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Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC.This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomisation was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up.Between Jan 28, 2016, and Feb 1, 2018, 449 eligible patients were enrolled and randomly assigned to treatment with ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7 months (IQR 15·8-27·2). At the time of primary analysis, progression-free survival was significantly longer in the ramucirumab plus erlotinib group (19·4 months [95% CI 15·4-21·6]) than in the placebo plus erlotinib group (12·4 months [11·0-13·5]), with a stratified hazard ratio of 0·59 (95% CI 0·46-0·76; p0·0001). Grade 3-4 treatment-emergent adverse events were reported in 159 (72%) of 221 patients in the ramucirumab plus erlotinib group versus 121 (54%) of 225 in the placebo plus erlotinib group. The most common grade 3-4 treatment-emergent adverse events in the ramucirumab plus erlotinib group were hypertension (52 [24%]; grade 3 only) and dermatitis acneiform (33 [15%]), and in the placebo plus erlotinib group were dermatitis acneiform (20 [9%]) and increased alanine aminotransferase (17 [8%]). Treatment-emergent serious adverse events were reported in 65 (29%) of 221 patients in the ramucirumab plus erlotinib group and 47 (21%) of 225 in the placebo plus erlotinib group. The most common serious adverse events of any grade in the ramucirumab plus erlotinib group were pneumonia (seven [3%]) and cellulitis and pneumothorax (four [2%], each); the most common in the placebo plus erlotinib group were pyrexia (four [2%]) and pneumothorax (three [1%]). One on-study treatment-related death due to an adverse event occurred (haemothorax after a thoracic drainage procedure for a pleural empyema) in the ramucirumab plus erlotinib group.Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of the individual compounds in advanced lung cancer. The RELAY regimen is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC.Eli Lilly.

The association between sepsis and segmented neutrophil-to-monocyte (SeMo) ratio is unclear. We postulated that an increase in dynamic SeMo ratio measurement can be applied in risk stratification. This retrospective study included 727 consecutive sepsis patients in medical intensive care units (ICUs), including a subpopulation of 153 patients. According to the leukocyte (white blood cell, WBC) count on day 3 (normal range, between 4,000/µL and 12,000/µL) and delta SeMo (value of SeMo ratio on day 3 minus value of SeMo ratio on day 1; normal delta SeMo

The aim of this study was to identify novel microRNAs related to obstructive sleep apnea (OSA) characterized by intermittent hypoxia with re-oxygenation (IHR) injury. Illumina MiSeq was used to identify OSA-associated microRNAs, which were validated in an independent cohort. The interaction between candidate microRNA and target genes was detected in the human THP-1, HUVEC, and SH-SY5Y cell lines. Next-generation sequencing analysis identified 22 differentially expressed miRs (12 up-regulated and 10 down-regulated) in OSA patients. Enriched predicted target pathways included senescence, adherens junction, and AGE-RAGE/TNF-α/HIF-1α signaling. In the validation cohort, miR-92b-3p and miR-15b-5p gene expressions were decreased in OSA patients, and negatively correlated with an apnea hypopnea index. PTGS1 (COX1) gene expression was increased in OSA patients, especially in those with depression. Transfection with miR-15b-5p/miR-92b-3p mimic in vitro reversed IHR-induced early apoptosis, reactive oxygen species production, MAOA hyperactivity, and up-regulations of their predicted target genes, including PTGS1, ADRB1, GABRB2, GARG1, LEP, TNFSF13B, VEGFA, and CXCL5. The luciferase assay revealed the suppressed PTGS1 expression by miR-92b-3p. Down-regulated miR-15b-5p/miR-92b-3p in OSA patients could contribute to IHR-induced oxidative stress and MAOA hyperactivity through the eicosanoid inflammatory pathway via directly targeting PTGS1-NF-κB-SP1 signaling. Over-expression of the miR-15b-5p/miR-92b-3p may be a new therapeutic strategy for OSA-related depression.

Pei-Wen Lin,1,2 Hsin-Ching Lin,2– 5 Chun-Tuan Chang,5 Michael Friedman,6,7 Anna M Salapatas,7 Meng-Chih Lin,2,8 Chih-Yun Lin9 1Division of Glaucoma, Department of Ophthalmology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City; Chang Gung University College of Medicine, Taoyuan City, Taiwan; 2Sleep Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, Taiwan; 3Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City; Chang Gung University College of Medicine, Taoyuan City, Taiwan; 4Robotic Surgery Center and Center for Quality Management, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, Taiwan; 5Department of Business Management, Institute of Healthcare Management, National Sun Yat-sen University, Kaohsiung City, Taiwan; 6Department of Otolaryngology, Division of Sleep Surgery, Rush University Medical Center, Chicago City, IL, USA; 7Department of Otolaryngology, Advanced Center for Specialty Care, Advocate Illinois Masonic Medical Center, Chicago City, IL, USA; 8Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City; Chang Gung University College of Medicine, Taoyuan City, Taiwan; 9Biostatistics Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, TaiwanCorrespondence: Hsin-Ching Lin, Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung District, Kaohsiung City, 833, Taiwan, Tel +886-7-7317123 ext.2533, Fax +886-7-7313855, Email hclin@adm.cgmh.org.tw; enthclin@aol.comPurpose: Obstructive sleep apnea/hypopnea syndrome (OSA) results in repeated oxygen desaturation, repeated arousals, and episodic nocturnal activation of sympathetic nervous system during sleep. Untreated OSA is strongly associated with an increase of cardio- and cerebrovascular disorders, as well as the damages of ophthalmological microstructures. However, previous literature only simply studied the association between the ophthalmic disorders and OSA. In the present study, we first investigated the alterations of ocular surface and tear film non-invasively with the innovated corneal topographer in untreated OSA patients and normal control subjects. Furthermore, we analyzed in depth whether the correlations between OSA severity and ocular surface exams exist.Participants and Methods: Participants underwent a full-night polysomnography to determine OSA occurrence and severity. All participants subsequently received Ocular Surface Disease Index questionnaire and comprehensive ocular exams, including floppy eyelid syndrome (FES) assessment, oculus scan for tear meniscus height, non-invasive keratograph tear film breakup time (NIKBUT), and ocular surface redness, endothelial cell density, and corneal fluorescein staining.Results: One hundred eighty-one participants were prospectively enrolled in the study. FES was found in 11.5% of the normal control group and 60.0% of the severe OSA group (p=0.0005). There were significant differences in the first-NIKBUT (F-NIKBUT) (p < 0.0001), average-NIKBUT (A-NIKBUT) (p = 0.0007), and redness scores over the nasal bulbar (p = 0.032), temporal bulbar (p < 0.0001), nasal limbal (p = 0.014), and temporal limbal (p < 0.0001) areas among the four groups. F-NIKBUT and A-NIKBUT were significantly shorter in the moderate/severe OSA group (apnea/hypopnea index (AHI) ≥ 15) than in the normal/mild OSA group (AHI < 15) (both p < 0.0001). The redness scores over the temporal bulbar (p < 0.0001) and temporal limbal (p < 0.0001) areas were also significantly different in these two OSA groups. Moreover, F-NIKBUT and A-NIKBUT negatively correlated with AHI. Nasal bulbar redness, temporal bulbar redness, nasal limbal redness, and temporal limbal redness positively correlated with AHI.Conclusion: OSA patients had higher occurrence of FES. The NIKBUT was significantly shorter, and the temporal conjunctival redness scores over bulbar and limbal areas were higher in the moderate/severe OSA group than in the normal/mild OSA group. NIKBUT and conjunctival hyperemia significantly correlated with the severity of untreated OSA.Keywords: snoring, obstructive sleep apnea, ocular surface and tear film

