Search

Hai-Hua Chuang,1– 3 Chao-Yung Wang,4 Li-Pang Chuang,5 Yu-Shu Huang,6 Hsueh-Yu Li,7 Tuan-Jen Fang,7 Rong-Ho Lin,2 Li-Ang Lee3,7 1Department of Family Medicine, Chang Gung Memorial Hospital, Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 2Department of Industrial Engineering and Management, National Taipei University of Technology, Taipei, Taiwan; 3School of Medicine, National Tsing Hua University, Hsinchu, Taiwan; 4Department of Cardiology, Chang Gung Memorial Hospital, Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 5Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 6Department of Child Psychiatry, Chang Gung Memorial Hospital, Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 7Department of Otorhinolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Linkou Main Branch, Chang Gung University, Taoyuan, TaiwanCorrespondence: Li-Ang Lee, Department of Otorhinolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Linkou Main Branch, No. 5, Fuhsing Street, Guishan District, Taoyuan, 33305, Taiwan, Tel +886 33281200 ext. 3972, Fax +886 33979361, Email 5738@cgmh.org.twBackground: Obstructive sleep apnea (OSA) and obesity are both directional risk factors of hypertension. Chronic intermittent hypoxemia (IH) is a commonly observed pathophysiological mechanism involved in multiple comorbidities of OSA. However, their interactions are not well understood in children. This study aimed to investigate the associations of IH indexes (oxygen desaturation index 3% [ODI3], mean peripheral oxygen saturation [SpO2], least SpO2, and time with SpO2 < 85%), apnea-hypopnea index, and weight status with hypertension in a sample of pediatric OSA patients.Methods: The medical records of 365 pediatric OSA patients were retrospectively reviewed in this cross-sectional study. Demographics, anthropometrics, standard in-laboratory polysomnography, and nocturnal blood pressure were collected. Multivariate logistic regression with forward selection was used to identify independent predictors of hypertension.Results: Multivariate logistic regression analysis showed that ODI3 (odds ratio [OR] = 1.02, 95% confidence interval [CI] = 1.01– 1.03) and body mass index z-score (OR = 1.34, 95% CI = 1.12– 1.60) were independent continuous predictors of pediatric hypertension, whilst severe OSA (OR = 2.62, 95% CI = 1.60– 4.29) and overweight/obesity (OR = 2.63, 95% CI = 1.59– 4.34) were independent categorical predictors. Traditional risk factors including male sex (OR = 2.33, 95% CI = 1.02– 5.33), late childhood/adolescence (OR = 1.98, 95% CI = 1.01– 3.88), and overweight/obesity (OR = 2.97, 95% CI = 1.56– 5.67) combined with sleep hypoxemia (least SpO2 ≤ 95%) (OR = 2.24, 95% CI = 1.16– 4.04) predicted hypertension (R2 = 0.21) in the severe IH subgroup (n = 205), while the no/mild IH subgroup (n = 160) had an entirely different predictor, severe OSA (OR = 3.81, 95% CI = 1.49– 9.74) (R2 = 0.07).Conclusion: The close relationships among IH, overweight/obesity, and hypertension highlight the importance of reducing IH and body weight in children with OSA.Keywords: children, oxygen desaturation index, intermittent hypoxemia, obesity, obstructive sleep apnea, predictive model

Ming-Shao Tsai,1– 4,&ast; Hung-Chin Chen,1,&ast; Hsueh-Yu Li,2,5 Yao-Te Tsai,1,2 Yao-Hsu Yang,4,6,7 Chia-Yen Liu,4 Yi‑Chan Lee,2,8 Cheng-Ming Hsu,1,2 Li-Ang Lee2,5,9 1Department of Otolaryngology – Head and Neck Surgery, Chiayi Chang Gung Memorial Hospital, Chiayi, 613, Taiwan; 2Faculty of Medicine, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; 3Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; 4Health Information and Epidemiology Laboratory of Chang Gung Memorial Hospital, Chiayi, 613, Taiwan; 5Department of Otolaryngology – Head and Neck Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan; 6Department of Traditional Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, 613, Taiwan; 7School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; 8Department of Otolaryngology – Head and Neck Surgery, Keelung Chang Gung Memorial Hospital, Keelung, 204, Taiwan; 9School of Medicine, National Tsing Hua University, Hsinchu, 300, Taiwan&ast;These authors contributed equally to this workCorrespondence: Li-Ang Lee, Department of Otolaryngology – Head and Neck Surgery, Linkou Chang Gung Memorial Hospital, No. 5, Fu-Hsing Street, Gueishan District, Taoyuan City, 33305, Taiwan, Tel +886 3 3281200 ext. 3968, Fax +886 3 3979361, Email 5738@cgmh.org.twPurpose: We executed the presented retrospective cohort study with the purpose of probing the risk of severe acute respiratory infection (SARI) following influenza in patients with sleep apnea.Materials and Methods: We executed this real-world study by gathering Taiwan National Health Insurance Research Database (NHIRD) data. From a database containing 1 million individuals sampled at random from the NHIRD, we identified all patients aged 20 years or older with a sleep apnea diagnosis between 1997 and 2013 as the study group. We established a comparison cohort of individuals without sleep apnea by randomly matching patients with respect to monthly income, gender, urbanization level, and age at a 1:4 ratio. Follow-up was performed until death or the end of 2015 for both groups. We determined the study outcome to be the occurrence of influenza-associated SARI.Results: We enrolled 6508 and 26,032 patients into the study and comparison groups, respectively. A significantly higher cumulative incidence of influenza-associated SARI was discovered in the study group (p < 0.001). In our multivariate analysis, sleep apnea, chronic obstructive pulmonary disease, and coronary artery disease were independent risk factors for influenza-associated SARI. The hazard ratio of sleep apnea for influenza-associated SARI was 1.98 (95% CI: 1.26– 3.10) after adjustment for all comorbidities, gender, age, monthly income, and urbanization level.Conclusion: Sleep apnea increased the risk of influenza-associated SARI. We suggest that physicians be cautious about the development of severe influenza illness in patients with sleep apnea. Vaccination and early oseltamivir administration should be actively considered in this group of patients.Keywords: sleep apnea, sleep disturbance, influenza, severe acute respiratory infection

