi,1,2,&ast; Yuanming Luo,3 Hailong Wei,4 Huiqing Ge,5 Huiguo Liu,6 Xianhua Li,7 Jianchu Zhang,8 Pinhua Pan,9 Hui Zhou,10 Chen Zhou,11 Mengqiu Yi,12 Lina Cheng,12 Liang Liu,10 Jiarui Zhang,1 Lige Peng,1 Adila Aili,1 Yu Liu,1 Haixia Zhou1 On behalf of the MAGNET AECOPD Registry Investigators1Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Sichuan Cancer Hospital and Institution, Sichuan Cancer Center, Cancer Hospital Affiliate to School of Medicine, UESTC, Chengdu, People’s Republic of China; 3State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, People’s Hospital of Leshan, Leshan, People’s Republic of China; 5Department of Respiratory and Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 6Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 7Department of Respiratory and Critical Care Medicine, the First People’s Hospital of Neijiang City, Neijiang, People’s Republic of China; 8Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 9Department of Respiratory and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 10Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Chengdu University, Chengdu, People’s Republic of China; 11West China School of Medicine, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 12Department of Emergency, First People’s Hospital of Jiujiang, Jiu Jiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haixia Zhou, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Guo-Xue-Xiang 37&num;, Wuhou District, Chengdu, Sichuan Province, 610041, People’s Republic of China, Tel/Fax +86-28-85422571, Email zhouhaixia@wchscu.cnPurpose: The prognostic value of blood eosinophils in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) remains controversial. This study aimed to evaluate whether blood eosinophils could predict in-hospital mortality and other adverse outcomes in inpatients with AECOPD.Methods: The patients hospitalized for AECOPD were prospectively enrolled from ten medical centers in China. Peripheral blood eosinophils were detected on admission, and the patients were divided into eosinophilic and non-eosinophilic groups with 2% as the cutoff value. The primary outcome was all-cause in-hospital mortality.Results: A total of 12,831 AECOPD inpatients were included. The non-eosinophilic group was associated with higher in-hospital mortality than the eosinophilic group in the overall cohort (1.8% vs 0.7%, P < 0.001), the subgroup with pneumonia (2.3% vs 0.9%, P = 0.016) or with respiratory failure (2.2% vs 1.1%, P = 0.009), but not in the subgroup with ICU admission (8.4% vs 4.5%, P = 0.080). The lack of association still remained even after adjusting for confounding factors in subgroup with ICU admission. Being consistent across the overall cohort and all subgroups, non-eosinophilic AECOPD was also related to greater rates of invasive mechanical ventilation (4.3% vs 1.3%, P < 0.001), ICU admission (8.9% vs 4.2%, P < 0.001), and, unexpectedly, systemic corticosteroid usage (45.3% vs 31.7%, P < 0.001). Non-eosinophilic AECOPD was associated with longer hospital stay in the overall cohort and subgroup with respiratory failure (both P < 0.001) but not in those with pneumonia (P = 0.341) or ICU admission (P = 0.934).Conclusion: Peripheral blood eosinophils on admission may be used as an effective biomarker to predict in-hospital mortality in most AECOPD inpatients, but not in patients admitted into ICU. Eosinophil-guided corticosteroid therapy should be further studied to better guide the administration of corticosteroids in clinical practice.Keywords: acute exacerbation of chronic obstructive pulmonary disease, peripheral blood eosinophils, inpatients, in-hospital mortality, clinical outcomes

Chen Zhou,1,&ast; Yujie Guang,1,&ast; Yuanming Luo,2 Huiqing Ge,3 Hailong Wei,4 Huiguo Liu,5 Jianchu Zhang,6 Pinhua Pan,7 Jiarui Zhang,8 Lige Peng,8 Adila Aili,8 Yu Liu,8 Jiaqi Pu,8 Xia Zhong,1 Yixi Wang,1 Qun Yi,8,9 Haixia Zhou8 On behalf of the MAGNET AECOPD Registry Investigators1West China School of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China; 2State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, Guangdong Province, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, People’s Hospital of Leshan, Leshan, Sichuan Province, People’s Republic of China; 5Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People’s Republic of China; 6Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People’s Republic of China; 7Department of Respiratory and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of China; 8Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China; 9Sichuan Cancer Hospital and Institution, Sichuan Cancer Center, Cancer Hospital Affiliate to School of Medicine, UESTC, Chengdu, Sichuan Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haixia Zhou, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Guo-Xue-Xiang 37&num;, Wuhou District, Chengdu, Sichuan Province, 610041, People’s Republic of China, Tel +86-28-85422571, Fax +86-28-85422571, Email zhouhaixia@wchscu.cnBackground: The optimal tool for risk prediction of venous thromboembolism (VTE) in inpatients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is still unknown. This study aimed to evaluate whether D-dimer could predict the risk of VTE in inpatients with AECOPD compared to the Padua Prediction Score (PPS).Methods: Inpatients with AECOPD were prospectively enrolled from seven medical centers in China between December 2018 and June 2020. On admission, D-dimer was detected, PPS was calculated for each patient, and the incidence of 2-month VTE was investigated. The receiver operating characteristic (ROC) curve was used to evaluate the predictive value of D-dimer and PPS on VTE development, and the best cut-off value for both methods was evaluated through the Youden index.Results: Among the 4468 eligible patients with AECOPD, 90 patients (2.01%) developed VTE within 2 months after admission. The area under the receiver operating characteristic curves (AUCs) of D-dimer for predicting VTE were significantly higher than those of the PPS both in the overall cohort (0.724, 95% CI 0.672– 0.776 vs 0.620, 95% CI 0.562– 0.679; P< 0.05) and the subgroup of patients without thromboprophylaxis (0.747, 95% CI 0.695– 0.799 vs 0.640, 95% CI 0.582– 0.698; P< 0.05). By calculating the Youden Index, the best cut-off value of D-dimer was determined to be 0.96 mg/L with an AUC of 0.689, which was also significantly better than that of the PPS with the best cut-off value of 2 (AUC 0.581, P=0.007). After the combination of D-dimer with PPS, the AUC (0.621) failed to surpass D-dimer alone (P=0.104).Conclusion: D-dimer has a superior predictive value for VTE over PPS in inpatients with AECOPD, which might be a better choice to guide thromboprophylaxis in inpatients with AECOPD due to its effectiveness and convenience.Clinical Trial Registration: Chinese Clinical Trail Registry NO. ChiCTR2100044625; URL: http://www.chictr.org.cn/showproj.aspx?proj=121626.Keywords: acute exacerbation of chronic obstructive pulmonary disease, inpatients, D-dimer, Padua Prediction Score, venous thromboembolism