Chiung-Zuei Chen,1 Chau-Chyun Sheu,2 Shih-Lung Cheng,3,4 Hao-Chien Wang,5 Meng-Chih Lin,6 Wu-Huei Hsu,7 Kang-Yun Lee,8 Diahn-Warng Perng,9 Hen-I Lin,10 Ming-Shian Lin,11 Sheng-Hao Lin,12 Jong-Rung Tsai,13 Chin-Chou Wang,6 Cheng-Yi Wang,10 Tsung-Ming Yang,14 Ching-Lung Liu,15 Tsai-Yu Wang,16 Ching-Hsiung Lin12,17,18 1Division of Pulmonary Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan; 3Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, 220, Taiwan; 4Department of Chemical Engineering and Materials Science, Yuan Ze University, Zhongli, Taoyuan, 320, Taiwan; 5Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan; 6Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, 404, Taiwan; 7Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 8Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 110, Taiwan; 9Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, 112, Taiwan; 10Department of Internal Medicine, Cardinal Tien Hospital, Fu-Jen Catholic University, Taipei, 242, Taiwan; 11Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, 600, Taiwan; 12Division of Chest Medicine, Changhua Christian Hospital, Changhua, 500, Taiwan; 13Division of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; 14Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Taoyuan City, Taiwan; 15Division of Chest Medicine, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, 104, Taiwan; 16Pulmonary Disease Research Centre, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taipei, Taiwan; 17Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, 402, Taiwan; 18Department of Recreation and Holistic Wellness, MingDao University, Changhua, 523, TaiwanCorrespondence: Ching-Hsiung LinDivision of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, 135 Nanhsiao Street, Changhua, 50006, TaiwanTel +886-4-7238595Fax +886-4-7232942Email 47822@cch.org.twBackground and Aim: Chronic obstructive pulmonary disease (COPD) is frequently underdiagnosed because of the unavailability of spirometers, especially in resource-limited outpatient settings. This study provides real-world evidence to identify optimal approaches for COPD case finding in outpatient settings.Methods: This retrospective study enrolled individuals who were at risk of COPD (age ≥ 40 years, ≥ 10 pack-years, and ≥ 1 respiratory symptom). Eligible participants were examined using various COPD case-finding tools, namely the COPD Population Screener (COPD-PS) questionnaire, a COPD prediction (PCOPD) model, and a microspirometer, Spirobank Smart; subsequently, the participants underwent confirmatory spirometry. The definition and confirmation of COPD were based on conventional spirometry. Receiver operating characteristic curve (ROC), area under the curve (AUC), and decision curve analyses were conducted, and a clinical impact curve was constructed.Results: In total, 385 participants took part in the study [284 without COPD (73.77%) and 101 with COPD (26.23%)]. The microspirometer exhibited a higher AUC value than did the COPD-PS questionnaire and the PCOPD model. The AUC for microspirometry was 0.908 (95% confidence interval [CI] = 0.87– 0.95), that for the PCOPD model was 0.788 (95% CI = 0.74– 0.84), and that for the COPD-PS questionnaire was 0.726 (95% CI = 0.67– 0.78). Decision and clinical impact curve analyses revealed that a microspirometry-derived FEV1/FVC ratio of < 74% had superior clinical utility to the other measurement tools.Conclusion: The PCOPD model and COPD-PS questionnaire were useful for identifying symptomatic patients likely to have COPD, but microspirometry was more accurate and had higher clinical utility. This study provides real-world evidence to identify optimal practices for COPD case finding; such practices ensure that physicians have convenient access to up-to-date evidence when they encounter a symptomatic patient likely to have COPD.Keywords: COPD, COPD case-finding, PCOPD model, COPD-PS questionnaire, microspirometry, spirometry

Background: To investigate the relationships among the clinical characteristics, different EGFR-TKIs, and osimertinib treatment in different treatment lines.Methods: We retrospectively screened a total of 3807 patients diagnosed between 2013 and 2019 at Kaohsiung Chang Gung Memorial Hospital. Furthermore, 98 patients after re-biopsy or liquid with EGFR T790M mutation who received osimertinib were enrolled for analysis. Results: Among all 98 patients, the median PFS of those who received osimertinib therapy was 10.48 months, and the median OS of those who received osimertinib therapy was 42.21 months. The OS of those who received osimertinib therapy after previous gefitinib, afatinib, or erlotinib therapy was 87.93, 49.00, and 42.00 months, respectively (P=0.006). There was a significant difference in disease control rate between those who received osimertinib treatment after previous chemotherapy (Group A) or immediately following EGFR-TKI therapy (Group B) (93.3% vs. 77.4%, P=0.029). There was also a significant difference in PS between those who received osimertinib as a second-line treatment and those who received it as a third-line treatment (10.83 vs. 17.33 months, P=0.044). In addition, COPD tended to be a poor prognostic factor for PFS and OS.Conclusion: In this retrospective real‐world analysis, it was determined that pretreatment with gefitinib and previous chemotherapy could affect the treatment outcomes of NSCLC patients treated with osimertinib. Furthermore, COPD tended to a poor prognostic factor for PFS and OS in such patients.

Yu Lee,1 Pao-Yen Lin,1 Meng-Chih Lin,2 Chin-Chou Wang,2 Hung-I Lu,3 Yung-Che Chen,2 Mian-Yoon Chong,4 Chi-Fa Hung11Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung, Kaohsiung, Taiwan; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung, Kaohsiung, Taiwan; 3Department of Cardiothoracic Vascular Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung, Kaohsiung, Taiwan; 4Chang Gung Memorial Hospital, Chiayi, and Chang Gung University School of Medicine, Kaohsiung, TaiwanObjective: The aim of this study was to assess morbidity and associated factors in patients with lung cancer (LC).Methods: This study used a cross-sectional design with consecutive sampling. Study subjects were recruited from the LC outpatient clinic and inpatient ward in a medical center from March 2016 to February 2018. Patients with LC were enrolled and assessed using the Mini International Neuropsychiatric Interview, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Brief Fatigue Inventory, Numeric Pain Rating Scale, and the List of Threatening Experiences Questionnaire.Results: One hundred and four patients were included in the study. The most prevalent psychiatric disorder was depressive disorder (25.0%), followed by adjustment disorder (17.3%), alcohol use disorder (3.8%), and insomnia disorder (3.8%). Fifty percent of patients had a psychiatric diagnosis. Using logistic regression analysis, it was found that severity of fatigue (OR=1.77; 95% CI, 1.03–3.03; p

Objective The aim of this study was to assess morbidity and associated factors in patients with lung cancer (LC). Methods This study used a cross-sectional design with consecutive sampling. Study subjects were recruited from the LC outpatient clinic and inpatient ward in a medical center from March 2016 to February 2018. Patients with LC were enrolled and assessed using the Mini International Neuropsychiatric Interview, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Brief Fatigue Inventory, Numeric Pain Rating Scale, and the List of Threatening Experiences Questionnaire. Results One hundred and four patients were included in the study. The most prevalent psychiatric disorder was depressive disorder (25.0%), followed by adjustment disorder (17.3%), alcohol use disorder (3.8%), and insomnia disorder (3.8%). Fifty percent of patients had a psychiatric diagnosis. Using logistic regression analysis, it was found that severity of fatigue (OR=1.77; 95% CI, 1.03-3.03; p

To identify standard clinical parameters that may predict the presence and severity of obstructive sleep apnea/hypopnea syndrome (OSA).Case series with chart review.Tertiary academic medical center.A total of 325 adult patients (274 men and 51 women; mean age, 44.2 years) with habitual snoring completed comprehensive polysomnography and anthropometric measurements, including modified Mallampati grade (also known as updated Friedman's tongue position [uFTP]), tonsil size grading, uvular length, neck circumference, waist circumference, hip circumference, and body mass index (BMI).When the aforementioned physical parameters were correlated singly with the apnea/hypopnea index (AHI), we found that sex, uFTP, tonsil size grading, neck circumference, waist circumference, hip circumference, thyroid-mental distance, and BMI grade were reliable predictors of OSA. When all important factors were considered in a multiple stepwise regression analysis, an estimated AHI can be formulated by factoring sex, uFTP, tonsil size grading, and BMI grade as follows: -43.0 + 14.1 × sex + 12.8 × uFTP + 5.0 × tonsil size + 8.9 × BMI grade. Severity of OSA can be predicted with a receiver operating characteristic curve. Predictors of OSA can be further obtained by the "OSA score."This study has distinguished the correlations between sex, uFTP, tonsil size, and BMI grade and the presence and severity of OSA. An OSA score might be beneficial in identifying patients who should have a full sleep evaluation.

Dysphagia has been reported to be associated with the descent of the hyolaryngeal complex. Further, suprahyoid muscles play a greater role than infrahyoid muscles in elevation of the hyolarngeal complex. Respiratory muscle training (RMT) can improve lung function, and expiratory muscle strength training can facilitate elevation of the hyoid bone and increase the motor unit recruitment of submental muscles during normal swallowing. This study aimed to investigate the surface electromyography (sEMG) of the swallowing muscles, bilaterally, and the effect of RMT on swallowing muscles in stroke patients with respiratory muscle weakness.Forty patients with first episode of unilateral stroke were included in this retrospective controlled trial. After exclusion of 11 patients with respiratory muscle strength stronger than 70% of the predicted value, 15 were allocated to the RMT group and 14 to the control group. However, eventually, 11 patients in RMT group and 11 patients in control group completed the study. The sEMG of the orbicularis oris, masseter, submental, and infrahyoid muscles were recorded during dry swallowing, water swallowing (2 mL), and forced exhalation against a threshold breathing trainer set at different intensities, at baseline and after 6-week RMT.Regarding the sEMG of submental muscles, there were significant between-group differences on the latency of the unaffected side (P = .048), significant change from baseline force on the unaffected side (P = .035), and significant between-side difference (P = .011) in the RMT group during dry swallowing. Significant change in the duration from baseline was observed on the affected side of the RMT group when blowing was set at 50% maximal expiratory pressure (MEP; P = .015), and on the unaffected side of the control group when blowing set at 15% MEP (P = .005). Significant difference was observed in the duration between 50% MEP and 15% MEP after 6-week program in the control group (P = .049).A 6-week RMT can improve the electric signal of the affected swallowing muscles with more effect on the unaffected side than on the affected side during dry swallowing. Furthermore, RMT with 50% MEP rather than 15% MEP can facilitate greater submental muscle activity on the affected side in stroke patients with respiratory muscle weakness.