I-Chun Kuo,1,2 Li-Jen Hsin,1,2 Li-Ang Lee,1,2 Tuan-Jen Fang,1,2 Ming-Shao Tsai,2,3 Yi-Chan Lee,2,4 Shih-Chieh Shen,2,5 Hsueh-Yu Li1,2 1Departments of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital, Linkou Main Branch, Tao-yuan City, Taiwan; 2College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; 3Departments of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital, Chiayi Branch, Chiayi City, Taiwan; 4Departments of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital, Keelung Branch, Keelung City, Taiwan; 5Departments of Otolaryngology-Head & Neck Surgery, New Taipei City Municipal Tucheng Hospital, New Taipei City, TaiwanCorrespondence: Hsueh-Yu LiDepartments of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital, Linkou Main Branch, Tao-yuan City, TaiwanTel +886-3-328-1200 ext.3966Fax +886-3-397-9361Email hily38@cgmh.org.twObjective: This study aims to explore the factors that contribute to epiglottic collapse (EC) in patients with obstructive sleep apnea (OSA).Methods: This study enrolled 35 patients (34 males; median age, 39 years; median apnea–hypopnea index (AHI), 55.4 events/h; median body mass index (BMI), 26.9 kg/m2). EC (epiglottis attaching onto the posterior pharyngeal wall) was diagnosed by drug-induced sleep computed tomography (DI-SCT). Three dimensions were assessed for comparison between the EC and non-EC (NEC) groups that included anatomical measurement: epiglottic length and angle, endoscopic classification of epiglottis obstructing the glottis (Type I, none; Type II, partial; and Type III, total), and dynamic hyoid movement during DI-SCT (Δ hyoid = √(x2 + y2), maximal displacement of hyoid in x and y axes during sleep breathing cycle).Results: EC was found in 12 patients (34%). No difference in age, gender, AHI, and BMI between the two groups was noted. The anatomical measurement revealed that epiglottis length was significantly different between the EC and NEC groups (21.2 vs 15.8 mm; p < 0.001), with a cutoff value of 16.6 mm (sensitivity, 100%; specificity, 65.2%). The EC group patients showed larger hyoid movement than the NEC group patients (Δ hyoid, 4.8 vs 3.0 mm; p = 0.027). By contrast, epiglottic angle and endoscopic classification revealed an insignificant difference between the two groups.Conclusion: Epiglottis is a potential collapse site among multilevel obstruction in moderate to severe OSA patients. Epiglottic length is highly sensitive in predicting EC, with the cutoff value of 16.6 mm. Hyoid movement plays a role in contributing to EC in OSA patients.Keywords: obstructive sleep apnea, epiglottic collapse, drug-induced sleep computed tomography, epiglottic length, hyoid bone movement