The rupture of intracranial aneurysms (IAs) is a complicated phenomenon of which the mechanism is not fully understood. The purpose of this study is to associate local solid mechanical, hemodynamic, and morphological characteristics with rupture regions through statistical means, in an attempt to identify the parameters that are indicative of rupture propensity for IAs. Twenty patient-specific ruptured IA models were reconstructed from digital subtraction angiography (DSA), and applied in the analysis of wall tension, wall shear stress (WSS) and curvature. The precise rupture locations were marked out through intraoperative videos. Pearson correlation analysis was employed to investigate the correlations of these three parameters with patient characteristics and global geometric features. Univariate and multivariate logistic regression analysis were further performed on wall tension, WSS and curvature with regards to rupture and nonrupture regions. Receiver operating characteristic (ROC) analysis defining area under the curve (AUC) was performed on these three parameters. The univariate model of wall tension (AUC, 0.9750), WSS (AUC, 0.9300), curvature (0.8150) and their combined multivariate model (AUC, 0.9875) all present high AUC values. The wall tension, WSS and curvature are acceptable parameters relating to rupture regions. The rupture odd is more sensitive to the wall tension and WSS than curvature. Each logistic model is capable in discriminating ruptures from nonrupture regions, while the multivariate model is the most efficient.

With wide applications of genomics, transcriptomics, proteomics and metabolomics in the post-genome era, functional explanation has become the central task in life science research, and multi-omics data integrative analysis has become an indispensable strategy for uncovering the underlying biological mechanism. This special issue aimed to introduce the related research advances and applications in multi-omics by inviting the domestic experts. In total, 28 papers have been collected in this issue, for researcher's reference in multi-omics.

With technological advances in high-throughput sequencing, high resolution mass-spectrometry, and multi-omics data integrative tools and data repositories, the omics research in life sciences are evolving from single-omics strategy to multi-omics strategy. The research of system biology driven by multi-omics will bring a new paradigm in life sciences. This paper briefly summarizes the development of genomics, epigenomics, transcriptomics, proteomics and metabolomics, highlights the composition and function of multi-omics platforms as well as the applications of multi-omics technology, and prospects future applications of multi-omics in synthetic biology and biomedicine.

STUDY OBJECTIVES: Uncertainty exists over whether continuous positive airway pressure (CPAP) treatment improves moderate to vigorous physical activity levels in those with obstructive sleep apnea. We aimed to determine effects of CPAP on moderate to vigorous physical activity among participants with co-occurring cardiovascular disease and obstructive sleep apnea. METHODS: The Sleep Apnea cardioVascular Endpoints (SAVE) trial recruited participants with confirmed cardiovascular disease history and obstructive sleep apnea, 45–75 years old. The 2,687 participants (1,346 randomized to CPAP plus usual care and 1,341 to usual care alone) were followed up for a mean of 3.7 years. Self-reported physical activity was recorded at baseline, 6, 24, and 48 months using the Godin-Shepard Leisure Time Exercise Questionnaire (LTEQ). We also determined effects on any limitation of physical activity reported on the physical functioning subscale of the 36-item short form questionnaire (SF-36) and proportions of participants reaching guideline recommended physical activity levels. RESULTS: Among 2,601 participants with available data, those in the CPAP group reported significantly more physical activity compared to the usual care group, with approximately 20% higher reported moderate activities on the LTEQ during follow-up (adjusted mean 95% confidence interval) scores: 8.7, 7.5–9.9 vs 7.3, 6.1–8.5; P = .003). Those in the CPAP group also reported less limitation in physical activity (adjusted between-group difference in SF-36 physical functioning subscale score 1.66, 95% confidence interval 0.87–2.45; P < 0.001), and more reported sufficient levels of physical activity to meet recommendations. CONCLUSIONS: CPAP has positive effects on improving physical activity levels, consistent with long-term health benefits. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea to Prevent Cardiovascular Disease (SAVE); URL: https://clinicaltrials.gov/ct2/show/NCT00738179; Identifier: NCT00738179; and Registry: Australian New Zealand Clinical Trials Registry; Name: Sleep Apnea cardioVascular Endpoints study—An investigation of continuous positive airway pressure for the treatment of obstructive sleep apnea to prevent cardiovascular disease; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=83062&isReview=true; Identifier: ACTRN12608000409370. CITATION: Stevens D, Loffler KA, Buman MP, et al. CPAP increases physical activity in obstructive sleep apnea with cardiovascular disease. J Clin Sleep Med. 2021;17(2):141–148.

Study objectives Sleep is associated with a reduction in ventilation and an increase in upper airway resistance (UAR) in patients with obstructive sleep apnea (OSA). However, there is no consensus on the standard for assessment of UAR and therefore it is important to develop a method to reliably assess UAR in patients with OSA. The purpose of the present study is to determine whether the ratio of neural respiratory drive (NRD) to flow can be used to assess changes in UAR in OSA during sleep. Methods A total of 24 patients (21 men) with OSA and 10 normal subjects (6 males) were studied. The UAR was assessed by the ratio of NRD to flow, which measured by esophageal pressure (Poes), diaphragm electromyography (EMGdi) and superficial diaphragm electromyography (SEMGdi) in various stages including wakefulness, N2 sleep, N2 sleep with snoring, hypopneas, the in the “preapnea” states in OSA versus wakefulness, sleeponset, N2 sleep, N3 sleep in normal subjects. All subjects underwent overnight full polysomnography using standard techniques. Results Our study indicate that UAR was progressively higher from wakefulness to N2 sleep, N2 sleep with snoring, hypopneas, and the in the “preapnea” states in patients with OSA and had obvious difference in statistical significance (p Conclusions It is feasible to use the ratio of neural respiratory drive to flow to assess UAR in patients with OSA during sleep.

Approximately 20% of chronic obstructive pulmonary disease (COPD) patients have been considered to have a “nonhyperinflator phenotype.” However, this judgment depends on patients making a fully maximal inspiratory capacity (IC) maneuver at rest, since the IC during exercise is compared with this baseline measurement. We hypothesized that IC maneuvers at rest are sometimes submaximal and tested this hypothesis by measuring IC and associated neural respiratory drive at rest and during inhalation of CO2 and exercise in patients with COPD. Twenty-six COPD patients [age 66 ± 6 yr, mean forced expiratory volume in 1 s (FEV1) 40 ± 11% predicted] and 39 healthy subjects (age 39 ± 14 yr, FEV1 98 ± 12% predicted) were studied. IC and the diaphragm electromyogram (EMGdi) associated with it (EMGdi-IC) and forced inspiratory vital capacity (FIVC) and its corresponding EMGdi (EMGdi-FIVC) were measured during inhalation of 8% CO2 (8% CO2-92% O2) and room air. Incremental exhaustive cycle ergometer exercise was also performed in both patients with COPD and healthy subjects. IC, EMGdi-IC, FIVC, and EMGdi-FIVC during breathing 8% CO2 were significantly greater than those during breathing room air in both patients with COPD and healthy subjects (all P < 0.001). EMGdi-IC in patients with COPD constantly increased during exercise from 145 ± 40 µV at rest to 185 ± 52 µV at the end of exercise but change in IC was variable. Neural respiratory drive and its relevant IC increased during hypercapnia. Exercise-related hypercapnia in patients with COPD raises neural respiratory drives, which compensate for IC reduction, leading to underestimation of dynamic hyperinflation measured by IC at rest breathing room air. NEW & NOTEWORTHY Inspiratory capacity measured during hypercapnia is higher than that during eucapnia. Thus total lung capacity is not always be achieved by a standard inspiratory capacity maneuver, leading to risk of underestimation of dynamic hyperinflation in patients with severe chronic obstructive pulmonary disease after exhaustive exercise.

