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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

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

Objective: Metabolic syndrome (MS) represents a constellation of conditions, which, taken together, increase an individual's risk for the development of type 2 diabetes and cardiovascular disease. Numerous guidelines have been suggested; however, increasing evidence has suggested that universal recommendations are not applicable across different ethnic groups. To date, no specific screening recommendations exist for the Taiwanese population.Materials and Methods: A total of 8913 Taiwanese (>18 years) were enrolled and evaluated for MS based on the International Diabetes Federation (IDF) criteria established for the Asian population, in an attempt to reevaluate the appropriate guidelines for diagnosing MS in the Taiwanese population.Results: Among the risk factors assessed, hypertension (24.72%), hyperglycemia (6.86%), and elevated triglycerides (18.50%) were significantly more prevalent among men (p < 0.01). Low high-density lipoprotein was not significantly different between genders. The prevalence of MS was 24.83% (1171/4716) for men and 15.48% (650/4197) for women. When modified cutoff points for waist circumference (WC) were analyzed (≥ 86.0 cm for men, ≥ 76.0 cm for women), the prevalence of MS increased to 40.88% (1928/4716) for men and 27.88% (1170/4197) for women. Not unexpectedly, the odds ratio for developing MS increased with an increasing WC, as well as with an increasing number of risk factors for MS.Conclusions: The suggested IDF guidelines for defining MS in the Asian population, including WC, seem appropriate for use in the Taiwanese population but need modification. Further studies are warranted to identify other anthropometric measures specific to the population that would enhance the ability to diagnose MS. [ABSTRACT FROM AUTHOR]

Children with obstructive sleep apnea (OSA) frequently experience chronic low-grade systemic inflammation, with the inflammasome playing a central role in OSA. This cross-sectional study evaluated the relationship between weight status, autonomic function, and systemic inflammation in a cohort of 55 children with OSA, predominantly boys (78%) with an average age of 7.4 ± 2.2 years and an apnea-hypopnea index of 14.12 ± 17.05 events/hour. Measurements were taken of body mass index (BMI), sleep heart-rate variability, morning circulatory levels of interleukin-1β, interleukin-1 receptor antagonist, and interleukin-6, and tumor necrosis factor-α, anthropometry, and polysomnography. Multiple linear regression modeling showed that an apnea-hypopnea index was significantly associated with BMI, the standard deviation of successive differences between normal-to-normal intervals during N3 sleep, and the proportion of normal-to-normal interval pairs differing by more than 50 ms during rapid-eye-movement sleep. A moderated mediation model revealed that interleukin-1 receptor antagonist levels mediated the association between BMI and interleukin-6 levels, with sympathovagal balance during N3 sleep and minimum blood oxygen saturation further moderating these relationships. This study highlights the complex relationships between BMI, polysomnographic parameters, sleep heart-rate-variability metrics, and inflammatory markers in children with OSA, underlining the importance of weight management in this context.