Chin-Kuo Chen,1,2 Shih Chieh Shen,1– 3 Li-Ang Lee,1,2 Ming-Hui Sun,2,4 Ning-Hung Chen,2,5 Li-Pang Chuang,2,5 Hsueh-Yu Li1,2 1Department of Otolaryngology-Head and Neck Surgery, Sleep Center, Chang Gung Memorial Hospital (Linkou), Taoyuan City, Taiwan; 2College of Medicine, Chang Gung University, Taoyuan City, Taiwan; 3Department of Otolaryngology-Head and Neck Surgery, New Taipei Municipal Tucheng Hospital, New Taipei City, Taiwan; 4Department of Ophthalmology, Chang Gung Memorial Hospital (Linkou), Taoyuan City, Taiwan; 5Department of Pulmonary and Critical Care Medicine, Sleep Center, Chang Gung Memorial Hospital (Linkou), Taoyuan City, TaiwanCorrespondence: Hsueh-Yu Li; Shih Chieh ShenDepartment of Otolaryngology-Head and Neck Surgery, Sleep Center, Chang Gung Memorial Hospital (Linkou), 33, No. 5, Fushing Street, Gueishan Shiang, Taoyuan City, TaiwanTel +886-3-3281200 ext.3966Fax +886-3-3979361Email hyli38@cgmh.org.tw; b9102083@cgmh.org.twPurpose: Obstructive sleep apnea (OSA) is characterized by recurring hypoxic-apneic events during sleep, and labyrinthine vascular compromise is a pathophysiologic hallmark of idiopathic sudden sensorineural hearing loss (ISSNHL). Some reports have discussed the relationship between OSA and hearing impairment; however, few have examined hearing prognosis in OSA and patients without OSA with ISSNHL. We aimed to investigate clinical manifestations of ISSNHL in patients with OSA, including severity of hearing loss and response to treatment.Patients and Methods: A case-control study was conducted by extracting data from the sleep center and cochlea center databases of the Chang Gung Memorial Hospital. A retrospective chart review was performed to include confirmed adult OSA patients diagnosed with unilateral ISSNHL. Age and sex-matched patients without OSA with ISSNHL were enrolled as controls. Pure-tone average (PTA) thresholds were measured at specific frequencies. Changes in PTA before and after standard treatment with oral prednisolone (1mg/kg/day for 5 days, then tapered) and between participants with OSA and without OSA were compared. Standard treatment was given to all ISSNHL patients.Results: Twenty-eight out of 8500 (0.33%) OSA patients experienced subsequent ISSNHL in 9 years. Patients with OSA (n=28) had poorer high-frequency perception in the unaffected ear than the patients without OSA (n=120), although the difference was not significant. Hearing in the affected ear among patients with OSA was comparable to that patients without OSA at individual frequencies and average, suggesting no difference in hearing loss in the affected ear between the two groups. In terms of high-frequencies (4000 and 8000 Hz) perception, patients with OSA had significantly poorer responses to steroid treatment than patients without OSA.Conclusion: ISSNHL may be one of the auditory complications associated with OSA. Patients with OSA had poorer prednisolone related hearing improvement in high frequencies than patients without OSA. Despite study limitations, OSA-related hypoxia and snoring noise is hazardous to hearing and standard treatments with CPAP is suggested in OSA patients for both holistic and auditory health.Keywords: obstructive sleep apnea, idiopathic sudden sensorineural hearing loss, high-frequency, hypoxemia, pure-tone average, frequencies

Soichiro Hozawa,1 Hiroyuki Ohbayashi,2 Michiko Tsuchiya,3 Yu Hara,4 Laurie A Lee,5 Takashi Nakayama,6 Jun Tamaoki,6 Andrew Fowler,7 Takanobu Nishi6 1Hiroshima Allergy and Respiratory Clinic, Hiroshima, Japan; 2Tohno Chuo Clinic, Gifu, Japan; 3Department of Respiratory Medicine, Rakuwakai Otowa Hospital, Kyoto, Japan; 4Department of Pulmonology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan; 5GSK, Collegeville, PA, USA; 6GSK, Tokyo, Japan; 7GSK, Brentford, Middlesex, UKCorrespondence: Takanobu NishiGlaxoSmithKline K.K., 1-8-1 Akasaka, Minato-ku, Tokyo, 107-0052, JapanTel +81-70-4135-5303Fax +81-3-4231-5974Email takanobu.2.nishi@gsk.comPurpose: The pivotal CAPTAIN study reported a favorable safety profile with once-daily inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β2-agonist (ICS/LAMA/LABA) triple combination of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) in patients with inadequately controlled asthma, some of whom were Japanese. Here, we evaluate the long-term (52 weeks) safety of FF/UMEC/VI in Japanese patients with asthma.Patients and Methods: This was a Phase III, 52-week, multicenter, non-comparator, non-randomized, open-label study (NCT03184987) in Japanese adults receiving maintenance therapy with ICS/LABA, with or without LAMA. At enrollment, patients were allocated to either FF/UMEC/VI 100/62.5/25mcg (Group 1) or 200/62.5/25mcg (Group 2). Patients in Group 1 could have their treatment stepped up to 200/62.5/25mcg at Week 24 if their Asthma Control Questionnaire (ACQ)-7 score was > 0.75. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs). Secondary endpoints included vital signs, electrocardiogram measurements, and clinical laboratory tests (biochemistry, hematology, urinalysis). Efficacy was assessed as “other” endpoints.Results: A total of 111 Japanese patients were included in the intention-to-treat (ITT) population. Overall, 77 (69%) patients reported ≥ 1 AE (Group 1: n=30 [64%]; step-up group: n=7 [78%]; Group 2: n=40 [73%]). SAEs were reported for 1 (2.1%) and 2 (3.6%) patients in Groups 1 and 2, respectively. All SAEs were considered unrelated to study treatment. One AE and one SAE led to study withdrawal: oropharyngeal discomfort (Group 1); eosinophilic granulomatosis with polyangiitis (Group 2). No new safety concerns were identified throughout the 52-week treatment period.Conclusion: In this uncontrolled open-label study, no new safety concerns were observed with long-term (52 weeks) treatment with once-daily FF/UMEC/VI among 111 Japanese patients with asthma.Keywords: asthma, inhalers, Japan, safety, treatment outcome