Background and aim Controversy exists regarding cardiovascular risk in relation to sleep duration. We determined sleep duration and major recurrent cardiovascular event associations in patients with obstructive sleep apnoea and established cardiovascular disease. Methods Secondary analyses of the international, multicenter, Sleep Apnea Cardiovascular Endpoints trial. Sleep duration was estimated from overnight home oximetry (ApneaLink monitor) used for obstructive sleep apnoea diagnosis. Cox proportional hazards models were used to determine associations of categorized sleep duration (8 h) and major cardiovascular outcomes: primary composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and any hospitalization for unstable angina, heart failure, or transient ischemic attack; secondary composite of cardiac and cerebral (stroke/transient ischemic attack) events. Results Oximetry-derived sleep duration estimates were available in 2687 participants (mean 61.2 years, 80.9% males) who experienced a total of 436 cardiovascular events over a mean follow-up of 3.7 years. Compared to the reference category, sleep duration was not associated with risk of the primary composite cardiovascular outcome (adjusted hazard ratio (HR) 1.00, 95% confidence interval 0.76–1.33, and HR 1.22, 95% confidence interval 0.98–1.52, for sleep duration 8 h, respectively). However, long sleep was associated with increased cerebral events (HR 1.67, 95% confidence interval 1.17–2.39; P = 0.005) and stroke alone (HR 1.79, 95% confidence interval 1.22–2.63; P = 0.003). Conclusions Long sleep duration is associated with an increased risk of stroke but not cardiac events in obstructive sleep apnoea patients with existing cardiovascular disease. Clinical trial registration The trial is registered at ClinicalTrials.gov (NCT00738179).

Background: Prone position ventilation (PPV) is an important strategy for patients with severe acute respiratory distress syndrome (ARDS). This prospective study investigated the use of electromyography of the diaphragm (EMGdi) for monitoring respiratory drive in patients with moderate to severe ARDS during long-term PPV Methods: An integrated nostril-gastric feeding tube containing an esophageal electrode and balloon was placed in 14 patients with severe ARDS prior to PPV. EMGdi and trans-pulmonary pressure (∆PL) data were collected before PPV (baseline), every 2 h during PPV, and 2 h after the restoration of supine position ventilation (post-2 h SPV). Results: In ARDS patients, the static compliance of the chest wall was significantly decreased after PPV. EMGdi levels were slightly lower in the early, middle, and late stages of PPV compared with baseline. Patients who received neuromuscular blocker experienced a greater drop in EMGdi from baseline than those who did not. Conclusions: For ARDS patients, EMGdi was slightly decreased after prolonged PPV. This is contrary to the change in diaphragm electromyography during normal body position changes. Monitoring EMGdi regularly during PPV in ARDS patients is feasible and can be used as a reference for lung protective ventilation strategies.

Background Inpatients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) are at increased risk for venous thromboembolism (VTE); however, the prophylaxis for VTE is largely underused in China. Identifying high-risk patients requiring thromboprophylaxis is critical to reduce the mortality and morbidity associated with VTE. This study aimed to evaluate and compare the validities of the Padua Prediction Score and Caprini risk assessment model (RAM) in predicting the risk of VTE in inpatients with AECOPD in China. Methods The inpatients with AECOPD were prospectively enrolled from seven medical centers of China between September 2017 and January 2020. Caprini and Padua scores were calculated on admission, and the incidence of 3-month VTE was investigated. Results Among the 3,277 eligible patients with AECOPD, 128 patients (3.9%) developed VTE within 3 months after admission. The distribution of the study population by the Caprini risk level was as follows: high, 53.6%; moderate, 43.0%; and low, 3.5%. The incidence of VTE increased by risk level as high, 6.1%; moderate, 1.5%; and low, 0%. According to the Padua RAM, only 10.9% of the study population was classified as high risk and 89.1% as low risk, with the corresponding incidence of VTE of 7.9 and 3.4%, respectively. The Caprini RAM had higher area under curve compared with the Padua RAM (0.713 ± 0.021 vs. 0.644 ± 0.023, p = 0.029). Conclusion The Caprini RAM was superior to the Padua RAM in predicting the risk of VTE in inpatients with AECOPD and might better guide thromboprophylaxis in these patients.

Background Whether continuous positive airway pressure (CPAP) treatment can improve depression or anxiety symptoms in obstructive sleep apnoea (OSA) patients remains uncertain. Methods Secondary analysis of the Sleep Apnea Cardiovascular Endpoints (SAVE) trial, combined with a systematic review of randomised evidence. The SAVE secondary analyses involved 2410 patients with co-existing moderate–severe OSA and established cardiovascular disease randomly allocated to CPAP treatment plus usual care or usual care alone and followed up for 3·7 (SD 1·6) years. We evaluated the effect of CPAP treatment on depression and anxiety caseness (scores ≥ 8 on the Hospital Anxiety and Depression Scale depression and anxiety subscales [HADS-D and HADS-A]) for OSA patients. Findings CPAP treatment was associated with reduced odds of depression caseness (adjusted odds ratio [OR] 0·80, 95% confidence interval [CI] 0·65–0·98, P = 0·031) compared to usual care in the SAVE trial and the treatment effect was greater in those with pre-existing depression symptoms. A systematic review of 20 randomised trials including 4255 participants confirmed a benefit of CPAP in reducing depression symptoms in OSA patients: the overall effect (standardised mean difference) was − 0·18 (95% CI − 0·24 to − 0·12). No effect of CPAP treatment on anxiety caseness was found both in patients of the SAVE study (adjusted OR 0·98, 95% CI 0·78–1·24, P = 0·89) and the systematic review. Interpretation CPAP reduces depression symptoms in patients with co-existing OSA and CVD independently of improvements in sleepiness., Highlights • Depression and anxiety are prevalent in patients with chronic conditions, such as obstructive sleep apnoea (OSA) and cardiovascular disease, and they adversely impact on prognosis and quality of life. Whether continuous positive airway pressure (CPAP) treatment can improve depression or anxiety symptoms in OSA patients still remains uncertain. We searched PubMed for studies in English language published before 1 Jan 2019 reporting of CPAP effect on depression and anxiety symptoms using the terms “continuous positive airway pressure”, “obstructive sleep apnoea”, “depression” and “anxiety”. A recent systematic review of randomised trials on the effect of CPAP on depression symptoms had found modest benefit of CPAP treatment for improving depression symptoms, however there was high heterogeneity. Existing findings are variable across studies due, in part, to different study designs, small patient numbers, short periods of follow-up, and from an emphasis on depression over anxiety patterns of abnormal mood. • Added value of this study: Analysis of the Sleep Apnea Cardiovascular Endpoints (SAVE) cohort of over 2400 patients with moderate to severe OSA and concomitant cardiovascular diseases who were followed up for an average of 3.7 years showed that the CPAP reduced depression symptoms within few months of treatment, independently of improvements in daytime sleepiness. The NNT (i.e. 15) for CPAP to prevent depression caseness (as defined by Hospital Anxiety and Depression Scale – Depression subscale score ≥ 8) is comparable to remission rates achieved for some established antidepressant drugs. However, analyses of the SAVE study showed no clear clinical benefit for anxiety symptoms. Systematic review of 20 included randomised controlled studies showed similar results as our SAVE secondary analyses. • Implications of all the available evidence: Our findings provide further support for the broader beneficial effects of CPAP in those with OSA, and especially those at high cardiovascular risk, where there is the potential for enhanced mood to improve long-term cardiovascular outcomes.