Chronic obstructive pulmonary disease (COPD) is preventable and treatable. However, many patients remain undiagnosed and untreated due to the underutilization or unavailability of spirometers. Accordingly, we used Spirobank Smart, an app-based spirometer, for facilitating the early detection of COPD in outpatient clinics. This prospective study recruited individuals who were at risk of COPD (i.e., with age of ≥40 years, ≥10 pack-years of smoking, and at least one respiratory symptoms) but had no previous COPD diagnosis. Eligible participants were examined with Spirobank Smart and then underwent confirmatory spirometry (performed using a diagnostic spirometer), regardless of their Spirobank Smart test results. COPD was defined and confirmed using the postbronchodilator forced expiratory volume in 1 s/forced vital capacity values of &lt, 0.70 as measured by confirmatory spirometry. A total of 767 participants were enrolled and examined using Spirobank Smart, 370 participants (94.3% men, mean age of 60.9 years and mean 42.6 pack-years of smoking) underwent confirmatory spirometry. Confirmatory spirometry identified COPD in 103 participants (27.8%). At the optimal cutoff point of 0.74 that was determined using Spirobank Smart for COPD diagnosis, the area under the receiver operating characteristic was 0.903 (95% confidence interval (CI) = 0.860–0.947). Multivariate logistic regression revealed that participants who have an FEV1/FVC ratio of &lt, 74% that was determined using Spirobank Smart (odds ratio (OR) = 58.58, 95% CI = 27.29–125.75) and old age (OR = 3.23, 95% CI = 1.04–10.07 for 60 ≤ age &lt, 65, OR = 5.82, 95% CI = 2.22–15.27 for age ≥ 65) had a higher risk of COPD. The Spirobank Smart is a simple and adequate tool for early COPD detection in outpatient clinics. Early diagnosis and appropriate therapy based on GOLD guidelines can positively influence respiratory symptoms and quality of life.

We hypothesized that epigenetics is a link between smoking/allergen exposures and the development of Asthma and chronic obstructive pulmonary disease (ACO). A total of 75 of 228 COPD patients were identified as ACO, which was independently associated with increased exacerbations. Microarray analysis identified 404 differentially methylated loci (DML) in ACO patients, and 6575 DML in those with rapid lung function decline in a discovery cohort. In the validation cohort, ACO patients had hypermethylated PDE9A (+ 30,088)/ZNF323 (− 296), and hypomethylated SEPT8 (− 47) genes as compared with either pure COPD patients or healthy non-smokers. Hypermethylated TIGIT (− 173) gene and hypomethylated CYSLTR1 (+ 348)/CCDC88C (+ 125,722)/ADORA2B (+ 1339) were associated with severe airflow limitation, while hypomethylated IFRD1 (− 515) gene with frequent exacerbation in all the COPD patients. Hypermethylated ZNF323 (− 296) / MPV17L (+ 194) and hypomethylated PTPRN2 (+ 10,000) genes were associated with rapid lung function decline. In vitro cigarette smoke extract and ovalbumin concurrent exposure resulted in specific DNA methylation changes of the MPV17L / ZNF323 genes, while 5-aza-2′-deoxycytidine treatment reversed promoter hypermethylation-mediated MPV17L under-expression accompanied with reduced apoptosis and decreased generation of reactive oxygen species. Aberrant DNA methylations may constitute a determinant for ACO, and provide a biomarker of airflow limitation, exacerbation, and lung function decline.

Circadian clock is synchronized to the 24-hour day by the daily light-dark cycle and proper function of circadian rhythm is essential for many physiological processes. Disruption of circadian rhythm can affect disease processes and influence disease severity, treatment responses, and even survivorship. In this retrospective case-controlled study, we tried to explore whether expression of circadian clock genes was disturbed in patients with bronchial asthma.We performed real-time quantitative reverse transcriptase-polymerase chain reactions to examine the expression of the nine core circadian clock genes (Expression levels of the nine circadian clock genes were significantly different between patients and healthy individuals, but not associated with the asthma control status. We also noted the difference ofOur results showed altered expression of circadian clock genes in patients with bronchial asthma and down-regulated

Supplemental material, sj-pdf-1-tam-10.1177_17588359211018022 for The relative importance of predictive factors for single first-generation EGFR-TKI use for more than 5 years in patients with advanced non-small cell lung cancer: Taiwan multicenter TIPS-5 study by Yen-Hsiang Huang, Jen-Yu Hung, How-Wen Ko, Po-Lan Su, Chun-Liang Lai, Huang-Chih Chang, Te-Chun Hsia, Sheng-Hao Lin, Kuan-Li Wu, Cheng-Ta Yang, Wu-Chou Su, Yi-Chun Chu, Chin-Chou Wang, Wei-Yu Liao, Yen-Ting Lin, Ching-Hsiung Lin, Meng-Chih Lin, Kuo-Hsuan Hsu, Jeng-Sen Tseng, Tsung-Ying Yang, Kun-Chieh Chen, Mei-Hsuan Lee, Sung-Liang Yu, Chao-Chi Ho and Gee-Chen Chang in Therapeutic Advances in Medical Oncology

Introduction Obstructive sleep apnea (OSA)‐associated hypoxemia, sleep fragmentation, and cerebral vascular dysfunction are implicated in cognitive dysfunction. Functional connectivity within default mode network (DMN) is a possible mechanism underlying the cognitive impairment. The aim of this study was to investigate the impact of hypoxemia and sleep fragmentation on functional connectivity and on cognitive performance in patients with OSA. Methods Twenty‐eight patients with OSA were included (mean age = 58.0 ± 8.5 years). We correlated the functional connectivity in DMN with cognitive performances and further analyzed the relationship of functional connectivity in DMN with hypoxemia severity, as revealed by apnea‐hypopnea index (AHI), oxygen desaturation index (ODI), and nadir SaO2 (%), and with degree of sleep fragmentation, as shown by sleep efficiency and wake after sleep onset. Results Functional connectivity in DMN was associated with AHI, ODI, and nadir SaO2 (%) (p .05). Functional connectivity that was associated with AHI, ODI, and nadir SaO2 (%) was in the areas of bilateral middle temporal gyri, bilateral frontal pole, and bilateral hippocampus and was positively correlated with Cognitive Abilities Screening Instrument (CASI) total score (ρ = 0.484; p = .012), CASI‐List‐generating, CASI‐Attention, and composite score of CASI‐List‐generating plus CASI‐Attention (p, The functional connectivity within the DMN was associated with hypoxemia severity, as revealed by apnea‐hypopnea index, oxygen desaturation index, and nadir SaO2 (%), rather than with degree of sleep disruption, as shown by sleep efficiency and wake after sleep onset.

Introduction In the phase 3 ASCEND-4 study, ceritinib exhibited improved progression-free survival (PFS) by Blinded Independent Review Committee (BIRC) assessment versus the standard first-line chemotherapy in patients with advanced ALK-rearranged NSCLC. Here, we assessed the efficacy and safety of ceritinib in the subgroup of Asian patients from the ASCEND-4 trial. Methods Treatment-naive patients with stage IIIB or IV ALK-rearranged nonsquamous NSCLC were randomized in a one-to-one ratio to receive either oral ceritinib 750 mg/day (fasted) daily or intravenous chemotherapy ([cisplatin 75 mg/m2 or carboplatin area under the curve 5–6 plus pemetrexed 500 mg/m2] every three wk, followed by pemetrexed maintenance). The primary end point was PFS by BIRC assessment. Results Of 376 randomized patients, 158 (42.0%) were Asian (ceritinib arm: N = 76; chemotherapy arm: N = 82). The median time from randomization to the cutoff date (June 24, 2016) was 18.3 months (range = 13.5–34.2) in the Asian subgroup. The median PFS (by BIRC assessment) was 26.3 months (95% confidence interval [CI]: 8.6–not estimable) and 10.6 months (95% CI: 6.7–15.0), with an estimated 34% risk reduction in PFS (hazard ratio = 0.66, 95% CI: 0.41–1.05) in the ceritinib arm versus chemotherapy arm. The most common adverse events of any grade were diarrhea (85.5%), increased alanine aminotransferase and vomiting (73.7% each), and increased aspartate aminotransferase and nausea (69.7% each) in the ceritinib arm, and nausea (49.3%), vomiting (42.7%), and anemia (40.0%) in the chemotherapy arm. Conclusion Ceritinib was effective and safe in treatment-naive Asian patients with advanced ALK-rearranged NSCLC. The findings were largely consistent with that of the overall study population.