Hai-Hua Chuang,1– 3 Chi-Hung Liu,4 Chao-Yung Wang,5 Yu-Lun Lo,6 Guo-She Lee,7,8 Yi-Ping Chao,4,9 Hsueh-Yu Li,10 Terry BJ Kuo,11 Cheryl CH Yang,11 Liang-Yu Shyu,12 Li-Ang Lee10,11 1Department of Family Medicine, Chang Gung Memorial Hospital, Taipei Branch and Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 2Department of Industrial Engineering and Management, National Taipei University of Technology, Taipei, Taiwan; 3Genomic Medicine Institute & Obesity Institute, Geisinger Medical, Danville, PA, USA; 4Department of Neurology, Chang Gung Memorial Hospital, Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 5Department of Cardiology, Chang Gung Memorial Hospital, Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 6Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 7Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan; 8Department of Otolaryngology, Taipei City Hospital, Ren-Ai Branch, Taipei, Taiwan; 9Department of Computer Science and Information Engineering, Chang Gung University, Taoyuan, Taiwan; 10Department of Otorhinolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 11Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan; 12Department of Biomedical Engineering, Chung Yuan Christian University, Taoyuan, TaiwanCorrespondence: Li-Ang LeeDepartments of Otorhinolaryngology-Head and Neck Surgery, Sleep Center, Chang Gung Memorial Hospital, Linkou Main Branch, No. 5, Fu-Hsing Street, Guishan District, Taoyuan, 33305, TaiwanTel +886 33281200 ext. 3972Fax +886 33979361Email 5738@cgmh.org.twBackground: Obstructive sleep apnea (OSA) and snoring have been reported to be modifiable risk factors for thick carotid intima-media thickness (CIMT) and carotid atherosclerosis, which are closely linked to cardiovascular disease.Methods: This cross-sectional study prospectively recruited 70 participants with OSA and without a history of carotid artery disorder, who primarily sought surgical Intervention. OSA and snoring were assessed with the Epworth Sleepiness Scale, Snore Outcomes Survey, polysomnography, and snoring sound recording. The carotid arteries were evaluated with ultrasonography and divided into three types of carotid artery profiles (normal carotid artery, thick CIMT, or significant carotid atherosclerosis). Multivariate linear/logistic/categorical regressions were performed with the forward selection approaches/logistic least absolute shrinkage and selection operator, as appropriate.Results: Normalized snoring sound energy (301– 850 Hz) was independently associated with the carotid intima-media thickness (regression coefficient [β] = 0.01, standard error [SE] = 0.004, P = 0.03; R2 = 0.067) and type of carotid profile (β = 0.40, SE = 0.09, P < 0.001; R2 = 0.156). Normalized snoring sound energy (4– 300 Hz) (β = − 0.10, SE = 0.04, P = 0.01) and female sex (β = 1.90, SE = 0.94, P = 0.04) were independently related to the presence of carotid stenosis (R2 = 0.159). The optimal regression model of the type of carotid artery profile included normalized snoring sound energy (301– 850 Hz) (β = 0.33, SE = 0.14, P = 0.03), snoring time (β = 0.26, SE = 0.13, P = 0.047), female sex (β = 0.26, SE = 0.13, P = 0.047), and increased age (β = 0.20, SE = 0.10, P = 0.04) under the control of the Snore Outcomes Survey score, 3% oxygen desaturation index, snoring sound energy (4– 1500 Hz), normalized snoring sound energy (851– 1500 Hz), cigarette smoking, and hyperlipidemia (R2 = 0.427).Conclusion: Our findings suggested that snoring sound characteristics are associated with carotid artery profiles among early OSA patients who cannot be noticed by ultrasound because organic changes of the carotid artery have not yet started. Future studies are warranted to verify the clinical significance of the results.Keywords: atherosclerosis, common carotid artery, categorical regression, obstructive sleep apnea, snoring, ultrasound

Steven J Pascoe,1 Wei Wu,2,3 Kathryn A Collison,1 Linda M Nelsen,4 Keele E Wurst,5 Laurie A Lee6 1Respiratory Medicines Development Center, GSK, Research Triangle Park, NC, USA; 2Biostatistics, PAREXEL International, Research Triangle Park, NC, USA; 3Clinical Statistics, GSK, Research Triangle Park, NC, USA; 4Value Evidence and Outcomes, GSK, Collegeville, PA, USA; 5Epidemiology, GSK, Collegeville, PA, USA; 6Research and Development, GSK, Stevenage, UK Background: There is no consensus on how to define patients with symptoms of asthma and chronic obstructive pulmonary disease (COPD). A diagnosis of asthma–COPD overlap (ACO) syndrome has been proposed, but its value is debated. This study (GSK Study 201703 [NCT02302417]) investigated the ability of statistical modeling approaches to define distinct disease groups in patients with obstructive lung disease (OLD) using medical history and spirometric data.Methods: Patients aged ≥18 years with diagnoses of asthma and/or COPD were categorized into three groups: 1) asthma (nonobstructive; reversible), 2) ACO (obstructive; reversible), and 3) COPD (obstructive; nonreversible). Obstruction was defined as a post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity

Luis A Lee, Vassilis Athanassoglou, Jaideep J Pandit Nuffield Department of Anaesthetics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK Abstract: Neuromuscular blockade is a desirable or even essential component of general anesthesia for major surgical operations. As the population continues to age, and more operations are conducted in the elderly, due consideration must be given to neuromuscular blockade in these patients to avoid possible complications. This review considers the pharmacokinetics and pharmacodynamics of neuromuscular blockade that may be altered in the elderly. Compartment distribution, metabolism, and excretion of drugs may vary due to age-related changes in physiology, altering the duration of action with a need for reduced dosage (eg, aminosteroids). Other drugs (atracurium, cisatracurium) have more reliable duration of action and should perhaps be considered for use in the elderly. The range of interpatient variability that neuromuscular blocking drugs may exhibit is then considered and drugs with a narrower range, such as cisatracurium, may produce more predictable, and inherently safer, outcomes. Ultimately, appropriate neuromuscular monitoring should be used to guide the administration of muscle relaxants so that the risk of residual neuromuscular blockade postoperatively can be minimized. The reliability of various monitoring is considered. This paper concludes with a review of the various reversal agents, namely, anticholinesterase drugs and sugammadex, and the alterations in dosing of these that should be considered for the elderly patient. Keywords: anesthesia, elderly, drugs, pharmacokinetics, pharmacodynamics

Somatic mutations that lead to constitutive activation of NRAS and KRAS proto-oncogenes are among the most common in human cancer and frequently occur in acute myeloid leukemia (AML). An inducible NRAS(V12)-driven AML mouse model has established a critical role for continued NRAS(V12) expression in leukemia maintenance. In this model genetic suppression of NRAS(V12) expression results in rapid leukemia remission, but some mice undergo spontaneous relapse with NRAS(V12)-independent (NRI) AMLs providing an opportunity to identify mechanisms that bypass the requirement for Ras oncogene activity and drive leukemia relapse. We found that relapsed NRI AMLs are devoid of NRAS(V12) expression and signaling through the major oncogenic Ras effector pathways, phosphatidylinositol-3-kinase and mitogen-activated protein kinase, but express higher levels of an alternate Ras effector, Ralb, and exhibit NRI phosphorylation of the RALB effector TBK1, implicating RALB signaling in AML relapse. Functional studies confirmed that inhibiting CDK5-mediated RALB activation with a clinically relevant experimental drug, dinaciclib, led to potent RALB-dependent antileukemic effects in human AML cell lines, induced apoptosis in patient-derived AML samples in vitro and led to a 2-log reduction in the leukemic burden in patient-derived xenograft mice. Furthermore, dinaciclib potently suppressed the clonogenic potential of relapsed NRI AMLs in vitro and prevented the development of relapsed AML in vivo. Our findings demonstrate that Ras oncogene-independent activation of RALB signaling is a therapeutically targetable mechanism of escape from NRAS oncogene addiction in AML.

Loneliness has been linked to a host of harmful physical and mental health outcomes, detrimental effects that may stem from increases in threat-responding caused by altered fear learning in lonely individuals. In particular, the heightened threat-vigilance that is a hallmark of loneliness may augment the processes by which fear learning occurs, ultimately resulting in a greater number of perceived threatening cues in the environment. However, almost no research has examined how loneliness alters fear learning processes in humans. Here, we investigated the effect of loneliness on fear learning during an evaluative learning procedure in which participants (n = 782) were taught to associate fearful, positive, or neutral control stimuli with neutral images. Results showed that reduced extinction of evaluative fear associations occurred in high (vs. low) lonely individuals, but there was no difference in extinction of evaluative appetitive (also known as positive or reward) associations, suggesting this effect is specific to fear learning. In addition to shedding light on the link between loneliness and poor health, these results represent an important step forward in the growing understanding of the powerful impact of social bonds on fear learning processes.

More than 16 million Americans provide unpaid care for someone with Alzheimer’s disease and related dementias (ADRD). During the COVID-19 pandemic, unpaid caregivers experienced increased chronic severe stress from widespread closures and social distancing. We conducted eight surveys from March 2020 to March 2021 among a cohort of over 10,000 individuals. Cross-sectional analysis was conducted to investigate frequency and ratios of groups reporting increased stress across surveys. A longitudinal analysis was also performed with the 1,030 participants who took more than one survey. We found a growing crisis among dementia caregivers: By Survey 8, current caregivers reported 2.9 times higher stress levels than the comparator group. By that time, 64% of current caregivers reported having multiple stress symptoms typically found in people experiencing severe stress. Both analyses reported increased levels of stressors over time that were more associated with certain caregiver groups. Our findings underscore the urgent need for public policy initiatives and supportive community infrastructure to support ADRD caregivers.