Obstructive sleep apnoea (OSA) is a global health problem of increasing prevalence. Effective treatments are available with continuous positive airway pressure (CPAP) therapy and mandibular advancement devices (MAD). However, there is limited long-term adherence to therapy, as CPAP and MAD require permanent usage to avoid recurrence of the symptoms and adverse ill health. Alternative treatments would aid in the treatment cascade to manage OSA effectively whenever standard therapy has been trialled and failed. Hypoglossal nerve stimulation (HNS), an invasive approach to stimulate the pharyngeal dilator muscles of the upper airway during sleep, has been approved for the treatment of OSA by several healthcare systems in recent years. In parallel to the development of HNS, a non-invasive approach has been developed to deliver electrical stimulation. Transcutaneous electrical stimulation in obstructive sleep apnoea (TESLA) uses non-invasive electrical stimulation to increase neuromuscular tone of the upper airway dilator muscles of patients with OSA during sleep. Data from previous feasibility studies and randomised controlled trials have helped to identify a subgroup of patients who are “responders” to this treatment. However, further investigations are required to assess usability, functionality and task accomplishment of this novel treatment. Consideration of these factors in the study design of future clinical trials will strengthen research methodology and protocols, improve patient related outcome measures and assessments, to optimise this emerging therapeutical option. In this review, we will introduce a conceptual framework for the TESLA home programme highlighting qualitative aspects and outcomes.

Background Although recent evidence suggests that OSA treatment may cause weight gain, the long-term effects of CPAP on weight are not well established. Methods This study was a post hoc analysis of the Sleep Apnea Cardiovascular Endpoints (SAVE) study, a multicenter, randomized trial of CPAP plus standard care vs standard care alone in adults with a history of cardiac or cerebrovascular events and moderate to severe OSA. Participants with weight, BMI, and neck and waist circumferences measured at baseline and during follow-up were included. Linear mixed models were used to examine sex-specific temporal differences, and a sensitivity analysis compared high CPAP adherers (≥ 4 h per night) with propensity-matched control participants. Results A total of 2,483 adults (1,248 in the CPAP group and 1,235 in the control group) were included (mean 6.1 ± 1.5 measures of weight available). After a mean follow-up of 3.78 years, there was no difference in weight change between the CPAP and control groups, for male subjects (mean [95% CI] between-group difference, 0.07 kg [–0.40 to 0.54]; P = .773) or female subjects (mean [95% CI] between-group difference, –0.14 kg [–0.37 to 0.09]; P = .233). Similarly, there were no significant differences in BMI or other anthropometric measures. Although male participants who used CPAP ≥ 4 h per night gained slightly more weight than matched male control subjects without CPAP (mean difference, 0.38 kg [95% CI, 0.04 to 0.73]; P = .031), there were no between-group differences in other anthropometric variables, nor were there any differences between female high CPAP adherers and matched control subjects. Conclusions Long-term CPAP use in patients with comorbid OSA and cardiovascular disease does not result in clinically significant weight change. Trial Registry ClinicalTrials.gov; No.: NCT00738179 ; URL: www.clinicaltrials.gov .

Background: In 2007 and 2012, the American Academy of Sleep Medicine (AASM) updated their scoring criteria for nocturnal respiratory events. We hypothesised that this could have led to changes in the apnoea-hypopnoea index (AHI) of patients with chronic obstructive pulmonary disease (COPD)/obstructive sleep apnoea (OSA) overlap syndrome. Methods: In a retrospective study, polysomnographic (PSG) recordings of 34 patients with COPD/OSA overlap syndrome were independently analysed using the AASM criteria from 2007 (AASM2007) and 2012 (AASM2012). The primary outcome was the difference in AHI, the secondary outcomes were frequency of hypopnoeas, diagnosis of overlap syndrome and differences between the AASM 2007 recommended (AASM2007Rec) and altered (AASM2007Alt) classifications. Data are presented as mean (standard deviation) if normally distributed, and as median (interquartile range) if non-normally distributed. Results: The PSGs of 34 elderly [aged 67 (7.0) years] and predominantly male (m:f, 31:3) patients with COPD [FEV1%pred 48.4% (19.6%)] were analysed. The AHI using AASM2007Rec criteria was 5.9 (2.0, 15.1) events/hour vs. 20.4 (11.5, 28.0) events/hour using the 2012 criteria (P

Background: Electrical current can be used to stimulate upper airway dilator muscles to treat obstructive sleep apnoea (OSA). Ultrasound devices are widely available and may be used to detect contraction of the upper airway dilator muscles assessing the functionality of electrical stimulation (ES) used for this treatment. Methods: In a physiological sub-study of a randomised controlled trial, patients with OSA underwent ultrasound examination to assess contraction of the upper airway dilator muscles in response to transcutaneous ES. Ultrasound scans were scored according to the picture quality (poor = ‘0’, acceptable = ‘1’ and good = ‘2’). Tongue base thickness was assessed in mid-sagittal and coronal planes with (D2, A2) and without ES (D1, A1), while awake and seated. The primary outcome was to determine the increase in tongue thickness during ES in both views (D2 – D1 = ΔD), as well as any increase in the cross-sectional area (CSA) in the coronal view (A2 – A1 = ΔA). Data were presented as mean and standard deviation (SD). Results: Fourteen patients [eight male, age 57.5 (9.8) years, body mass index (BMI) 29.5 (2.8) kg/m2] with OSA [Apnea-Hypopnea Index (AHI) 19.5 (10.6) × hour-1] were studied. Quality of the ultrasound scans was acceptable or good with 1.5 (0.5) points. In the mid-sagittal plane, ΔD was +0.17 (0.07) cm in midline and +0.21 (0.09) cm in the widest diameter, a percentual change of 12.2% (4%) and 12.8% (5.2%) (P