Background Sepsis-associated acute kidney injury (AKI) often worsens with the deterioration of a patient's condition. Therefore, we hypothesized that monitoring AKI dynamically from day1 to day 3 was potential to predict hospital mortality. Specifically, we explored whether monitoring AKI dynamically in the intensive care unit (ICU) could be a sepsis phenotype predictive of mortality. A new classification was established based on the change in the AKI stage from admission day 1 and day 3. We compared the hospital mortality, cytokines, and immune response pattern between each group. Material and methods We retrospectively enrolled 523 patients with sepsis, and we calculated the AKI stages on day 1 and day 3 admission to ICUs. Among these 523 people, 388 of them were assigned to normal, improved, and deteriorated groups according to the changes in the AKI stages. 263 of which did not develop AKI on day1 and day 3 (normal group). The AKI stage improved in 68 patients (improved group) and worsened in 57 (deteriorated group). We compared the mortality rates between the groups, and identified the relationship between the dynamic AKI status, immune response patterns, and cytokine levels. Results The hospital mortality rate in the deteriorated group was higher than that in the non-deteriorated group (combination of normal and improved group) (p = 0.004). Additionally, according to the Kaplan–Meier analysis, the non-deteriorated group had a distinct hospital survival curve (p = 0.004). Furthermore, both the overexpression of tumor necrosis factor-α and decreased monocyte expression of human leukocyte antigen-DR were present in the deteriorated group. Conclusions The deteriorated group was associated with a higher hospital mortality rate, potentially resulting from an abnormal inflammatory response. Worsening AKI in the first 3 days of ICU admission may be a sepsis phenotype predictive of hospital mortality.

We hypothesized that Ventilator-Associated Event (VAE) within 28 days upon admission to medical intensive care units (ICUs) can be a predictor for poor outcomes in sepsis patients. We aimed to determine the risk factors and associated outcomes of VAE. A total of 453 consecutive mechanically ventilated (MV) sepsis patients were enrolled. Of them, 136 patients had immune profile study. Early VAE (

Objectives This study aims to explore the role of M2a polarization and formyl peptide receptor (FPR) regulation in the reactivation of Mycobacterium tuberculosis (Mtb) infection. Methods M1/M2a monocyte percentage and FPR1/2/3 protein expression of blood immune cells were measured in 38 patients with sputum culture (+) active pulmonary TB disease, 18 subjects with latent TB infection (LTBI), and 28 noninfected healthy subjects (NIHS) using flow cytometry method. Results M1 percentage was decreased in active TB versus either NIHS or LTBI group, while M2a percentage and M2a/M1 percentage ratio were increased. FPR1 expression on M1/M2a, FPR2 expression on M1, and FPR3 expression of M1 were all decreased in active TB versus LTBI group, while FPR1 over FPR2 expression ratio on NK T cell was increased in active TB versus either NIHS or LTBI group. In 11 patients with active TB disease, M1 percentage became normal again after anti-TB treatment. In vitro Mtb-specific antigen stimulation of monocytic THP-1 cells resulted in M2a polarization in association with increased FPR2 expression on M2a. Conclusions Increased M2a and decreased M1 phenotypes of blood monocyte may serve as a marker for active TB disease, while decreased FPR1 on blood monocyte may indicate LTBI status.

To use computer-assisted quantitative measurements of upper airway changes during drug-induced sleep endoscopy (DISE) and to correlate these parameters with disease severities and physiologic changes in patients with obstructive sleep apnea/hypopnea syndrome (OSA).A retrospective study.Tertiary academic medical center.A total of 170 patients who failed continuous positive airway pressure therapy and then underwent upper airway surgery were enrolled. All patients received polysomnography and DISE preoperatively. We used ImageJ 1.48v to obtain maximal and minimal measurements, including cross-sectional areas and anterior-posterior and lateral diameters at 4 anatomic levels (retropalatal, oropharyngeal, retroglossal, and retroepiglottic) under DISE, and then computed the percentage changes. We analyzed the clinical values of DISE changes by computer-assisted analysis in patients with OSA and any correlations between these changes and polysomnography parameters.The percentage changes of upper airway showed significant collapses at all 4 anatomic levels (allComputer-assisted quantitative analysis could evaluate upper airway changes of OSA in an objective way and may help identify the sites of obstruction during DISE more accurately. Upper airway showed multilevel collapse with independent significant changes in patients with OSA, with the retropalatal and retroglossal levels playing important roles in particular.

The current coronavirus disease 2019 (COVID-19) pandemic has caused significant challenges throughout the world and a rapid, reliable diagnostic test is in high demand. Real-time reverse transcription polymerase chain reaction (RT-PCR) was one of the most quickly established methods of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection and is considered to be the gold standard. In this report, we share our experience of using two different testing platforms: the cobas 6800 SARS-CoV-2 test, an automated system that was recently granted Emergency Use Authorization by the FDA, and a laboratory-developed test based on the protocol from the Taiwan Centers for Disease Control (CDC). There was an overall 96.2% agreement between the two platforms. However, the positive agreement between the two platforms was only 80.0%. We found 3 instances of discordance between the two systems and this emphasized the need for timely diagnosis with a reliable testing platform.

The relationship between left ventricular ejection fraction (LVEF) and cardiovascular (CV) outcome is documented in patients with low LVEF. Ventilatory inefficiency is an important prognostic predictor. We hypothesized that the presence of ventilatory inefficiency influences the prognostic predictability of LVEF in heart failure (HF) outpatients. In total, 169 HF outpatients underwent the cardiopulmonary exercise test (CPET) and were followed up for a median of 9.25 years. Subjects were divided into five groups of similar size according to baseline LVEF (&le, 39%, 40&ndash, 58%, 59&ndash, 68%, 69&ndash, 74%, and &ge, 75%). The primary endpoints were CV mortality and first HF hospitalization. The Cox proportional hazard model was used for simple and multiple regression analyses to evaluate the interrelationship between LVEF and ventilatory inefficiency (ventilatory equivalent for carbon dioxide (VE/VCO2) at anaerobic threshold (AT) &gt, 34.3, optimized cut-point). Only LVEF and VE/VCO2 at AT were significant predictors of major CV events. The lower LVEF subgroup (LVEF &le, 39%) was associated with an increased risk of CV events, relative to the LVEF &ge, 75% subgroup, except for patients with ventilatory inefficiency (p = 0.400). In conclusion, ventilatory inefficiency influenced the prognostic predictability of LVEF in reduced LVEF outpatients. Ventilatory inefficiency can be used as a therapeutic target in HF management.