Background: This study focused on the relationship between adiposity and Rest-Activity Rhythms (RAR), utilizing both parametric cosine-based models and non-parametric algorithms. The emphasis was on the impact of varying measurement periods (7-28 days) on this relationship., Methods: We retrieved actigraphy data from two datasets, encompassing a diverse cohort recruited from an obesity outpatient clinic and a workplace health promotion program. Participants were required to wear a research-grade wrist actigraphy device continuously for a minimum of four weeks. The final dataset included 115 individuals (mean age 40.7 ± 9.5 years, 51 % female). We employed both parametric and non-parametric methods to quantify RAR using six standard variables. Additionally, the study evaluated the correlations between three key adiposity indices - Body Mass Index (BMI), Visceral Adipose Tissue (VAT) area, and Body Fat Percentage (BF%) - and circadian rhythm indicators, controlling for factors like physical activity, age, and gender., Results: The obesity group displayed a significantly lower relative amplitude (RA) as per non-parametric algorithm findings, with a decreased amplitude noted in the parametric algorithm analysis, in comparison to the overweight and control groups. The relationship between circadian rhythm indicators and adiposity metrics over 7- to 28-day periods was examined. A notable negative correlation was observed between RA and both BMI and VAT, while correlation coefficients between adiposity indicators and non-parametric circadian parameters increased with extended durations of actigraphy data. Specifically, RA over a 28-day period was significantly correlated with BF%, a trend not seen in the 7-day measurement (p = 0.094) in multivariate linear regression. The strength of the correlation between BF% and 28-day RA was more pronounced than that in the 7-day period (p = 0.044). However, replacing RA with amplitude as per parametric cosinor fitting yielded no significant correlations for any of the measurement periods., Conclusion: The study concludes that a 28-day measurement period more effectively captures the link between disrupted circadian rhythms and adiposity. Non-parametric algorithms, in particular, were more effective in characterizing disrupted circadian rhythms, especially when extending the measurement period beyond the standard 7 days., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Human biological rhythms are commonly assessed through physical activity (PA) measurement, but mental activity may offer a more substantial reflection of human biological rhythms., Objective: This study proposes a novel approach based on human-smartphone interaction to compute mental activity, encompassing general mental activity (GMA) and working mental activity (WMA)., Methods: A total of 24 health care professionals participated, wearing wrist actigraphy devices and using the "Staff Hours" app for more than 457 person-days, including 332 workdays and 125 nonworkdays. PA was measured using actigraphy, while GMA and WMA were assessed based on patterns of smartphone interactions. To model WMA, machine learning techniques such as extreme gradient boosting and convolutional neural networks were applied, using human-smartphone interaction patterns and GPS-defined work hours. The data were organized by date and divided into person-days, with an 80:20 split for training and testing data sets to minimize overfitting and maximize model robustness. The study also adopted the M10 metric to quantify daily activity levels by calculating the average acceleration during the 10-hour period of highest activity each day, which facilitated the assessment of the interrelations between PA, GMA, and WMA and sleep indicators. Phase differences, such as those between PA and GMA, were defined using a second-order Butterworth filter and Hilbert transform to extract and calculate circadian rhythms and instantaneous phases. This calculation involved subtracting the phase of the reference signal from that of the target signal and averaging these differences to provide a stable and clear measure of the phase relationship between the signals. Additionally, multilevel modeling explored associations between sleep indicators (total sleep time, midpoint of sleep) and next-day activity levels, accounting for the data's nested structure., Results: Significant differences in activity levels were noted between workdays and nonworkdays, with WMA occurring approximately 1.08 hours earlier than PA during workdays (P<.001). Conversely, GMA was observed to commence about 1.22 hours later than PA (P<.001). Furthermore, a significant negative correlation was identified between the activity level of WMA and the previous night's midpoint of sleep (β=-0.263, P<.001), indicating that later bedtimes and wake times were linked to reduced activity levels in WMA the following day. However, there was no significant correlation between WMA's activity levels and total sleep time. Similarly, no significant correlations were found between the activity levels of PA and GMA and sleep indicators from the previous night., Conclusions: This study significantly advances the understanding of human biological rhythms by developing and highlighting GMA and WMA as key indicators, derived from human-smartphone interactions. These findings offer novel insights into how mental activities, alongside PA, are intricately linked to sleep patterns, emphasizing the potential of GMA and WMA in behavioral and health studies., (©Hung-Hsun Chen, Chen Lin, Hsiang-Chih Chang, Jen-Ho Chang, Hai-Hua Chuang, Yu-Hsuan Lin. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 17.06.2024.)

Background: Analyzing bacterial microbiomes consistently using next-generation sequencing (NGS) is challenging due to the diversity of synthetic platforms for 16S rRNA genes and their analytical pipelines. This study compares the efficacy of full-length (V1-V9 hypervariable regions) and partial-length (V3-V4 hypervariable regions) sequencing of synthetic 16S rRNA genes from human gut microbiomes, with a focus on childhood obesity., Methods: In this observational and comparative study, we explored the differences between these two sequencing methods in taxonomic categorization and weight status prediction among twelve children with obstructive sleep apnea., Results: The full-length NGS method by Pacbio ® identified 118 genera and 248 species in the V1-V9 regions, all with a 0% unclassified rate. In contrast, the partial-length NGS method by Illumina ® detected 142 genera (with a 39% unclassified rate) and 6 species (with a 99% unclassified rate) in the V3-V4 regions. These approaches showed marked differences in gut microbiome composition and functional predictions. The full-length method distinguished between obese and non-obese children using the Firmicutes / Bacteroidetes ratio, a known obesity marker ( p = 0.046), whereas the partial-length method was less conclusive ( p = 0.075). Additionally, out of 73 metabolic pathways identified through full-length sequencing, 35 (48%) were associated with level 1 metabolism, compared to 28 of 61 pathways (46%) identified through the partial-length method. The full-length NGS also highlighted complex associations between body mass index z-score, three bacterial species ( Bacteroides ovatus , Bifidobacterium pseudocatenulatum , and Streptococcus parasanguinis ATCC 15912), and 17 metabolic pathways. Both sequencing techniques revealed relationships between gut microbiota composition and OSA-related parameters, with full-length sequencing offering more comprehensive insights into associated metabolic pathways than the V3-V4 technique., Conclusion: These findings highlight disparities in NGS-based assessments, emphasizing the value of full-length NGS with amplicon sequence variant analysis for clinical gut microbiome research. They underscore the importance of considering methodological differences in future meta-analyses., Competing Interests: S-HC was employed by Biotools Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Chuang, Huang, Chou, Li, Lee and Lee.)