OBJECTIVE Despite evidence of a relationship among obstructive sleep apnea (OSA), metabolic dysregulation, and diabetes, it is uncertain whether OSA treatment can improve metabolic parameters. We sought to determine effects of long-term continuous positive airway pressure (CPAP) treatment on glycemic control and diabetes risk in patients with cardiovascular disease (CVD) and OSA. RESEARCH DESIGN AND METHODS Blood, medical history, and personal data were collected in a substudy of 888 participants in the Sleep Apnea cardioVascular Endpoints (SAVE) trial in which patients with OSA and stable CVD were randomized to receive CPAP plus usual care, or usual care alone. Serum glucose and glycated hemoglobin A1c (HbA1c) were measured at baseline, 6 months, and 2 and 4 years and incident diabetes diagnoses recorded. RESULTS Median follow-up was 4.3 years. In those with preexisting diabetes (n = 274), there was no significant difference between the CPAP and usual care groups in serum glucose, HbA1c, or antidiabetic medications during follow-up. There were also no significant between-group differences in participants with prediabetes (n = 452) or new diagnoses of diabetes. Interaction testing suggested that women with diabetes did poorly in the usual care group, while their counterparts on CPAP therapy remained stable. CONCLUSIONS Among patients with established CVD and OSA, we found no evidence that CPAP therapy over several years affects glycemic control in those with diabetes or prediabetes or diabetes risk over standard-of-care treatment. The potential differential effect according to sex deserves further investigation.

Objective: Despite evidence of a relationship between obstructive sleep apnea (OSA), metabolic dysregulation and diabetes mellitus (DM), it is uncertain whether OSA treatment can improve metabolic parameters. We sought to determine effects of long-term continuous positive airway pressure (CPAP) treatment on glycemic control and DM risk in patients with cardiovascular disease (CVD) and OSA. Research Design and Methods: Blood, medical history, and personal data were collected in a substudy of 888 participants in the Sleep Apnea Cardiovascular Endpoints (SAVE) trial in which patients with OSA and stable CVD were randomized to receive CPAP plus Usual Care, or Usual Care alone. Serum glucose and glycated hemoglobin A1c (HbA1c) were measured at baseline, and six months, two- and four years, and incident diabetes diagnoses recorded. Results: Median follow-up was 4.3 years. In those with pre-existing DM (n=274), there was no significant difference between CPAP and Usual Care groups in serum glucose, HbA1c or anti-diabetic medications during follow-up. There were also no significant between-group differences in participants with pre-diabetes (n=452), nor in new diagnoses of DM. Interaction testing suggested that women with diabetes did poorly in the Usual Care group while their counterparts on CPAP therapy remained stable. Conclusions: Among patients with established CVD and OSA, we found no evidence that CPAP therapy over several years affected glycemic control in those with diabetes or pre-diabetes, or DM risk over standard of care treatment. The potential differential effect according to sex deserves further investigation.

Supplemental material, WSO904913 Supplemental Material1 for Sleep duration and risk of cardiovascular events: The SAVE study by Jingwei Li, Danni Zheng, Kelly A Loffler, Xia Wang, R Doug McEvoy, Richard J Woodman, Yuanming Luo, Geraldo Lorenzi-Filho, Ferran Barbe, Manjari Tripathi, Craig S Anderson and for the SAVE Investigators in International Journal of Stroke

Protein O-mannosyltransferases (PMTs) initiate O-mannosylation of proteins in the ER. Trichoderma reesei strains displayed a single representative of each PMT subfamily, Trpmt1, Trpmt2 and Trpmt4. In this work, two knockout strains ΔTrpmt1and ΔTrpmt4were obtained. Both mutants showed retarded growth, defective cell walls, reduced conidiation and decreased protein secretion. Additionally, the ΔTrpmt1strain displayed a thermosensitive growth phenotype, while the ΔTrpmt4 strain showed abnormal polarity. Meanwhile, OETrpmt2 strain, in which the Trpmt2 was over-expressed, exhibited increased conidiation, enhanced protein secretion and abnormal polarity. Using a lectin enrichment method and MS/MS analysis, 173 O-glycoproteins, 295 O-glycopeptides and 649 O-mannosylation sites were identified as the targets of PMTs in T. reesei. These identified O-mannoproteins are involved in various physiological processes such as protein folding, sorting, transport, quality control and secretion, as well as cell wall integrity and polarity. By comparing proteins identified in the mutants and its parent strain, the potential specific protein substrates of PMTs were identified. Based on our results, TrPMT1 is specifically involved inO-mannosylation of intracellular soluble proteins and secreted proteins, specially glycosidases. TrPMT2 is involved inO-mannosylation of secreted proteins and GPI-anchor proteins, and TrPMT4 mainly modifies multiple transmembrane proteins. The TrPMT1-TrPMT4 complex is responsible for O-mannosylation of proteins involved in cell wall integrity. Overexpression of TrPMT2 enhances protein secretion, which might be a new strategy to improve expression efficiency in T. reesei.

Background: Obstructive sleep apnoea (OSA) is a common comorbidity in patients with cardiovascular (CV) disease. We aimed to identify specific OSA clinical phenotypes relating to risks of serious CV events and response to continuous positive airway pressure (CPAP) treatment. Methods: Post-hoc analyses of the Sleep Apnea Cardiovascular Endpoints (SAVE) study in participants with moderate-to-severe OSA and coronary artery disease (CAD) and/or cerebrovascular disease (CeVD) randomised to CPAP plus usual care or usual care alone. Latent class analysis (LCA) was used to identify OSA clinical phenotypes among 2649 (out of 2687 total) patients with complete data on 19 patient-centered variables, supported by Bayesian information criteria and clinical interpretability. Cox regression models were used to evaluate risks of composite cardiac and stroke outcome events in phenotype groups. Preferential response to CPAP treatment was evaluated using interaction terms as well as the Chi-square test. Findings: LCA identified four OSA clinical phenotypes: CAD alone and with diabetes mellitus (CAD+DM), and CeVD alone and with DM (CeVD+DM), in 39%, 15%, 37% and 9% of participants, respectively. The rates of composite CV events were the highest in CAD+DM phenotype (HR 2.08, 95% CI 1.57–2.76) and for stroke were highest in CeVD+DM phenotype (HR 6.84, 95% CI 3.77–12.42). Adherence to CPAP treatment (nil or