MINI: In this study, respiratory function at the time of extubation can be useful optimal clinical guidelines for weaning and extubation attempts in patients with acute cervical spinal cord injury. Serum thiobarbituric acid-reactive substances level at admission can be a useful predictor for severity in acute cervical patients with spinal cord injury.Patients who had suffered from acute blunt cervical spinal cord injury (SCI) and admitted our hospital within 24 hours after injury were included in the study.We compared the respiratory function and serum reactive oxidative stress (ROS) after acute cervical SCI, and tried to find out the valuable predictors of weaning in patients with acute cervical SCI.Ventilation impairment is a major complication of acute cervical SCI. Evidence of oxygen radical formation in secondary injury from animal SCI models demonstrates an immediate postinjury increase in ROS production after SCI. We hypothesize that the serum ROS is associated with the severity of patients with acute cervical SCI.Thirty-eight adult patients who had acute cervical SCI and 58 healthy volunteers were enrolled. Respiratory function at admission, at the time of extubation and at 48 hours after extubation, serum oxidative stress, Injury Severity Score and Japanese Orthopaedic Association score at admission were compared.The most notable predictor of mechanical ventilation more than 48 hours was serum thiobarbituric acid-reactive substances (TBARS) level at admission (P = 0.027), and the cut-off value of serum TBARS level was 731.7 μmol/L (sensitivity 87.5% and specificity 78.9%). For the reventilation ≤5 days, the notable predictors were respiratory function at the time of extubation (maximal inspiratory pressure, P = 0.040; maximal expiratory pressure, P = 0.020; and tidal volume, P = 0.036) and serum TBARS level at admission (P = 0.013), the cut-off value of serum TBARS level at admission was 762.3 μmol/L (sensitivity 100% and specificity 90.0%).In this study, respiratory function (maximal inspiratory pressure, maximal expiratory pressure, and tidal volume) at the time of extubation can be useful optimal clinical guidelines for weaning and extubation attempts in patients with acute cervical SCI. Serum TBARS level at admission can be a useful predictor for severity in acute cervical SCI patients.3.Patients who had suffered from acute blunt cervical spinal cord injury (SCI) and admitted our hospital within 24 hours after injury were included in the study. We compared the respiratory function and serum reactive oxidative stress (ROS) after acute cervical SCI, and tried to find out the valuable predictors of weaning in patients with acute cervical SCI. Ventilation impairment is a major complication of acute cervical SCI. Evidence of oxygen radical formation in secondary injury from animal SCI models demonstrates an immediate postinjury increase in ROS production after SCI. We hypothesize that the serum ROS is associated with the severity of patients with acute cervical SCI. Thirty-eight adult patients who had acute cervical SCI and 58 healthy volunteers were enrolled. Respiratory function at admission, at the time of extubation and at 48 hours after extubation, serum oxidative stress, Injury Severity Score and Japanese Orthopaedic Association score at admission were compared. The most notable predictor of mechanical ventilation more than 48 hours was serum thiobarbituric acid-reactive substances (TBARS) level at admission (P = 0.027), and the cut-off value of serum TBARS level was 731.7 μmol/L (sensitivity 87.5% and specificity 78.9%). For the reventilation ≤5 days, the notable predictors were respiratory function at the time of extubation (maximal inspiratory pressure, P = 0.040; maximal expiratory pressure, P = 0.020; and tidal volume, P = 0.036) and serum TBARS level at admission (P = 0.013), the cut-off value of serum TBARS level at admission was 762.3 μmol/L (sensitivity 100% and specificity 90.0%). In this study, respiratory function (maximal inspiratory pressure, maximal expiratory pressure, and tidal volume) at the time of extubation can be useful optimal clinical guidelines for weaning and extubation attempts in patients with acute cervical SCI. Serum TBARS level at admission can be a useful predictor for severity in acute cervical SCI patients. Level of Evidence: 3.

Comparative long-term efficacy of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) for prevention of disease progression to hepatocellular carcinoma (HCC) among high-risk patients with chronic hepatitis B (CHB)-related compensated cirrhosis is controversial.To compare the long-term efficacy of ETV and TDF in HCC prevention in patients with CHB-related cirrhosis, and to evaluate predictive risk factors for HCC development.From January 2008 to March 2018, 894 treatment-naïve patients with CHB-related compensated cirrhosis on ETV or TDF were enrolled based on the longitudinal cohort study. Data were originally collected for 7.3 years of follow-up or after the launch of TDF in 2011. Only the 5-year cumulative incidence and risk factors of HCC were assessed.Total 678 and 216 patients received ETV and TDF, respectively. The cumulative risk of HCC at 1, 3 and 5 years of follow-up was 1.6%, 11.3% and 18.7%, respectively, in the ETV group; and 0.9%, 6.7% and 10.7%, respectively, in the TDF group (P = 0.0305). Univariate and adjusted-multivariable models revealed that platelet count, alpha-fetoprotein (AFP) levels and upper gastrointestinal (UGI) varices were independent risk factors for HCC development. TDF resulted in risk of HCC development compared to ETV with adjusted hazard ratios (aHRs) of 0.66 (95% confidence interval [CI]:0.40, 1.08; P = 0.0971), 0.69 (95% CI: 0.42, 1.14; P = 0.1488) and 0.66 (95% CI: 0.38, 1.14; P = 0.1407) under stepwise selection, propensity score adjustment, and propensity score matching multivariable models, respectively.For treatment-naïve patients with CHB-related compensated cirrhosis with 5-year follow-up, after variable adjustments, propensity score approaches and subgroup analyses, TDF showed a lower rate of HCC development that did not reach statistical significance, compared to the ETV.

Supplemental material, Reviewer_1_v.1 for LABA/LAMA fixed-dose combinations versus LAMA monotherapy in the prevention of COPD exacerbations: a systematic review and meta-analysis by Ching-Yi Chen, Wang-Chun Chen, Chi-Hsien Huang, Yi-Ping Hsiang, Chau-Chyun Sheu, Yung-Che Chen, Meng-Chih Lin, Kuo-An Chu, Cheng-Hung Lee and Yu-Feng Wei in Therapeutic Advances in Respiratory Disease

Supplemental material, Author_Response_2 for LABA/LAMA fixed-dose combinations versus LAMA monotherapy in the prevention of COPD exacerbations: a systematic review and meta-analysis by Ching-Yi Chen, Wang-Chun Chen, Chi-Hsien Huang, Yi-Ping Hsiang, Chau-Chyun Sheu, Yung-Che Chen, Meng-Chih Lin, Kuo-An Chu, Cheng-Hung Lee and Yu-Feng Wei in Therapeutic Advances in Respiratory Disease

Obstructive sleep apnea (OSA) is a syndrome leading to chronic intermittent hypoxia, and the up-regulation of toll-like receptors (TLR) 2 and 6 on peripheral blood cells has been reported. We hypothesized that DNA methylation in TLR2 and TLR6 genes may play a role in the development of OSA and its excessive daytime sleepiness (EDS) phenotype. DNA methylation over 28 cytosine-phosphate-guanine (CpG) sites of the TLR2 promoter region and 3 CpG sites of the TLR6 gene body, and their protein expressions were measured by using pyrosequencing and ELISA methods in 18 heathy subjects (HS) and 58 patients with severe OSA (divided into 18 non-EDS and 40 EDS group). Patients with severe OSA had higher DNA methylation levels over five CpG sites (#1, #2, #3, #25 and #28) and lower DNA methylation levels over CpG site #18 of the TLR2 promoter region, higher DNA methylation levels over two CpG sites (#1 and #3) of the TLR6 gene body, and higher protein expressions of TLR6 than HS. The CpG site #2 of the TLR6 gene body was hypermethylated in severe OSA patients with EDS. Both DNA methylation levels over CpG site #1 of the TLR6 gene body and protein expressions of TLR6 were reduced after more than 6 months of nasal CPAP treatment in seven selected patients. Aberrant DNA methylation of the TLR2 promoter region and TLR6 gene body are associated with the consequence of severe OSA and its EDS phenotype.

Introduction: Onsite scoring is common in traditional OSCEs although there is the potential for an audience effect facilitating or inhibiting performance. We aim to (1) analyze the reliability between onsite scoring (OS) and remote scoring (RS); and (2) explore the factors that affect the scoring in different locations. Methods: A total of 154 students and 84 raters were enrolled in a single-site during 2013-2015. We selected six stations randomly from a 12-station national high-stakes OSCE. We applied generalisability theory for the analysis and investigated the perceptions that affected RS scoring. Results: The internal consistency reliability Cronbach's α of the checklists was 0.92. The kappa agreement was 0.623 and the G value was 0.93. The major source of variance comes from the students themselves, but some from locations and raters. The three-component analysis including Technical Feasibility, Facilitates Wellbeing, and Observational and Attention Deficits explained 73.886% of the total variance in RS scoring. Conclusions: Our study has demonstrated moderate agreement and good reliability between OS and RS ratings. We validated the factors of facility operation and quality for RS raters. Remote scoring can provide an alternative forum for the raters to overcome the barriers of distance, space, and avoid the audience effect.

Introduction: The aim of this study was to evaluate the effects of upper airway surgery on daytime sleepiness in nonobese patients with obstructive sleep apnea/hypopnea syndrome (OSA). Methods: This retrospective study included 121 consecutive adult nonobese patients with OSA from a tertiary academic medical center. Patients with OSA who refused continuous positive airway pressure therapy, or in whom it was unsuccessful, and then underwent OSA surgery were enrolled. Evaluations of excessive daytime sleepiness using the Epworth Sleepiness Scale (ESS) and major parameters of objective full-night polysomnography were collected preoperatively and at least 3 months postoperatively. Statistical analysis was performed using the Wilcoxon signed rank test and Wilcoxon rank sum test. Results: When pre- and postoperative ESS and polysomnographic parameters were compared in all patients, ESS scores, apnea/hypopnea index, and snoring index showed statistically significant improvements ( P = .007, P < .001, and P < .001, respectively). When patients were classified into mild, moderate, and severe OSA groups, snoring index had statistically significant improvements in all 3 groups, and apnea/hypopnea index had statistically significant decreases in the moderate and severe OSA groups. Although reductions in ESS scores were found in all 3 groups, the most statistically significant improvement was noted only in the severe OSA group. Conclusions: OSA surgery can improve daytime sleepiness in nonobese patients with OSA, especially for patients with severe OSA. This study elucidates the effects of OSA surgery on daytime sleepiness by excluding the major confounding factor of obesity. This study adds to the literature on the effects of upper airway surgery for nonobese patients with OSA on daytime quality of life.