Background: This study aimed to investigate the relationships between adiposity and circadian rhythm and compare the measurement of circadian rhythm using both actigraphy and a smartphone app that tracks human-smartphone interactions., Objective: We hypothesized that the app-based measurement may provide more comprehensive information, including light-sensitive melatonin secretion and social rhythm, and have stronger correlations with adiposity indicators., Methods: We enrolled a total of 78 participants (mean age 41.5, SD 9.9 years; 46/78, 59% women) from both an obesity outpatient clinic and a workplace health promotion program. All participants (n=29 with obesity, n=16 overweight, and n=33 controls) were required to wear a wrist actigraphy device and install the Rhythm app for a minimum of 4 weeks, contributing to a total of 2182 person-days of data collection. The Rhythm app estimates sleep and circadian rhythm indicators by tracking human-smartphone interactions, which correspond to actigraphy. We examined the correlations between adiposity indices and sleep and circadian rhythm indicators, including sleep time, chronotype, and regularity of circadian rhythm, while controlling for physical activity level, age, and gender., Results: Sleep onset and wake time measurements did not differ significantly between the app and actigraphy; however, wake after sleep onset was longer (13.5, SD 19.5 minutes) with the app, resulting in a longer actigraphy-measured total sleep time (TST) of 20.2 (SD 66.7) minutes. The obesity group had a significantly longer TST with both methods. App-measured circadian rhythm indicators were significantly lower than their actigraphy-measured counterparts. The obesity group had significantly lower interdaily stability (IS) than the control group with both methods. The multivariable-adjusted model revealed a negative correlation between BMI and app-measured IS (P=.007). Body fat percentage (BF%) and visceral adipose tissue area (VAT) showed significant correlations with both app-measured IS and actigraphy-measured IS. The app-measured midpoint of sleep showed a positive correlation with both BF% and VAT. Actigraphy-measured TST exhibited a positive correlation with BMI, VAT, and BF%, while no significant correlation was found between app-measured TST and either BMI, VAT, or BF%., Conclusions: Our findings suggest that IS is strongly correlated with various adiposity indicators. Further exploration of the role of circadian rhythm, particularly measured through human-smartphone interactions, in obesity prevention could be warranted., (©Hai-Hua Chuang, Chen Lin, Li-Ang Lee, Hsiang-Chih Chang, Guan-Jie She, Yu-Hsuan Lin. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 05.06.2024.)

Background/Objectives : The inhibitory effects of tyrosine kinase inhibitors (TKIs) on glucose uptake through their binding to human glucose transporter-1 (GLUT-1) have been well documented. Thus, our research aimed to explore the potential impact of various TKIs of GLUT-1 on the standard [ 18 F]FDG-PET monitoring of tumor response in patients. Methods : To achieve this, we conducted an analysis on three patients who were undergoing treatment with different TKIs and harbored actionable alterations. Alongside the assessment of FDG data (including SUVmax, total lesion glycolysis (TLG), and metabolic tumor volume (MTV)), we also examined the changes in tumor sizes through follow-up [ 18 F]FDG-PET/CT imaging. Notably, our patients harbored alterations in BRAFV600, RET, and c-KIT and exhibited positive responses to the targeted treatment. Results : Our analysis revealed that FDG data derived from SUVmax, TLG, and MTV offered quantifiable outcomes that were consistent with the measurements of tumor size. Conclusions : These findings lend support to the notion that the inhibition of GLUT-1, as a consequence of treatment efficacy, could be indirectly gauged through [ 18 F] FDG-PET/CT imaging in cancer patients undergoing TKI therapy., Competing Interests: V.S. reports research funding for clinical trials paid to the institution from Abbvie, Agensys, Alfasigma, Altum, Amgen, Bayer, BERG Health, Blueprint Medicine, Boston Biomedical, Boston Pharmaceuticals, D3 Bio, Dragonfly Therapeutics, Exelixis, Fujifilm, GlaxoSmith-Kline, Idera Pharmaceuticals, Incyte, Inhibrix, Eli Lilly/Loxo Oncology, MedImmune, NanoCarrier, Novartis, PharmaMar, Pfizer, Relay Therapeutics, Roche/Genentech, Takeda, Turning Point Therapeutics, and Vegenics. Consulting/advisory role funding was paid to the institution from Abbvie, Astex Pharmaceuticals, AstraZeneca, Bayer, Genmab, Incyte, Lilly/Loxo Oncology, Novartis, Obsidian Therapeutics, Pfizer, Pheon Therapeutics, Regeneron, Relay Therapeutics, Roche, Endeavor Biomedicines, and RevMed. Other consulting/advisory roles/CME funds came from Helsinn Healthcare, Jazz Pharmaceuticals, Incyte, Loxo Oncology/Lilly, Novartis, Relay Therapeutics, Daiichi Sankyo, Illumina, Bayer, Medscape, OncLive, Clinical Care Communications, PERS, and the Med learning group. All other authors declare no conflicts of interest.

The process of dissociation for two hydrofluorocarbon molecules in low triplet states excited by electron impact in plasma is investigated by ab initio molecular dynamics (AIMD). The interest in the dissociation of hydrofluorocarbons in plasma is motivated by their role in plasma etching in microelectronic technologies. Dissociation of triplet states is very fast, and the reaction products can be predicted. In this work, it was found that higher triplet states relax into the lowest triplet state within a few femtoseconds due to nonadiabatic dynamics, such that the simplest ab initio MD on the lowest triplet state seems to give a reasonable estimate of the reaction channels branching ratios. We provide evidence of the existence of simple rules for the dissociation of hydrofluorocarbon molecules in triplet states. For molecules with a double bond, the bonds adjacent to the double bond dissociate faster than the other bonds.