Background In 2007 and 2012, the American Academy of Sleep Medicine (AASM) updated their scoring criteria for nocturnal respiratory events. We hypothesised that this could have led to changes in the apnoea-hypopnoea index (AHI) and thus diagnosis of COPD associated obstructive sleep apnoea (OSA) overlap syndrome. Patients and methods In a retrospective study, polysomnographical recordings (PSG) of 11 patients with COPD/OSA overlap syndrome were independently analysed using the AASM criteria from 2007 and 2012. The primary outcome was the difference in AHI between the AASM 2012 and the AASM 2007 recommended and alternative scoring rules, secondary outcomes were the percentage of hypopnoeas and the diagnosis of overlap syndrome. Data are presented as mean (standard deviation) if normally distributed, and as median (interquartile range) for non-normally distributed data. Results The PSG of 11 obese, elderly and predominantly male patients with mild-moderate COPD were analysed (table). The AHI using AASM 2007 (recommended) criteria was 12.9 (5.8, 16.9) h-1 vs 18.7 (11.3, 24.7) h-1 using the 2012 criteria (p Conclusion The AHI significantly increases when the AASM 2012 instead of 2007 criteria are used in patients with COPD/OSA overlap syndrome, in parts due to a higher number of arousal-associated hypopnoeas. These observations will impact on the definition of the COPD/OSA overlap syndrome.

Background In COPD, functional status is improved by pulmonary rehabilitation (PR) but requires specific facilities. Tai Chi, which combines psychological treatment and physical exercise and requires no special equipment, is widely practiced in China and is becoming increasingly popular in the rest of the world. We hypothesized that Tai Chi is equivalent (ie, difference less than ±4 St. George's Respiratory Questionnaire [SGRQ] points) to PR. Methods A total of 120 patients (mean FEV 1 , 1.11 ± 0.42 L; 43.6% predicted) bronchodilator-naive patients were studied. Two weeks after starting indacaterol 150 μg once daily, they randomly received either standard PR thrice weekly or group Tai Chi five times weekly, for 12 weeks. The primary end point was change in SGRQ prior to and following the exercise intervention; measurements were also made 12 weeks after the end of the intervention. Results The between-group difference for SGRQ at the end of the exercise interventions was –0.48 (95% CI PR vs Tai Chi, –3.6 to 2.6; P = .76), excluding a difference exceeding the minimal clinically important difference. Twelve weeks later, the between-group difference for SGRQ was 4.5 (95% CI, 1.9 to 7.0; P 1 was observed. Conclusions Tai Chi is equivalent to PR for improving SGRQ in COPD. Twelve weeks after exercise cessation, a clinically significant difference in SGRQ emerged favoring Tai Chi. Tai Chi is an appropriate substitute for PR. Trial Registry ClinicalTrials.gov; No.: NCT02665130; URL: www.clinicaltrials.gov.

OBJECTIVES: Continuous positive airway pressure (CPAP) improves upper airway obstruction in patients with obstructive sleep apnoea (OSA), who often are overweight-obese. Although it is thought that CPAP improves long-term blood pressure control (BP), the impact of acute and short-term CPAP use on the cardiovascular system in obese patients has not been described in detail.METHODS: Obese patients (body mass index, BMI > 25 kg/m2) with OSA were studied awake, supine during incremental CPAP titration (4-20 cmH2O, +2 cmH2O/3 mins). BP was measured continuously with a beat-to-beat BP monitor (Ohmeda 2300, Finapres Medical Systems, Amsterdam/NL), BP variability (BPV) was calculated as the standard deviation of BP at each CPAP level, the 95% confidence interval (95%CI) was calculated and changes in BP and BPV were reported.RESULTS: 15 patients (12 male, 48 ± 10) years, BMI 38.9 ± 5.8 kg/m2) were studied; the baseline BP was 131.0 ± 10.2/85.1 ± 9.1 mmHg. BP and BPV increased linearly with CPAP titration (systolic BP r = 0.960, p CONCLUSION: Short-term incremental CPAP leads to significant increases in BP and BPV in obese patients with OSA while awake. Careful titration of pressures is required to minimise the risk of nocturnal awakenings while improving BP control.

Exercise-induced laryngeal obstruction (EILO), a phenomenon in which the larynx closes inappropriately during physical activity, is a prevalent cause of exertional dyspnea in young individuals. The physiological ventilatory impact of EILO and its relationship to dyspnea are poorly understood. The objective of this study was to evaluate exercise-related changes in laryngeal aperture on ventilation, pulmonary mechanics, and respiratory neural drive. We prospectively evaluated 12 subjects (6 with EILO and 6 healthy age- and gender-matched controls). Subjects underwent baseline spirometry and a symptom-limited incremental exercise test with simultaneous and synchronized recording of endoscopic video and gastric, esophageal, and transdiaphragmatic pressures, diaphragm electromyography, and respiratory airflow. The EILO and control groups had similar peak work rates and minute ventilation (V̇e) (work rate: 227 ± 35 vs. 237 ± 35 W; V̇e: 103 ± 20 vs. 98 ± 23 l/min; P > 0.05). At submaximal work rates (140–240 W), subjects with EILO demonstrated increased work of breathing ( P < 0.05) and respiratory neural drive ( P < 0.05), developing in close temporal association with onset of endoscopic evidence of laryngeal closure ( P < 0.05). Unexpectedly, a ventilatory increase ( P < 0.05), driven by augmented tidal volume ( P < 0.05), was seen in subjects with EILO before the onset of laryngeal closure; there were however no differences in dyspnea intensity between groups. Using simultaneous measurements of respiratory mechanics and diaphragm electromyography with endoscopic video, we demonstrate, for the first time, increased work of breathing and respiratory neural drive in association with the development of EILO. Future detailed investigations are now needed to understand the role of upper airway closure in causing exertional dyspnea and exercise limitation. NEW & NOTEWORTHY Exercise-induced laryngeal obstruction is a prevalent cause of exertional dyspnea in young individuals; yet, how laryngeal closure affects breathing is unknown. In this study we synchronized endoscopic video with respiratory physiological measurements, thus providing the first detailed commensurate assessment of respiratory mechanics and neural drive in relation to laryngeal closure. Laryngeal closure was associated with increased work of breathing and respiratory neural drive preceded by an augmented tidal volume and a rise in minute ventilation.