The function of RNA binding proteins within innate lymphoid cells (ILC) has been partially characterised. Here the authors show that RBM3 functions to limit the type 2 immunity promoting activity of ILC2 partially through cysteinyl leukotriene 1 receptor.

Eye tracking is growing in popularity for multiple application areas, yet analysing and exploring the large volume of complex data remains difficult for most users. We present a comprehensive eye tracking visual analytics system to enable the exploration and presentation of eye-tracking data across time and space in an efficient manner. The application allows the user to gain an overview of general patterns and perform deep visual analysis of local gaze exploration. The ability to link directly to the video of the underlying scene allows the visualisation insights to be verified on the fly. The system was motivated by the need to analyse eye-tracking data collected from an ‘in the wild’ study with energy network operators and has been further evaluated via interviews with 14 eye-tracking experts in multiple domains. Results suggest that, thanks to state-of-the-art visualisation techniques and by providing context with videos, our system could enable an improved analysis of eye-tracking data through interactive exploration, facilitating comparison between different participants or conditions, thus enhancing the presentation of complex data analysis to non-experts. This research paper provides four contributions: (1) analysis of a motivational use case demonstrating the need for rich visual-analytics workflow tools for eye-tracking data; (2) a highly dynamic system to visually explore and present complex eye-tracking data; (3) insights from our applied use case evaluation and interviews with experienced users demonstrating the potential for the system and visual analytics for the wider eye-tracking community.

Abstract Background Combating viral outbreaks extends beyond biomedical and clinical approaches; thus, public health prevention measures are equally important. Public engagement in preventive efforts can be viewed as the social responsibility of individuals in controlling an infectious disease and are subjected to change due to human behaviour. Understanding individuals’ perception of social responsibility is crucial and is not yet explored extensively in the academic literature. We adopted the grounded theory method to develop an explanatory substantive theory to illustrate the process of how individual responded to the outbreak from a social responsibility perspective. Methods In-depth interviews were conducted among 23 Malaysians either through telephone or face-to-face depending on the participant’s preference. Both purposive and theoretical sampling were used. Participants were invited to share their understanding, perceptions and activities during the COVID-19 pandemic. They were further probed about their perceptions on complying with the public health interventions imposed by the authorities. The interviews were audio-recorded and transcribed verbatim. Data was analysed via open coding, focus coding and theoretical coding, facilitated by memoing, sketching and modelling. Results Study findings showed that, social responsibility is perceived within its role, the perceived societal role responsibility. In a particular context, an individual assumed only one of the many expected social roles with their perceived circle of responsibility. Individuals negotiated their actions from this perspective, after considering the perceived risk during the outbreak. The four types of behaviour depicted in the matrix diagram facilitate the understanding of the abstract concept of negotiation in the human decision-making process, and provide the spectrum of different behaviour in relation to public response to the COVID-19 pandemic. Conclusions Our study adopted the grounded theory approach to develop a theoretical model that illustrates how individual response to COVID-19 preventive measures is determined by the negotiation between perceived societal role responsibility and perceived infection risk. This substantive theoretical model is abstract, thus has relevance for adoption within similar context of an outbreak.

Abstract Introduction Evidence shows physical distancing of one metre or more is important to reduce person-to-person SARS-CoV-2 transmission. This puts the Malaysian public healthcare system to a test when overcrowding has always been an issue. A new clinical appointment structure was proposed in the Malaysian public healthcare system amidst the pandemic to reduce the transmission risk. We aim to explore the general public’s view on the proposed clinic appointment structure. Methods A cross-sectional anonymous web-based survey was conducted between 10th September 2020 and 30th November 2020. The survey was open to Malaysian aged 18 years and older via various social media platforms. The questionnaire consists of sociodemographic, experience of utilising healthcare facilities, and views on clinic appointment structure. Results A total of 1,144 complete responses were received. The mean age was 41.4 ± 12.4 years and more than half of the respondents had a preference for public healthcare. Among them, 77.1% reported to have a clinical appointment scheduled in the past. Less than a quarter experienced off-office hour appointments, mostly given by private healthcare. 70.2% answered they would arrive earlier if they were given a specific appointment slot at a public healthcare facility, as parking availability was the utmost concern. Majority hold positive views for after office hour clinical appointments, with 68.9% and 63.2% agreed for weekend and weekday evening appointment, respectively. The top reason of agreement was working commitment during office hours, while family commitment and personal resting time were the main reasons for disagreeing with off-office hour appointments. Conclusion We found that majority of our respondents chose to come early instead of arriving on time which disrupts the staggered appointment system and causes over crowdedness. Our findings also show that the majority of our respondents accept off-office hour appointments. This positive response suggests that off-office hour appointments may have a high uptake amongst the public and thus be a possible solution to distribute the patient load. Therefore, this information may help policy makers to initiate future plans to resolve congestions within public health care facilities which in turn eases physical distancing during the pandemic.