Objectives: This study aimed to present the Asia-Pacific consensus on long-term and sequential therapy for osteoporosis, offering evidence-based recommendations for the effective management of this chronic condition. The primary focus is on achieving optimal fracture prevention through a comprehensive, individualized approach., Methods: A panel of experts convened to develop consensus statements by synthesizing the current literature and leveraging clinical expertise. The review encompassed long-term anti-osteoporosis medication goals, first-line treatments for individuals at very high fracture risk, and the strategic integration of anabolic and antiresorptive agents in sequential therapy approaches., Results: The panelists reached a consensus on 12 statements. Key recommendations included advocating for anabolic agents as the first-line treatment for individuals at very high fracture risk and transitioning to antiresorptive agents following the completion of anabolic therapy. Anabolic therapy remains an option for individuals experiencing new fractures or persistent high fracture risk despite antiresorptive treatment. In cases of inadequate response, the consensus recommended considering a switch to more potent medications. The consensus also addressed the management of medication-related complications, proposing alternatives instead of discontinuation of treatment., Conclusions: This consensus provides a comprehensive, cost-effective strategy for fracture prevention with an emphasis on shared decision-making and the incorporation of country-specific case management systems, such as fracture liaison services. It serves as a valuable guide for healthcare professionals in the Asia-Pacific region, contributing to the ongoing evolution of osteoporosis management., Competing Interests: The authors disclosed the following conflicts of interest.1.Ta-Wei Tai received honoraria for lectures, meetings, and/or travel from Amgen and Alvogen/Lotus.2.Swan Sim Yeap has received honoraria for lectures from Amgen.3.Natthinee Charatcharoenwitthaya received honoraria for lectures, meetings, and/or travel from Amgen, Alvogen, and Zuellig Pharma.4.Akira Taguchi has received lecture fees from Asahi Kasei Pharma Corp., Daiichi Sankyo Co. Ltd, Chugai Pharmaceutical Co. Ltd, and Teijin Pharma Ltd.5.Peter R Ebeling has received research funding from Amgen, Alexion and Sanofi, and honoraria from Amgen, Alexion and Kyowa Kirin.6.Fernando Marin has received honoraria for lectures from DKSH and Zuellig Pharma. He is a former employee of Eli Lilly and Company.7.Yoon-Sok Chung has received research funding from Samsung Bioepis and honoraria from Amgen, Alvogen, Celltrion, Daewoong, Hanlim, and Yuyu.8.Ian R Reid has received speaking fees from Amgen and Medison Pharma.9.Manju Chandran has received honoraria and travel sponsorships from Amgen, DKSH, and Kyowa Kirin.10.E. Michael Lewiecki - Amgen: investigator, consultant, speaker; Radius: investigator, consultant; Kyowa Kirin: consultant, speaker; Ultragenyx: investigator; Angitia: consultant; Ascendis: consultant.11.Fen Lee Hew has received honoraria from Amgen and DKSH.12.Tuan Van Nguyen has received a global competitive grant from Amgen and honoraria from Amgen, DKSH, and Bridge Health Care, for giving lectures and travelling to meetings.13.Chung-Hwan Chen received honoraria for lectures, attending meetings, and/or travel from Amgen, and Alvogen/Lotus.14.Chih-Hsing Wu received honoraria for lectures, attending meetings, and/or travel from Eli Lilly, Roche, Amgen, Merck, Servier laboratories, GE Lunar, Harvester, TCM Biotech, and Alvogen/Lotus.15.The other authors reported that they have nothing to declare for potential conflicts of interest., (© 2024 The Korean Society of Osteoporosis. Publishing services by Elsevier B.V.)

Background: The sleep and circadian rhythm patterns associated with smartphone use, which are influenced by mental activities, might be closely linked to sleep quality and depressive symptoms, similar to the conventional actigraphy-based assessments of physical activity., Objective: The primary objective of this study was to develop app-defined circadian rhythm and sleep indicators and compare them with actigraphy-derived measures. Additionally, we aimed to explore the clinical correlations of these indicators in individuals with insomnia and healthy controls., Methods: The mobile app "Rhythm" was developed to record smartphone use time stamps and calculate circadian rhythms in 33 patients with insomnia and 33 age- and gender-matched healthy controls, totaling 2097 person-days. Simultaneously, we used standard actigraphy to quantify participants' sleep-wake cycles. Sleep indicators included sleep onset, wake time (WT), wake after sleep onset (WASO), and the number of awakenings (NAWK). Circadian rhythm metrics quantified the relative amplitude, interdaily stability, and intradaily variability based on either smartphone use or physical activity data., Results: Comparisons between app-defined and actigraphy-defined sleep onsets, WTs, total sleep times, and NAWK did not reveal any significant differences (all P>.05). Both app-defined and actigraphy-defined sleep indicators successfully captured clinical features of insomnia, indicating prolonged WASO, increased NAWK, and delayed sleep onset and WT in patients with insomnia compared with healthy controls. The Pittsburgh Sleep Quality Index scores were positively correlated with WASO and NAWK, regardless of whether they were measured by the app or actigraphy. Depressive symptom scores were positively correlated with app-defined intradaily variability (β=9.786, SD 3.756; P=.01) and negatively correlated with actigraphy-based relative amplitude (β=-21.693, SD 8.214; P=.01), indicating disrupted circadian rhythmicity in individuals with depression. However, depressive symptom scores were negatively correlated with actigraphy-based intradaily variability (β=-7.877, SD 3.110; P=.01) and not significantly correlated with app-defined relative amplitude (β=-3.859, SD 12.352; P=.76)., Conclusions: This study highlights the potential of smartphone-derived sleep and circadian rhythms as digital biomarkers, complementing standard actigraphy indicators. Although significant correlations with clinical manifestations of insomnia were observed, limitations in the evidence and the need for further research on predictive utility should be considered. Nonetheless, smartphone data hold promise for enhancing sleep monitoring and mental health assessments in digital health research., (©Chen Lin, I-Ming Chen, Hai-Hua Chuang, Zih-Wen Wang, Hsiao-Han Lin, Yu-Hsuan Lin. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 15.12.2023.)