A fall of ≥ 20 % in forced expiratory volume in the first second (FEV1) with a cumulative dose of histamine ≤ 7.8 μmol is considered to indicate bronchial hyperactivity, but no method exists for patients who cannot perform spirometry properly. Here we hypothesized that increases in respiratory central output measured by chest wall electromyography of the diaphragm (EMGdi-c) expressed as a function of tidal volume (EMGdi-c/VT) would have discriminative power to detect a 'positive' challenge test.In a physiological study EMGdi was recorded from esophageal electrode (EMGdi-e) in 16 asthma patients and 16 healthy subjects during a histamine challenge test. In a second study, EMGdi from chest wall surface electrodes (EMGdi-c) was measured during a histamine challenge in 44 asthma patients and 51 healthy subjects. VT was recorded from a digital flowmeter during both studies.With histamine challenge test the change in EMGdi-e/VT in patients with asthma was significantly higher than that in healthy subjects (104.2 % ± 48.6 % vs 0.03 % ± 17.1 %, p0.001). Similarly there was a significant difference in the change of EMGdi-c/VT between patients with asthma and healthy subjects (90.5 % ± 75.5 % vs 2.4 % ± 21.7 %, p0.001). At the optimal cut-off point (29 % increase in EMGdi-c/VT), the area under the ROC curve (AUC) for detection of a positive test was 0.91 (p0.001) with sensitivity 86 % and specificity 92 %.We conclude that EMGdi-c/VT may be used as an alternative for the assessment of bronchial hypersensitivity and airway reversibility to differentiate patients with asthma from healthy subjects.

Background The mechanisms underlying sleep-related hypoventilation in patients with coexisting COPD and obstructive sleep apnoea (OSA), an overlap syndrome, are incompletely understood. We compared neural respiratory drive expressed as diaphragm electromyogram (EMGdi) and ventilation during stage 2 sleep in patients with COPD alone and patients with overlap syndrome. Methods EMGdi and airflow were recorded during full polysomnography in 14 healthy subjects, 14 patients with OSA and 39 consecutive patients with COPD. The ratio of tidal volume to EMGdi was measured to indirectly assess upper airway resistance. Results Thirty-five patients with COPD, 12 healthy subjects and 14 patients with OSA completed the study. Of 35 patients with COPD, 19 had COPD alone (FEV1 38.5%±16.3%) whereas 16 had an overlap syndrome (FEV1 47.5±16.2%, AHI 20.5±14.1 events/hour). Ventilation (VE) was lower during stage 2 sleep than wakefulness in both patients with COPD alone (8.6±2.0 to 6.5±1.5 L/min, p

Plant plasma membrane (PM) plays important roles in immune response. Here, we utilized quantitative mass spectrometry to explore rice PM protein composition and dynamic changes during Magnaporthe oryzae infection. We report, thus far, the largest rice PM proteome dataset with 3,906 identified proteins, among which 484 proteins were differentially expressed after M. oryzae infection. One third of the identified proteins are predicted to have at least one transmembrane domain. Half of the identified proteins are predicted to have binding functions and over one third of the proteins have enzyme-related functions. In addition, Gene Ontology analyses revealed that abscisic acid (ABA) and cytokinin (CK) signaling were sequentially activated after M. oryzae infection in rice. We found that the activation of ABA signaling and the suppression of rice immune response occurred at the early infection stage, while the activation of CK signaling, the upregulation of sugar transporter genes expression, and the nutrient efflux of infected rice cells occurred at later infection stage. Thus, we further propose that M. oryzae activates ABA signaling to repress rice immune signaling for initial invasion and redirects nutrient efflux of infected cells for massive growth at the later infection stage.

Lignocelluloses contained in animal forage cannot be digested by pigs or poultry with 100% efficiency. On contrary, Aspergillus fumigatus, a saprophytic filamentous fungus, is known to harbor 263 glycoside hydrolase encoding genes, suggesting that A. fumigatus is an efficient lignocellulose degrader. Hence the present study uses corn, wheat, or soybean as a sole carbon source to culture A. fumigatus under animal physiological condition to understand how cellulolytic enzymes work together to achieve an efficient degradation of lignocellulose. Our results showed that A. fumigatus produced different sets of enzymes to degrade lignocelluloses derived from corn, wheat, or soybean cell wall. In addition, the cellulolytic enzymes produced by A. fumigatus were stable under acidic condition or at higher temperatures. Using isobaric tags for a relative and absolute quantification (iTRAQ) approach, a total of ∼600 extracellular proteins were identified and quantified, in which ∼50 proteins were involved in lignocellulolysis, including cellulases, hemicellulases, lignin-degrading enzymes, and some hypothetical proteins. Data are available via ProteomeXchange with identifier PXD004670. On the basis of quantitative iTRAQ results, 14 genes were selected for further confirmation by RT-PCR. Taken together, our results indicated that the expression and regulation of lignocellulolytic proteins in the secretome of A. fumigatus were dependent on both nature and complexity of cellulose, thus suggesting that a different enzyme system is required for degradation of different lignocelluloses derived from plant cells. Although A. fumigatus is a pathogenic fungus and cannot be directly used as an enzyme source, as an efficient lignocellulose degrader its strategy to synergistically degrade various lignocelluloses with different enzymes can be used to design enzyme combination for optimal digestion and absorption of corn, wheat, or soybean that are used as forage of pig and poultry.

Protein O-mannosyltransferases (PMTs) have been identified in fungi but not in plants and nematodes, which makes PMTs become attractive targets for developing a new strategy against phytopathogens. Three PMTs have been identified in Fusarium oxysporum, a fungal pathogen that causes vascular wilt in a broad range of economical crops. By deletion or suppression of the pmt genes, we showed that all mutants displayed retarded growth, reduced conidiation, cell wall defects, ER stress and attenuated virulence in F. oxysporum f.sp. cucumerinum. In addition, the Δpmt1 exhibited reduced thermotolerance, while the Δpmt4 and the pmt2 conditional mutant exhibited abnormal polarized growth. Comparative glycoproteome analysis of these pmt mutants revealed that PMTs preferentially modified random coils with flanking regions rich in Ser, Thr, Ala, Glu, Asp and Lys at the stem region of membrane proteins, the N-terminal region close to signal peptide of secreted proteins, or surface of soluble proteins. PMT1 specifically acted on nuclear proteins and proteins that are responsible for protein folding, which might contribute to thermotolerance. PMT4 specifically acted on the membrane and soluble proteins in secretory pathways, especially the GPI anchoring pathway, which might contribute to synthesis and transportation of GPI anchored proteins and thus polarized growth. PMT2 was responsible for modification of proteins that are required for protein folding and cell wall synthesis, which might make PMT2 essential. Our results gave an insight to understanding of the roles of each O-mannosyltransferase in F. oxysporum f.sp. cucumerinum and provide a new perspective to prevent Fusarium wilt.