Objectives: Following a cluster of COVID-19 cases in a Singapore public hospital in April 2021, the local health authority mandated the use of N95 respirators in all inpatient wards. This increased the demand for N95 mask fit-testing to ensure that healthcare workers were donning respirators that fit their facial characteristics and hence provided protection through a good facial seal. The demand for fit-testing during the pandemic highlighted the scarcity of manpower and ergonomics concern, such as carpel tunnel syndrome experienced in long hours of qualitative fit-testing sessions. We evaluated the operational efficiency, cost-effectiveness, and difference in passing rate after the introduction of the quantitative method. Methods: Conventional qualitative fit-testing was conducted using manual pumping of a challenge agent, enabling the user to determine the fit of the respirator. The quantitative fit-testing protocol used a condensation particle counter (CPC) to measure the concentration of particles inside the mask and the atmosphere to determine the fit of respirator. The Occupational Safety and Health Administration (OSHA)–approved minimum fit factor of 100 was used as the criterion for a successful N95 respirator fit. Tubes used during quantitative fit-testing were reprocessed using thermal disinfection. Results: Quantitative mask fit-testing provided an objective numerical measure to assess adequate fit of N95 respirator, which provided users with confidence in the respirator fit. It addressed a manpower limitation issue because it did not require qualified trainers to conduct the test, and automation also prevented any potential occupational hazard from repeated actions required in qualitative fit-testing. An increase in the passing rate for N95 fit-testing from 94.5% to 95.5% was observed. However, the high cost of equipment, annual recalibration, and consumables must be considered. Conclusions: Quantitative N95 fit-testing, when adopted with careful consideration of its cost, is an approach to consider for hospital-wide fit-testing.

Objectives: Improper reprocessing of endoscopes may result in healthcare-associated infections. Regular microbiological surveillance is an important means of evaluating the quality of endoscope reprocessing. We evaluated the effectiveness of reprocessing endoscopes (including the protocols on steps to be taken in the event of any positive microbiological results) in a sterile supply unit (SSU) and an endoscopy unit in a Singapore tertiary-care academic hospital. Methods: Singapore General Hospital (SGH) is a 1,750-bed, tertiary-care, academic medical center in Singapore with 2 main SSUs: 1 inpatient endoscopy unit and 1 outpatient endoscopy unit. We reviewed microbiological surveillance results from endoscopes following reprocessing from January 2018 to December 2021. In total, 160 endoscopes (27 bronchoscopes, 58 gastroscopes, 52 colonoscopes, 6 duodenoscopes, 5 echoscopes, 5 cystoscopes, 5 rhinolaryngoscopes, and 5 enteroscopes) and 15 automated endoscope reprocessors (AERs) were evaluated for the presence of microorganisms. Samples were obtained by swabbing the tip of the scope and the biopsy channel. Fluid was flushed from the biopsy channel after reprocessing, and this water from the AERs was sampled after waterline disinfection. Results: Of the 15,783 samples collected, 15,667 (99.3%) yielded no growth; 36 (0.2%) were positive for gut and environmental flora; and 80 (0.5%) were positive for low-concern organisms such as skin flora. Conclusions: Microbiological surveillance yielded a high percentage of negative results confirming the effectiveness of endoscope reprocessing. This quality-assurance process is necessary and beneficial in achieving patient safety.

Objectives: Streptococcus mitis is a gram-positive coccus and is a common commensal found in the throat, nasopharynx, and mouth. In an immunocompromised host, S. mitis opportunistically multiplies and can translocate to other sites. At baseline, the prevalence of S. mitis remained stable among hematological patients, averaging ~1 case monthly. However, in August–September 2020, 5 S. mitis cases were documented in a hematology ward and included overlapping inpatient stays. In this descriptive cluster report, we sought to identify the reasons for the increased prevalence of S. mitis in our institution. Methods: A literature review was undertaken to gain a better understanding of the bacteriology of S. mitis. Subsequently, geographical mapping was performed to identify epidemiological links. Further culture and sensitivity testing was requested. Hand hygiene compliance, environmental audit, and handling of central lines within the ward were examined for any lapses in practice. Results: Based on geographical mapping, no epidemiological linkages were established between patients; they were admitted to different rooms and did not share any equipment. Moreover, based on the antibiogram, different bacteria sensitivities were recorded across the isolates from these patients. A hand hygiene and environmental audit result showed 100% compliance. Nurses performed care of central lines in accordance with guidelines. However, an investigation of changes in practice revealed that the use of a toothbrush had only recently been permitted as part of streamlining oral care for hematology patients. Because toothbrushes were not provided by the hospital, patients were utilizing their personal toothbrushes with no direct supervision of their oral care regimen. Conclusions: The prevalence of S. mitis in hematological patients was likely due to the neutropenic condition of patients. This report provides valuable information supporting the optimization of oral hygiene in immunocompromised patients while minimizing the risk of opportunistic infections.