Introduction: Body status, categorized as sarcopenia or obesity and assessed using body mass index and body composition, affects the outcome of bladder cancer patients. However, studies comparing disease progression, recurrence, or overall survival in patients with non-muscle-invasive bladder cancer (NMIBC) with different body compositions are lacking. Therefore, we conducted a retrospective study to identify the impact of body composition, sarcopenia, and obesity on the oncological prognosis of patients with NMIBC who underwent transurethral resection of bladder tumor (TURBT) with Bacillus Calmette-Guerin (BCG) intravesical instillation (IVI)., Methods: Patients with NMIBC who had undergone TURBT with adjuvant IVI with BCG from March 2005 to April 2021 were included. Body composition parameters were evaluated using computed tomography images of the third lumbar vertebrae and further categorized by sarcopenia and obesity. Oncological outcomes including recurrence-free survival (RFS), progression-free survival, and overall survival (OS) after treatment were analyzed., Results: A total of 269 patients were enrolled. Subcutaneous adipose tissue (SAT) density was a significant predictor of RFS, whereas psoas muscle density was a significant predictor of OS in the multivariate analysis. Patients with sarcopenia but without obesity tolerated significantly fewer BCG IVIs than patients without sarcopenia or obesity. Patients with sarcopenia had poorer RFS and OS than those without sarcopenia. In contrast, patients with obesity had better OS than those without obesity., Discussion: Body composition parameters, including SAT density and psoas muscle density, emerged as significant predictors of OS and RFS, respectively. Hence, our findings indicate that body composition is a helpful measurement to assess the oncological outcomes of patients with NMIBC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Huang, Lin, Chuang, Chuang, Pang, Wu, Chang, Yu, Lin, Kan, Chu, Hung, Hsieh and Shao.)

Paraneoplastic nephrotic syndrome (PNS) is a complication seen in cancer patients. Ultrastructural examination shows the accumulation of proteins and the presence of foot process (FP) effacement in the glomeruli of PNS patients. Previously, we reported that orthotopic xenografts of Lewis lung carcinoma 1 in C57BL/6 mice caused them to develop lung cancer with albuminuria. This implies that these mice can be used as a model of human disease and suggests that Lewis lung carcinoma 1 cell-secreted proteins (LCSePs) contain nephrotoxic molecules and cause inflammation in renal cells. As podocyte effacement was present in glomeruli in this model, such podocyte injury may be attributable to either soluble LCSeP or LCSeP deposits triggering pathological progression. LCSePs in conditioned media was concentrated for nephrotoxicity testing. Integrin-focal adhesion kinase (FAK) signaling and inflammatory responses were evaluated in podocytes either exposed to soluble LCSePs or seeded onto substrates with immobilized LCSePs. FAK phosphorylation and interleukin-6 expression were higher in podocytes attached to LCSePs substrates than in those exposed to soluble LCSePs. Notably, LCSeP-based haptotaxis gave rise to altered signaling in podocytes. When podocytes were stimulated by immobilized LCSePs, FAK accumulated at focal adhesions, synaptopodin dissociated from F-actin, and disrupting the interactions between synaptopodin and α-actinin was observed. When FAK was inhibited by PF-573228 in immobilized LCSePs, the association between synaptopodin and α-actinin was observed in the podocytes. The association of synaptopodin and α-actinin with F-actin allowed FP stretching, establishing a functional glomerular filtration barrier. Therefore, in this mouse model of lung cancer, FAK signaling prompts podocyte FP effacement and proteinuria, indicative of PNS., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Dietary behavior is a main contributing yet modifiable factor to the body weight status of children and may be involved in the pathophysiology of childhood obstructive sleep apnea (OSA). This study aimed to investigate the dietary profile of pediatric OSA patients, effects of educational counseling after adenotonsillectomy, and predictor for disease resolution., Methods: This observational study included 50 pediatric OSA patients undergoing adenotonsillectomy with routine educational counseling (Group 1), 50 pediatric OSA patients undergoing adenotonsillectomy without formal educational counseling (Group 2), and 303 healthy children without OSA (Control). The three groups were matched by age. The consumption frequency of 25 food items/groups was assessed by the Short Food Frequency Questionnaire. Quality of life was evaluated by the OSA-18 questionnaire. Sleep architecture and OSA severity were measured by standard polysomnography. Between- and within-group comparisons were analyzed by non-parametric approaches and generalized estimating equations. Prediction of disease recovery was performed by multivariable logistic regression models., Results: Group 1 children consumed fruit drinks with sugar, vegetables, sweets, chocolate, rice, and noodles more frequently than Control Group children. At baseline, the distributions of sex, weight status, OSA-18 scores, and polysomnographic variables were comparable between Group 1 and Group 2. After a 12-month follow-up, Group 1 had better improvements in physical suffering, caregiver concerns, sleep architecture, and mean peripheral oxygen saturation compared to Group 2. Furthermore, Group 1 no longer had excessive consumption of fruit drinks with sugar, chocolate, and noodles; however, food consumption frequencies did not change significantly. Notably, younger age and reduced intake of butter/margarine on bread and noodles were independent predictors of cured OSA in Group 1., Conclusion: The present study preliminarily characterized an unhealthy dietary profile among pediatric OSA patients and suggested that routine educational counseling in addition to adenotonsillectomy yielded some clinical benefits. Certain items/groups of food frequencies may be associated with disease recovery and further investigations are warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chuang, Lin, Hsu, Chuang, Li, Fang, Huang, Yang, Lee, Kuo, Yang and Lee.)