Ascending thoracic aortic aneurysms (ATAAs) are focal dilatations in the aorta that are prone to rupture or dissection. To accurately evaluate the rupture risk, one must know the local mechanical conditions at the rupture site and understand how rupture is triggered in a layered fibrous media. A challenge facing experimental studies of ATAA rupture is that the ATAA tissue is highly heterogeneous; experimental protocols that operate under the premise of tissue homogeneity will have difficulty delineating the location conditions. In this work, we employed a previously established pointwise identification method to characterize wall stress, strain, and property distributions to a sub-millimeter resolution. Based on the acquired field data, we obtained the local mechanical properties at the rupture site in nine ATAA tissue samples. The rupture stress, ultimate strain, energy density, and the toughness of the tested samples were also reported. Our results show that the direction of the rupture is aligned with the direction of maximum stiffness, indicating that higher stiffness is not always related to higher strength. It was also found that the rupture generally occurs at a location of highest stored energy. As a higher stiffness and higher strain energy indicate a larger recruitment of collagen fibers in the tissue at the location and along the direction of rupture, the recruitment of collagen fibers in the deformation of the tissue is probably essential in ATAA rupture.A major challenge in the experimental study of aneurysm properties is that the tissues are heterogeneous. When the specimens are not reasonably homogeneous, traditional tests that work under the premise of tissue homogeneity cannot reliably delineate the local conditions at the rupture site. In this work, we investigated the local characteristics of rupture of human ascending aortic aneurysm tissue. We identified the stress, strain, and elastic properties to a submillimeter resolution. Based on the field values, we determined the local conditions - elastic properties, direction of maximum stiffness, stress, strain, energy consumption - at the rupture site. It was found that the tissues consistently cleave in the direction of the maximum stiffness, and generally occurs at the location of highest energy. Since a higher stiffness and higher strain energy indicate a larger recruitment of collagen fibers in the tissue at the location and along the direction of rupture, the work suggests that the recruitment of collagen fibers in the deformation of the tissue is probably essential in aneurysm rupture.

Wall stress in a curved membrane depends on the surface geometry and applied load, not the constitutive law of the wall material (static determinacy). This remarkable property suggests that the membrane stress can be determined without knowing of the material property. Being able to determine the wall stress without material knowledge is practically significant in numerous applications, particularly in in vivo biomedical stress analysis wherein patient-specific tissue properties are extremely difficult to obtain. In this article, we present two non-traditional methods that utilize the static determinacy to compute the membrane stress. A common theme is to start with a deformed configuration and use artificial material models. In one of these approaches, the equilibrium problem is formulated as an inverse elastostatic problem whereby the stress is determined by way of finding a (fictitious) reference configuration. The other approach utilizes the standard forward analysis, but in a penalty setting using artificially stiff material models. A continuum sensitivity analysis is implemented to quantitatively assess the influence of material parameters. These developments open new pathways of membrane analysis enabling stress prediction without using realistic material parameters. Numerical examples are provided to demonstrate and compare these two methods.

Mammalian target of rapamycin (mTOR) is a core component of raptor-mTOR (mTORC1) and rictor-mTOR (mTORC2) complexes that control diverse cellular processes. Both mTORC1 and mTORC2 regulate several elements downstream of type I insulin-like growth factor receptor (IGF-IR) and insulin receptor (InsR). However, it is unknown whether and how mTOR regulates IGF-IR and InsR themselves. Here we show that mTOR possesses unexpected tyrosine kinase activity and activates IGF-IR/InsR. Rapamycin induces the tyrosine phosphorylation and activation of IGF-IR/InsR, which is largely dependent on rictor and mTOR. Moreover, mTORC2 promotes ligand-induced activation of IGF-IR/InsR. IGF- and insulin-induced IGF-IR/InsR phosphorylation is significantly compromised in rictor-null cells. Insulin receptor substrate (IRS) directly interacts with SIN1 thereby recruiting mTORC2 to IGF-IR/InsR and promoting rapamycin- or ligand-induced phosphorylation of IGF-IR/InsR. mTOR exhibits tyrosine kinase activity towards the general tyrosine kinase substrate poly(Glu-Tyr) and IGF-IR/InsR. Both recombinant mTOR and immunoprecipitated mTORC2 phosphorylate IGF-IR and InsR on Tyr1131/1136 and Tyr1146/1151, respectively. These effects are independent of the intrinsic kinase activity of IGF-IR/InsR, as determined by assays on kinase-dead IGF-IR/InsR mutants. While both rictor and mTOR immunoprecitates from rictor(+/+) MCF-10A cells exhibit tyrosine kinase activity towards IGF-IR and InsR, mTOR immunoprecipitates from rictor(-/-) MCF-10A cells do not induce IGF-IR and InsR phosphorylation. Phosphorylation-deficient mutation of residue Tyr1131 in IGF-IR or Tyr1146 in InsR abrogates the activation of IGF-IR/InsR by mTOR. Finally, overexpression of rictor promotes IGF-induced cell proliferation. Our work identifies mTOR as a dual-specificity kinase and clarifies how mTORC2 promotes IGF-IR/InsR activation.

Background: Exercise induced laryngeal obstruction (EILO) is a prevalent cause of exertional dyspnoea and is associated with increased neural respiratory drive (NRD) and work of breathing. Laser surgery can be effective in reducing supra-glottic obstruction and EILO symptoms, however little is known about the physiological impact of this treatment. Case description: We described detailed physiological assessments of laser surgery in two patients with severe EILO: a 31-year old male elite cyclist and a 44-year old female recreational athlete. Prior treatment included optimization of co-morbidities and breathing re-training. Both patients underwent a symptom-limited incremental exercise test with simultaneous and synchronised laryngoscopic video, gastric-, oesophageal- and trans-diaphragmatic pressures, diaphragm electromyography and respiratory airflow to delineate how the condition impacted on respiratory mechanics and NRD. These physiological measures were repeated postoperatively within six months. Results: Surgical intervention led to a marked improvement in peak power, dyspnoea intensity, respiratory mechanics and a reduction of neural respiratory drive (fig. 1). Conclusion: In this small case series, supraglottopasty for severe EILO was associated with a reduction in NRD and respiratory work and this provides a physiological basis for the clinical outcomes reported from this intervention.

The magnitude of tidal volume (VT) depends on neural respiratory drive overcoming respiratory resistance. We hypothesized that the ratio of EMGdi, an index of neural drive, to VT could detect histamine induced changes in lower airway resistance given the assumption that respiratory resistance (except for the lower airway resistance) is unaffected by histamine. Conventional histamine challenge tests were undertaken in 44 asthma patients (age 47±14 years; FEV1% 76±14) diagnosed by a history of repeated attack of asthma and positive bronchial challenge test and 51 healthy subjects (age 36 ± 13 years; FEV1% 96 ± 11). Diaphragm EMG was recorded from chest wall surface electrodes (EMGdi) under the fixed breathing frequency (18 times/min.) and an additional inspiratory load to improve a signal–noise ratio. Airflow was recorded with a digital output flowmeter. ΔFEV1 correlated with ΔEMGdi /VT (r=0.63). Corresponding to ≥20% fall in FEV1 during histamine challenge test, change in EMGdi/VT in patients with asthma was significantly higher than that in healthy subjects who received maximal dose (7.8 µmol) of histamine (90.5% ± 75.5% vs 2.4% ± 21.7%, p