Objective: To develop an adequate model using reliable clinical and physical factors to predict pediatric obstructive sleep apnea/hypopnea syndrome (OSAS). Methods: Complete anthropometric measurements including BMI z score, tonsil size grading, and updated Friedman tongue position (uFTP) were evaluated. Subjective assessments of clinical symptoms/signs, including snoring visual analog scale (VAS), nasal obstruction, and mouth breathing, were recorded. Results: Eighty-eight children (57 boys and 31 girls, mean age = 9.0 years) were confirmed to have OSAS by comprehensive polysomnography (PSG). When the aforementioned variables were analyzed individually, the results indicated that snoring VAS, nasal obstruction, mouth breathing, and BMI z score were reliable predictors of apnea/hypopnea index (AHI/h) values (correlation coefficient r = 0.386, P < .001; r = 0.416, P < .001; r = 0.255, P = .02; and r = 0.243, P = .02, respectively). When all significant factors were included in the stepwise multiple linear regression analysis, the final predictive model is: Pediatric AHI = 0.108 + 0.103 snoring VAS + 0.894 nasal obstruction + 0.207 BMI z score ( F = 4.06, P = .01). Conclusion: The proposed noninvasive, simple, inexpensive, and easy to perform screening tool could be used to predict pediatric OSAS. An abnormal calculated AHI may prompt clinical physicians to conduct further PSG diagnostics and treatment.

We intended to develop a scoring system to predict mechanical ventilator dependence in patients who survive sepsis/septic shock with respiratory failure. This study evaluated 251 adult patients in medical intensive care units (ICUs) between August 2013 to October 2015, who had survived for over 21 days and received aggressive treatment. The risk factors for ventilator dependence were determined. We then constructed a ventilator dependence (VD) risk score using the identified risk factors. The ventilator dependence risk score was calculated as the sum of the following four variables after being adjusted by proportion to the beta coefficient. We assigned a history of previous stroke, a score of one point, platelet count less than 150,000/μL a score of one point, pH value less than 7.35 a score of two points, and the fraction of inspired oxygen on admission day 7 over 39% as two points. The area under the curve in the derivation group was 0.725 (p

Body mass index (BMI) influences the prognosis of patients with non-small cell lung cancer (NSCLC), including both early-stage and late-stage NSCLC patients that are undergoing chemotherapies. However, earlier research on the relationship between BMI and survival in patients taking epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) yielded contradictory results. These publications either had a limited number of patients or were getting TKIs in various lines of therapy, which might explain why the outcomes were contradictory. As a result, we undertook retrospective study to examine the effect of BMI on survival outcomes in patients with advanced EGFR mutant NSCLC receiving first-line EGFR-TKIs. We also compared the findings to those with wild-type EGFR. Between November 2010 and March 2014, 513 patients with advanced NSCLC were enrolled in the study. According to the adjusted BMI cut-off point for Asia, 35 out of 513 (6.8%) patients were underweight (BMI &lt, 18.5 kg/m2), whereas 197 (38.4%) were overweight (BMI &gt, 24 kg/m2). Overweight patients with wild-type EGFR exhibited longer progression-free survival (4.6 vs. 2.1 months, p = 0.003) and overall survival (OS) (8.9 vs. 4.3 months, p = 0.003) than underweight patients. Overweight patients with EGFR mutations had a longer OS than normal-weight patients (23.0 vs. 20.2 months, p = 0.025). Bodyweight reduction was related to a shorter OS in both the mutant EGFR patients (17.1 vs. 30.5 months, p &lt, 0.001) and the wild-type EGFR patients (7.8 vs. 18.7 months, p &lt, 0.001). In conclusion, advanced stages NSCLC patients with a lower BMI and early weight loss had a worse outcome that was independent of EGFR mutation status.

Obstructive sleep apnea syndrome (OSAS) is an important risk factor for atrial fibrillation (AF). GJA1 gene encoding connexin43, a major protein in cardiac gap junctions, plays a crucial role in the synchronized contraction of the heart and in cardiac arrhythmia. However, little is known regarding the role of GJA1 expression in the incidence of AF in patients with OSAS. All prospectively enrolled OSAS patients underwent polysomnography, electrocardiography, a 24-h Holter test, and echocardiography. Moderate-to-severe OSAS was defined as an apnea-hypopnea index (AHI) ≥ 15. Exosomes were purified from the plasma of all OSAS patients and incubated in HL-1 cells to investigate the effect of exosomes from patients with and without AF on GJA1 expression. A total of 129 patients were recruited for this study, 26 were excluded due to an AHI &lt, 15. Of the 103 enrolled patients, 21 had AF, and 82 did not. Multivariate analysis showed diabetes mellitus, lower sleep efficiency, lower left ventricular ejection fraction, and larger left atrial (LA) size were independent predictors of AF occurrence in OSAS patients. The area under the receiver operating characteristic curve for LA with a size ≥38.5 mm for predicting AF occurrence in OSAS patients was 0.795 (95% confidence interval [0.666, 0.925]), p &lt, 0.001). GJA1 expression in HL-1 cells incubated with exosomes from OSAS patients with AF was lower than that with exosomes from patients without AF after controlling for age and sex and was negatively correlated with the AHI and oxygen desaturation index (ODI), especially during the non-rapid eye movement period (NREM) of OSAS patients with AF (all p &lt, 0.05). LA size was an independent predictor of AF occurrence in OSAS patients. The AHI and ODI in the NREM period of OSAS patients with AF were negatively correlated with GJA1 expression in HL-1 cells, which offers a hint that GJA1 may play a crucial role in the development of AF in patients with OSAS.

We investigated the best timing for using the National Early Warning Score 2 (NEWS2) for predicting sepsis outcomes and whether combining the NEWS2 and the Sequential Organ Failure Assessment (SOFA) was applicable for mortality risk stratification in intensive care unit (ICU) patients with severe sepsis. All adult patients who met the Third International Consensus Definitions for Sepsis and Septic Shock criteria between August 2013 and January 2017 with complete clinical parameters and laboratory data were enrolled as a derivation cohort. The primary outcomes were the 7-, 14-, 21-, and 28-day mortalities. Furthermore, another group of patients under the same setting between January 2020 and March 2020 were also enrolled as a validation cohort. In the derivation cohort, we included 699 consecutive adult patients. The 72 h NEWS2 had good discrimination for predicting 7-, 14-, 21-, and 28-day mortalities (AUC: 0.780, 0.724, 0.700, and 0.667, respectively) and was not inferior to the SOFA (AUC: 0.740, 0.680, 0.684, and 0.677, respectively). With the new combined NESO tool, the hazard ratio was 1.854 (1.203–2.950) for the intermediate-risk group and 6.810 (3.927–11.811) for the high-risk group relative to the low-risk group. This finding was confirmed in the validation cohort using a separated survival curve for 28-day mortality. The 72 h NEWS2 alone was non-inferior to the admission SOFA or day 3 SOFA for predicting sepsis outcomes. The NESO tool was found to be useful for 7-, 14-, 21-, and 28-day mortality risk stratification in patients with severe sepsis.

It has been demonstrated that the traditional Chinese medicine rikkunshito, ameliorates anorexia in several types of human cancer and attenuates lung injury by inhibiting neutrophil infiltration. The current study investigated the clinical and hematological effects of rikkunshito and its underlying mechanisms of action in the treatment of advanced non-small cell lung cancer (NSCLC). The Illumina microarray BeadChip was used to analyze the whole-genome expression profiles of peripheral blood mononuclear cells in 17 patients with advanced NSCLC. These patients were randomized to receive combination chemotherapy (cisplatin and gemcitabine) with (n=9, CTH+R group) or without (n=8, CTH group) rikkunshito. The primary endpoint was the treatment response and the categories of the scales of anorexia, nausea, vomiting and fatigue; secondary endpoints included the hematological effect and whole genome gene expression changes. The results of the current study indicated that there were no significant differences in clinical outcomes, including treatment response and toxicity events, between the two groups. Median one-year overall survival (OS) was 12 months in the CTH group and 11 months in the CTH+R group (P=0.058 by log-rank test), while old age (>60 years old) was the only independent factor associated with one-year OS (hazard ratio 1.095, 95% confidence interval, 1.09-1.189, P=0.030). Patients in the CTH+R group experienced significantly greater maximum decreases in both white cell count (P=0.034) and absolute neutrophil count (P=0.030) from the baseline. A total of 111 genes associated with neutrophil apoptosis, the cell-killing ability of neutrophils, natural killer cell activation and B cell proliferation were up-regulated following rikkunshito treatment. A total of 48 genes associated with neutrophil migration, coagulation, thrombosis and type I interferon signaling were down-regulated following rikkunshito treatment. Rikkunshito may therefore affect the blood neutrophil count when used with combination chemotherapy in patients with NSCLC, potentially by down-regulating prostaglandin-endoperoxidase synthase 1, MPL, AMICA1 and junctional adhesion molecule 3, while up-regulating elastase, neutrophil expressed, proteinase 3, cathepsin G and cluster of differentiation 24.