Background: Adenotonsillar hypertrophy is the most common cause of pediatric obstructive sleep apnea (OSA). Although adenotonsillectomy considerably reduces OSA and systemic inflammation, whether and how systemic inflammation influences the effects of adenotonsillectomy on OSA has yet to be determined., Methods: This study investigated the associations between changes in anatomical variables, % changes in subjective OSA-18 questionnaire scores, % changes in 11 polysomnographic parameters, and % changes in 27 systemic inflammatory biomarkers in 74 children with OSA., Results: Fifty-six (75.6%) boys and 18 (24.4%) girls with the mean age of 7.4 ± 2.2 years and apnea-hypopnea index (AHI) of 14.2 ± 15.9 events/h were included in the statistical analysis. The mean period between before and after adenotonsillectomy was 5.6 ± 2.6 months. After adenotonsillectomy, the OSA-18 score, eight of 11 polysomnographic parameters, and 20 of 27 inflammatory biomarkers significantly improved (all p < 0.005). Notably, there were significant associations between change in tonsil size and % change in AHI ( r = 0.23), change in tonsil size and % changes in interleukin-8 (IL-8) ( r = 0.34), change in tonsil size and % change in and IL-10 ( r = -0.36), % change in IL-8 and % change in C-C chemokine ligand 5 (CCL5) ( r = 0.30), and % change in CCL5 and % change in AHI ( r = 0.38) (all p < 0.005). Interestingly, % change in IL-8 and % change in CCL5 serially mediated the relationship between change in tonsil size and % change in AHI (total effect: β = 16.672, standard error = 8.274, p = 0.048)., Conclusion: These preliminary findings suggest that systemic inflammation is not only a complication of OSA but also that it mediates the surgical effects, which may open avenues for potential interventions to reduce tonsil size and OSA severity through the regulation of IL-8 and CCL5., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2023, the Chinese Medical Association.)

Objective: To investigate the risk factors of postoperative elevated blood pressure (BP) in children with childhood obstructive sleep apnea syndrome (OSAS) after adenotonsillectomy (AT)., Study Design: Case series with planned data collection., Setting: Tertiary referral center., Methods: Two hundred forty-five consecutive children (180 boys and 65 girls, median age 6.6 years) with polysomnography-diagnosed OSAS who underwent AT between January 2010 and August 2019. Clinical, polysomnographic, and evening BP data were assessed preoperatively and postoperatively (≥3 months after AT). Changes in the variables before and after AT and between individuals with and without hypertension were compared., Results: Postoperatively, the median (interquartile range) apnea-hypopnea index significantly decreased from 10.4 (5.3-22.6) to 2.2 (1.0-3.8) events/h. In addition, the mean (standard deviation) evening diastolic BP z-score significantly decreased from 0.7 (0.94) to 0.5 (0.81) in the overall cohort, and both systolic (2.1 [0.94]-1.0 [1.31]) and diastolic BP z-scores (1.6 [0.98]-0.7 [0.85]) significantly decreased in the preoperative elevated BP subgroup. Multivariate logistic regression analysis showed that preoperative obesity (adjusted odds ratio = 4.36, 95% confidence interval = 2.24-8.49) and mean peripheral oxygen saturation <95% during sleep (adjusted odds ratio = 2.73, 95% confidence interval = 1.29-5.79) were independently associated with postoperative elevated BP., Conclusion: Preoperative obesity and mean peripheral oxygen saturation <95% during sleep were significantly associated with postoperative elevated BP in the children with OSAS, further indicating the importance of careful BP monitoring in this subgroup despite AT treatment., (© 2023 American Association of Otolaryngology-Head and Neck Surgery Foundation.)