The Parkinson’s Progression Markers Initiative (PPMI) has collected more than a decade’s worth of longitudinal and multi-modal data from patients, healthy controls, and at-risk individuals, including imaging, clinical, cognitive, and ‘omics’ biospecimens. Such a rich dataset presents unprecedented opportunities for biomarker discovery, patient subtyping, and prognostic prediction, but it also poses challenges that may require the development of novel methodological approaches to solve. In this review, we provide an overview of the application of machine learning methods to analyzing data from the PPMI cohort. We find that there is significant variability in the types of data, models, and validation procedures used across studies, and that much of what makes the PPMI data set unique (multi-modal and longitudinal observations) remains underutilized in most machine learning studies. We review each of these dimensions in detail and provide recommendations for future machine learning work using data from the PPMI cohort.

Abstract Objectives HPV‐associated (p16+) squamous cell carcinoma of the oropharynx (OPSCC) has improved survival as compared to HPV‐negative, smoking‐associated disease. Intermediate outcomes have been noted in patients with p16+ tumors and smoking exposure. However, the extent of smoking exposure required for outcomes to decrease has not been delineated due to low failure rates and poor availability of quantitative tobacco smoke exposure data. Our primary objective is to characterize the dose‐dependent relationship between recurrence‐free survival (RFS) and tobacco smoke exposure in p16+ OPSCC and secondarily correlate tobacco smoke exposure with genomic alterations. Methods Single institution chart review was performed of patients diagnosed with p16+ OPSCC from 2003 to 2015. Patients were excluded if staging, treatment details, recurrence status, or smoking exposure in pack‐years were not available. Two hundred and forty‐four patients were included. Results Patients with 25 pack‐years or greater smoking history exhibited a dose‐dependent decrease in RFS compared to never smokers. This was robust to multivariate analysis for including staging and demographic factors. Forty‐three patients with available targeted tumor sequencing data were identified. A strong trend was observed for increased C to A transversion mutations above 25 pack‐years, which are known to be associated with exposure to tobacco smoke. Similarly, the proportion of COSMIC Signature 4 mutations were also found to be more common in patients with more than 25 pack‐years of smoking exposure. Conclusion Evidence‐based smoking exposure thresholds are needed to define inclusion criteria for trials of de‐escalation therapy for p16+ OPSCC. Patients with smoking exposure greater than 20 pack‐years have increased risk of recurrence and a distinct pattern of genomic alterations. Further studies are needed to delineate the potential consequences of mild smoking exposure. Smoking‐related mutational signatures may hold potential for biomarker development in p16+ OPSCC. Level of Evidence 2B

Adolescence is marked by an increased sensitivity to the social environment as youth navigate evolving relationships with family, friends, and communities. Prosocial behavior becomes more differentiated such that older adolescents increasingly give more to known others (e.g., family, friends) than to strangers. This differentiation may be linked with changes in neural processing among brain regions implicated in social decision-making. A total of 269 adolescents from 9–15 and 19–20 years of age completed a decision-making task in which they could give money to caregivers, friends, and strangers while undergoing functional magnetic resonance imaging (fMRI). Giving to caregivers and friends (at a cost to oneself) increased with age, but giving to strangers remained lower and stable across age. Brain regions implicated in cognitive control (dorsolateral and ventrolateral prefrontal cortex) showed increased blood-oxygen-level-dependent (BOLD) activation with increasing age across giving decisions to all recipients; regions associated with reward processing (ventral striatum and ventral tegmental area) showed increased activation across all ages when giving to all recipients. Brain regions associated with social cognition were either not active (dorsomedial prefrontal cortex) or showed reduced activation (temporal parietal junction and posterior superior temporal sulcus) when giving to others across all ages. Findings have implications for understanding the role of brain development in the increased complexity of social decision-making during adolescence.

Despite growing evidence of increased saturated and trans fat contents in street foods, little is known about their fatty acid (FA) compositions. This study aimed to analyse the saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs), and trans fatty acids (TFAs) content of 70 selected and most commonly available street foods in Malaysia. The street foods were categorised into main meals, snacks, and desserts. TFAs were not detected in any of the street foods. Descriptively, all three categories mainly contained SFAs, followed by MUFAs, and PUFAs. However, the one-way ANOVA testing showed that the differences between each category were insignificant (p > 0.05), and each FA was not significantly different (p > 0.05) from one to another. Nearly half of the deep-fried street foods contained medium to high SFAs content (1.7 g/100 g–24.3 g/100 g), while the MUFAs were also high (32.0–44.4%). The Chi-square test of association showed that the type of preparation methods (low or high fat) used was significantly associated (p < 0.05) with the number of SFAs. These findings provide valuable information about fat composition in local street foods for the Malaysian Food Composition Database and highlight the urgency to improve nutritional composition.