// Chin-Chou Wang 1, 2, 3, * , Chia-Cheng Tseng 1, 4, * , Huang-Chih Chang 1, 4 , Kuo-Tung Huang 1, 4 , Wen-Feng Fang 1, 3 , Yu-Mu Chen 1 , Cheng-Ta Yang 5 , Chang-Chun Hsiao 4, 6, ** , Meng-Chih Lin 1, ** , Chi-Kung Ho 2, ** and Hon-Kan Yip 6, 7, 8, 9, 10, ** 1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan 2 Department of Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan 3 Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi Campus, Chiayi, Taiwan 4 Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung, Taiwan 5 Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan 6 Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 7 Division of cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 8 Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan 9 Department of Nursing, Asia University, Taichung, Taiwan 10 Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan * These authors contributed equally to this work and should be considered co-first authors ** These authors contributed equally to this work and should be considered co-correspondence authors Correspondence to: Hon-Kan Yip, email: han.gung@msa.hinet.net Keywords: advanced non-small cell lung cancer, microparticles, disease control, disease progression Received: January 09, 2017 Accepted: April 25, 2017 Published: June 06, 2017 ABSTRACT We investigated whether circulating microparticles (MPs) could serve as prognostic biomarkers in non-small cell lung cancer (NSCLC) patients. We enrolled 25 control subjects and 136 NSCLC patients categorized into disease-progression (DP, n=42) and disease-control (DC, n=94) groups. Flow cytometric analysis showed that levels of four types of circulating microparticles (EDAc-MPs, EDAp-MPs, PDAc-MPs and PDAp-MPs) were higher in the study patients than the control subjects ( P < 0.04). DP patients showed poor initially performance status and more non-adenocarcinomas than DC patients. DC patients showed more EGFR mutations and poorer performance to targeted therapy than DP patients ( P < 0.01). Three months after therapy, the levels of all four types of circulating MPs were lower in DC than DP patients ( P < 0.02), and were comparable to the levels in control subjects. In addition, the levels of circulating MPs after 3 months accurately predicted one-year prognostic outcomes ( P < 0.05). This study showed that circulating MPs are valuable prognostic biomarkers in advanced NSCLC patients.

// Yung-Che Chen 1, 6, * , Meng-Chih Lin 1, 6, * , Chang-Chun Hsiao 6, 7 , Yi-Xin Zheng 1 , Kuang-Den Chen 2 , Ming-Tse Sung 3 , Chung-Jen Chen 4 , Ting-Ya Wang 1 , Yong-Yong Lin 1 , Huang-Chih Chang 1, 6 , Yu-Mu Chen 1 and Jen-Chieh Chang 5 1 Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 2 Center of Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 3 Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 4 Division of Rheumatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 5 Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 6 Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan 7 Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan * These authors have contributed equally to this work Correspondence to: Yung-Che Chen, email: yungchechen@yahoo.com.tw Meng-Chih Lin, email: linmengchih@hotmail.com Chang-Chun Hsiao, email: cchsiao@mail.cgu.edu.tw Keywords: lung adenocarcinoma, S100A15, DNA methylation, next generation sequencing Received: November 02, 2016 Accepted: April 10, 2017 Published: April 24, 2017 ABSTRACT Purpose : This study aims to determine the functional role of S100A15 and its promoter DNA methylation patterns in lung cancer progression. Experimental Design : We analyzed 178 formalin-fixed paraffin embedded specimens from lung cancer patients, including 24 early stage and 91 advanced stage adenocarcinoma. S100A15 protein expression was evaluated by immunohistochemistry stain, and its DNA methylation levels were measured by pyrosequencing. Results : S100A15 nuclear staining was increased in lung adenocarcinoma patients with distant metastasis versus those without distant metastasis. There was reduced one/three-year overall survival in adenocarcinoma patients receiving first line target therapy and harboring high nuclear expressions of S100A15. Both DNA methylation levels over -423 and -248 CpG sites of the S100A15 gene promoter were decreased in adenocarcinoma patients with distant metastasis, and the former was associated with lower one-year overall survival. The highly invasive CL1-5 cell lines display decreased DNA methylation over –412/-248/-56 CpG sites of the S100A15 gene promoter and increased S100A15 gene/protein expressions as compared with the less invasive CL1-0 cell lines. Knockdown of S100A15 in CL1-5 cell line inhibited cell proliferation, migration, and invasion, while over-expression of S100A15 in CL1-0 cell line promoted cell proliferation, migration, and invasion. RNA sequencing analysis revealed potential biological effects of S100A15 over-expression and knock-down with CTNNB1, ZEB1, CDC42, HSP90AA1, BST2, and PCNA being the pivotal down-stream mediators. Conclusions : Increased S100A15 expression and decreased DNA methylation of its gene promoter region were associated with high metastasis potential and poor outcome in lung adenocarcinoma, probably through triggering CTNNB1 -centered pathways.

// Shih-Feng Liu 1, 2, 3 , Ho-Chang Kuo 2, 3, 4 , Meng-Chih Lin 1, 2, 3 , Shu-Chen Ho 4 , Mei-Lien Tu 2 , Yu-Mu Chen 1, 2, 3 , Yung-Che Chen 1, 2, 3 , Wen-Feng Fang 1, 2, 3 , Chin-Chou Wang 1, 2, 3 , Guan-Heng Liu 5 1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung, Taiwan 2 Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan 3 Chang Gung University College of Medicine, Kaohsiung, Taiwan 4 Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan 5 Department of Senior High School, Li-Chih Valuable School, Kaohsiung, Taiwan Correspondence to: Ho-Chang Kuo, email: erickuo48@yahoo.com.tw Meng-Chih Lin, email: mengchih@adm.cgmh.org.tw Keywords: inhaled corticosteroids, chronic obstructive pulmonary disease, lung cancer, incidence, hazard ratio Received: July 02, 2016 Accepted: January 31, 2017 Published: February 16, 2017 ABSTRACT Whether the use of inhaled corticosteroids (ICS) protects patients with chronic obstructive pulmonary disease (COPD) from lung cancer remains undetermined. In this retrospective nationwide population-based cohort study, we extracted data of 13,686 female COPD patients (ICS users, n = 1,290, ICS non-users, n = 12,396) diagnosed between 1997 and 2009 from the Taiwan’s National Health Insurance database. These patients were followed-up until 2011, and lung cancer incidence was determined. Cox regression analysis was used to estimate hazard ratios (HRs) for lung cancer incidence. The time to lung cancer diagnosis was significantly different between ICS users and non-users (10.75 vs. 9.68 years, P 39.48 mg was significantly associated with a lower risk of lung cancer [ICS users > 39.48 mg, HR = 0.45 (95% CI: 0.21–0.96)]. Age ≥ 60 years, pneumonia, diabetes mellitus, and hypertension decreased lung cancer risk, whereas pulmonary tuberculosis increased the risk. Our results suggest that ICS have a potential role in lung cancer prevention among female COPD patients.