Background: Pediatric hypertension contributes to adulthood hypertension and target organ damage. Obesity is a well-known predictor for pediatric hypertension; however, the relationship between physical fitness and blood pressure (BP) is unclear among children. This study aimed to compare the differences in demographics, anthropometrics, and physical fitness across BP subgroups and investigate whether physical fitness was related to pediatric hypertension independent of weight status., Methods: This quantitative, cross-sectional study investigated demographic, anthropometric, physical fitness, and BP measures among 360 healthy school-aged children. Continuous variables were compared across BP subgroups with the one-way analysis of variance. Mediation and moderation analyses were used to explore the mechanism. Multivariable regression models were used to assess independent associations for hypertension., Results: There were 177 (49.2%), 37 (10.3%), and 146 (40.6%) children in the normotensive, elevated BP, and hypertensive subgroups, respectively. The hypertensive subgroup had higher body mass index (BMI) and waist/height ratio percentiles and performed worse in 800-m run, standing long jump (SLJ), and 1-min sit-ups than the normotensive subgroup. Furthermore, the 800-m run percentile (total effect: β = 0.308, standard error = 0.044, p < 0.001) and sit and reach percentile (total effect: β = 0.308, standard error = 0.044, p < 0.001) mediated the relationship between the BMI percentile and systolic BP percentile; the SLJ percentile was directly associated with the diastolic BP percentile (β,-0.197, 95% confidence interval,-0.298-0.097; p < 0.001). The parsimonious model of multivariable regression models revealed that the SLJ percentile (adjusted exp (β), 0.992, 95% confidence interval, 0.985-0.999; p = 0.042) and BMI percentile (adjusted exp (β), 1.024, 95% confidence interval, 1.016-1.032; p < 0.001) were two independent predictors for pediatric hypertension., Conclusion: Physical fitness mediates the relationship between anthropometric and BP measures. The SLJ percentile is associated with pediatric hypertension independent of the BMI percentile. Proactive screening and health promotion for not only healthy weight status but also good physical fitness may be beneficial for BP control among school-aged students., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chuang, Cherng, Lin, Lee, Hsu and Lin.)

Background: Obstructive sleep apnea (OSA) is associated with impaired sleep quality and autonomic dysfunction. Adenotonsillectomy significantly improves subjective and objective sleep quality in children with OSA. However, the postoperative changes in heart rate variability (HRV) indices (indicators of cardiac autonomic function) and their importance remain inconclusive in childhood OSA. This retrospective case series aimed to investigate the association of sleep HRV indices, total OSA-18 questionnaire score (a subjective indicator of sleep quality) and polysomnographic parameters (objective indicators of sleep quality), and effects of adenotonsillectomy on HRV indices, total OSA-18 questionnaire score and polysomnographic parameters in children with OSA., Methods: Seventy-six children with OSA were included in baseline analysis, of whom 64 (84%) completed at least 3 months follow-up examinations after adenotonsillectomy and were included in outcome analysis. Associations between baseline variables, and relationships with treatment-related changes were examined., Results: Multivariable linear regression models in the baseline analysis revealed independent relationships between tonsil size and obstructive apnea-hypopnea index (OAHI), adenoidal-nasopharyngeal ratio and very low frequency (VLF) power of HRV (an indicator of sympathetic activity), and normalized low frequency power (an indicator of sympathetic activity) and OAHI. The outcome analysis showed that adenotonsillectomy significantly improved standard deviation of all normal-to-normal intervals, and high frequency power, QoL (in terms of reduced total OSA-18 questionnaire score), OAHI and hypoxemia. Using a conceptual serial multiple mediation model, % change in OSA-18 questionnaire score and % change in VLF power serially mediated the relationships between change in tonsil size and % change in OAHI., Conclusions: The improvement in OAHI after adenotonsillectomy was serially mediated by reductions in total OSA-18 questionnaire score and VLF power. These preliminary findings are novel and provide a direction for future research to investigate the effects of VLF power-guided interventions on childhood OSA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lee, Chuang, Hsieh, Wang, Chuang, Li, Fang, Huang, Lee, Yang, Kuo and Yang.)

Before caring for patients, video instruction is commonly used for undergraduate medical students, and 360° virtual reality (VR) videos have gained increasing interest in clinical medical education. Therefore, the effect of immersive 360° VR video learning compared with two-dimensional (2D) VR video learning in clinical skills acquisition should be evaluated. This randomized, intervention-controlled clinical trial was aimed to assess whether immersive 360° VR video improves undergraduate medical students' learning effectiveness and reduces the cognitive load in history taking and physical examination (H&P) training. From May 1 2018 to October 30 2018, 64 senior undergraduate medical students in a tertiary academic hospital were randomized to receive a 10-min immersive 360° (360° VR video group; n  = 32) or 2D VR instructional video (2D VR video group; n  = 32), including essential knowledge and competency of H&P. The demographic characteristics of the two groups were comparable for age, sex, and cognitive style. The total procedure skill score, physical examination score, learner's satisfaction score, and total cognitive load in the 360° VR video group were significantly higher than those in the 2D VR video group (effect sizes [95% confidence interval]: 0.72 [0.21-1.22], 0.63 [0.12-1.13], 0.56 [0.06-1.06], and 0.53 [0.03-1.03], respectively). This study suggested that a10-minute 360° VR video instruction helped undergraduate medical students perform fundamental H&P skills as effectively as 2D VR video. Furthermore, the 360° VR video might result in significantly better procedural metrics of physical examinations with higher learner satisfaction despite the higher cognitive load., Supplementary Information: The online version contains supplementary material available at 10.1007/s10055-022-00664-0., Competing Interests: Conflict of interestThe authors have no conflicts of interest to declare., (© The Author(s) 2022.)