Acquired resistance occurs in most non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations experiencing a response to EGFR-tyrosine kinase inhibitor (TKI) initially. We investigated EGFR-TKI retreatment in patients who had previously received EGFR-TKI followed by chemotherapy.This was a retrospective multicenter study. Patients with locally advanced or metastatic adenocarcinoma or TTF-1 (+) NSCLC, positive EGFR sensitive mutation, and EGFR-TKI reuse after initial EGFR-TKI followed by chemotherapy were enrolled. The objectives were to assess the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) of EGFR TKI switched retreatment.In total, 205 patients were enrolled, with a median age of 61.8 years (range 31.4-92.9). There was a larger proportion of females (62.9%) than males, and more never-smokers (73.2%) than ever-smokers. In the initial EGFR-TKI administration, 57.6% of patients showed a complete response (CR) or partial response (PR), and 34.6% had stable disease (SD); in the second-line chemotherapy, 13.7% had PR, and 58.0% had SD; in the EGFR-TKI retreatment, 7.3% had PR, and 37.1% had SD. The median PFS of first-line EGFR-TKI was 8.0 months (95% CI 7.3-8.2), and retreatment EGFR-TKI was 4.1 months (95% CI 2.7-4.6). The median OS since the start of the first-line EGFR-TKI therapy was 35.9 months (95% CI 28.8-50.9), and since the start of EGFR-TKI retreatment was 12.6 months (95% CI 10.4-20.9). In the univariable and multivariable regression analysis of factors associated with PFS of EGFR-TKI retreatment, time interval between the two EGFR TKIs equal to or more than 7 months was statistically significant (HR=0.62, 95% CI 0.44-0.86; HR=0.6, 95% CI 0.43-0.86), both p0.01. Females with exon 21 mutation also showed a significant difference between the two groups (HR=0.51, 95% CI 0.30-0.86; HR=0.52 (0.31-0.88), both p0.05).EGFR-TKI retreatment was effective in prolonging survival, and was shown to be a worthwhile option for EGFR-mutated NSCLC patients after failure of first-line EGFR-TKI and chemotherapy. The survival benefit was especially pronounced in patients with longer drug holidays from the initial EGFR-TKI and in females with the exon 21 mutation.

Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing andIn this trial, we randomly assigned 556 patients with previously untreated advanced NSCLC with anThe median overall survival was 38.6 months (95% confidence interval [CI], 34.5 to 41.8) in the osimertinib group and 31.8 months (95% CI, 26.6 to 36.0) in the comparator group (hazard ratio for death, 0.80; 95.05% CI, 0.64 to 1.00; P = 0.046). At 3 years, 79 of 279 patients (28%) in the osimertinib group and 26 of 277 (9%) in the comparator group were continuing to receive a trial regimen; the median exposure was 20.7 months and 11.5 months, respectively. Adverse events of grade 3 or higher were reported in 42% of the patients in the osimertinib group and in 47% of those in the comparator group.Among patients with previously untreated advanced NSCLC with an

Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. A phase 3 trial compared first-line osimertinib with other EGFR-TKIs in patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). The trial showed longer progression-free survival with osimertinib than with the comparator EGFR-TKIs (hazard ratio for disease progression or death, 0.46). Data from the final analysis of overall survival have not been reported. In this trial, we randomly assigned 556 patients with previously untreated advanced NSCLC with an EGFR mutation (exon 19 deletion or L858R allele) in a 1:1 ratio to receive either osimertinib (80 mg once daily) or one of two other EGFR-TKIs (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily, with patients receiving these drugs combined in a single comparator group). Overall survival was a secondary end point. The median overall survival was 38.6 months (95% confidence interval [CI], 34.5 to 41.8) in the osimertinib group and 31.8 months (95% CI, 26.6 to 36.0) in the comparator group (hazard ratio for death, 0.80; 95.05% CI, 0.64 to 1.00; P = 0.046). At 3 years, 79 of 279 patients (28%) in the osimertinib group and 26 of 277 (9%) in the comparator group were continuing to receive a trial regimen; the median exposure was 20.7 months and 11.5 months, respectively. Adverse events of grade 3 or higher were reported in 42% of the patients in the osimertinib group and in 47% of those in the comparator group. Among patients with previously untreated advanced NSCLC with an EGFR mutation, those who received osimertinib had longer overall survival than those who received a comparator EGFR-TKI. The safety profile for osimertinib was similar to that of the comparator EGFR-TKIs, despite a longer duration of exposure in the osimertinib group. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125.).

Pneumonia leads to changes in body composition and weakness due to the malnourished condition. In addition, patient family caregivers always have a lack of nutritional information, and they do not know how to manage patients&rsquo, nutritional intake during hospitalization and after discharge. Most intervention studies aim to provide nutritional support for older patients. However, whether long-term nutritional intervention by dietitians and caregivers from patients&rsquo, families exert clinical effects&mdash, particularly in malnourished pneumonia&mdash, on nutritional status and readmission rate at each interventional phase, from hospitalization to postdischarge, remains unclear. To investigate the effects of an individualized nutritional intervention program (iNIP) on nutritional status and readmission rate in older adults with pneumonia during hospitalization and three and six months after discharge. Eighty-two malnourished older adults with a primary diagnosis of pneumonia participated. Patients were randomly allocated to either a nutrition intervention (NI) group or a standard care (SC) group. Participants in the NI group received an iNIP according to energy and protein intake requirements in addition to dietary advice based on face-to-face interviews with their family caregivers during hospitalization. After discharge, phone calls were adopted for prescribing iNIPs. Anthropometry (i.e., body mass index, limb circumference, and subcutaneous fat thickness), blood parameters (i.e., albumin and total lymphocyte count), hospital stay, Mini-Nutritional Assessment-Short Form (MNA-SF) score, target daily calorie intake, total calorie intake adherence rate, and three-major-nutrient intakes were assessed during hospitalization and three and six months after discharge. Both groups received regular follow-up through phone calls. Furthermore, the rate of readmission resulting from pneumonia was recorded after discharge. During hospital stay, the NI group showed significant increases in daily calorie intake, total calorie intake adherence rate, and protein intake compared with the SC group (p &lt, 0.05), however, no significant difference was found in anthropometry, blood biochemical values, MNA-SF scores, and hospital stay. At three and six months after discharge, the NI group showed significantly higher daily calorie intake and MNA-SF scores (8.2 vs. 6.5 scores at three months, 9.3 vs. 7.6 scores at six months) than did the SC group (p &lt, 0.05). After adjusting for sex, the readmission rate for pneumonia significantly decreased by 77% in the NI group compared with that in the SC group (p = 0.03, OR: 0.228, 95% CI: 0.06&ndash, 0.87). A six-month iNIP under dietitian and patient family nutritional support for malnourished older adults with pneumonia can significantly improve their nutritional status and reduce the readmission rate.

This study is designed to investigate the effects of obstructive sleep apnea/hypopnea syndrome (OSA) surgery on serum leptin levels and metabolic disturbances, both of which contribute to the risk of cardiovascular diseases.Case series with planned data collection.Tertiary referral medical center.A retrospective chart review of 101 consecutive patients with OSA who refused or failed conservative therapy and who then underwent upper airway surgery for OSA treatment was conducted. The personal medical history, anthropometric measurements, subjective symptoms, and objective polysomnographic parameters and fasting morning blood samples for leptin and metabolic biomarkers measurements were collected preoperatively and at a minimum of 3 months postoperatively.Eighty patients with OSA (69 men and 11 women; mean [SD] age of 42.2 [10.2] years) with complete data were included in the final analysis. At least 3 months after surgery, serum leptin, low-density lipoprotein cholesterol (LDL-C), and triglyceride levels and the mean systolic blood pressure (SBP) (night and morning) significantly decreased. According to the classical definition of surgical success, 40 subjects had successful surgery and were categorized as surgical responders, and the other 40 patients who failed surgery were categorized as surgical nonresponders. Significant reductions in serum leptin, total cholesterol, LDL-C, and triglyceride levels and improvement of mean SBP (morning) occurred in surgical responders but not in nonresponders.Effective OSA surgery improves serum leptin, lipid profiles, and SBP. Further studies are needed to investigate the role of serial measurements of these biomarkers in monitoring surgical outcome of OSA treatment.

Circadian misalignment plays an important role in disease processes and can affect disease severity, treatment outcomes, and even survivorship. In this study, we aim to investigate whether expression and daily oscillation patterns of core circadian clock genes were disturbed in patients with obstructive sleep apnea/hypopnea (OSA) syndrome. We performed real-time quantitative reverse transcriptase-polymerase chain reactions to examine the expression of the nine core circadian clock genes in leukocytes of peripheral blood collected at 12 AM, 6 AM, 12 PM, and 6 PM from 133 patients with OSA and 11 normal controls. Daily expression patterns of the nine circadian clock genes were observed in normal controls, but three of these genes (BMAL1, CLOCK, CRY2) were disrupted in patients with OSA. The expressions of eight circadian clock genes (except PER1) at midnight were significantly downregulated in patients with severe OSA. Binary logistic regression analysis selected CRY1 and PER3 as independent factors for severe OSA and showed that the combined expressions of CRY1 and PER3 enhanced the capability of predicting severe OSA (Odds ratio, 5.800, 95% CI, 1.978 to 17.004, p = 0.001). Our results show that combined expressions of CRY1 and PER3 at midnight could be a potential predictor for severe OSA.