This prospective study investigated how exercise impacted chronological changes in anthropometrics, body composition, prostate-specific antigen (PSA) level and prognostic nutrition index (PNI) in high-risk prostate cancer (PCa) patients on androgen deprivation therapy (ADT). The patients were divided into either the usual care or exercise group. All patients received measurements a week before ADT initiation, six- and twelve months after treatment. The exercise group received both aerobic and resistance training. The analysis was conducted using appropriate statistical methods. There were 45 males enrolled (age 67.4 ± 8 years and BMI 25.5 ± 3.6 kg/m 2 ). Profound changes were observed at six months follow-up. The exercise group showed a significant increase in the trunk and leg lean mass, and a lesser loss of total and arm lean mass. A significant decrease in PSA was also observed among the exercise group. PNI and PSA were significantly associated with regional lean mass. Exercise can prevent loss or even increase lean mass in high-risk PCa, especially in the early stage of ADT treatment. Moreover, a strong bond between lean mass and PNI and PSA further underscores the importance of early and continuous exercise interventions.

Virtual reality (VR) applications could be beneficial for education, training, and treatment. However, VR may induce symptoms of simulator sickness (SS) such as difficulty focusing, difficulty concentrating, or dizziness that could impair autonomic nervous system function, affect mental workload, and worsen interventional outcomes. In the original randomized controlled trial, which explored the effectiveness of using a 360° VR video versus a two-dimensional VR video to learn history taking and physical examination skills, only the former group participants had SS. Therefore, 28 undergraduate medical students who participated in a 360° VR learning module were included in this post hoc study using a repeated measures design. Data of the Simulator Sickness Questionnaire (SSQ), heart rate variability (HRV) analysis, Task Load Index, and Mini-Clinical Evaluation Exercise were retrospectively reviewed and statistically analyzed. Ten (36%) participants had mild SS (total score > 0 and ≤ 20), and 18 (64%) had no SS symptom. Total SSQ score was positively related to the very low frequency (VLF) band power, physical demand subscale, and frustration subscale, and inversely related to physical examination score. Using multilevel modeling, the VLF power mediated the relationship between total SSQ score and physical examination score. Furthermore, frustration subscale moderated the mediating effects of the VLF power. Our results highlight the importance of documenting SS to evaluate a 360° VR training program. Furthermore, the combination of HRV analysis with mental workload measurement and outcome assessments provided the important clinical value in evaluating the effects of SS in VR applications in medical education., Competing Interests: Conflict of interestThe authors have no conflicts of interest to declare., (© The Author(s) 2022.)

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase overexpressed in various cancer types that plays a critical role in tumor progression. Accumulating evidence suggests that targeting FAK, either alone or in combination with other agents, may serve as an effective therapeutic strategy for numerous cancers. In addition to retarding proliferation, metastasis, and angiogenesis, FAK inhibition triggers cellular senescence in lung cancer cells. However, the detailed mechanism remains enigmatic. In the present study, we found that FAK inhibition not only elicits DNA-damage signaling but also downregulates enhancer of zeste homolog 2 (EZH2) expression. The manipulation of FAK expression influences EZH2 expression and corresponding signaling in vitro. Immunohistochemistry shows that active FAK signaling corresponds with the activation of the EZH2-mediated signaling cascade in lung-cancer-cells-derived tumor tissues. We also found that ectopic EZH2 expression attenuates FAK-inhibition-induced cellular senescence in lung cancer cells. Our results identify EZH2 as a critical downstream effector of the FAK-mediated anti-senescence pathway. Targeting FAK-EZH2 axis-induced cellular senescence may represent a promising therapeutic strategy for restraining tumor growth.

Background: Workplace health promotion (WHP) in the healthcare industry is an important yet challenging issue to address, given the high workload, heterogeneity of work activities, and long work hours of healthcare workers (HCWs). This study aimed to investigate the effectiveness and response differences of a multidisciplinary WHP program conducted in HCWs., Methods: This retrospective cohort study included HCWs participating in a multidisciplinary WHP program in five healthcare facilities. The 20-week intervention included multiple easy-to-access 90-min exercise classes, one 15-min nutrition consultation, and behavioral education. Pre- and post-interventional anthropometrics, body composition, and physical fitness (PF) were compared with paired sample t -tests. Response differences across sex, age, weight status, and shiftwork status were analyzed with a generalized estimating equation., Results: A total of 302 HCWs were analyzed. The intervention effectively improved all anthropometric (body mass index, waist circumference, waist-hip ratio, and waist-to-height ratio), body composition (body fat percentage, muscle weight, visceral fat area), and PF (grip strength, high jump, sit-up, sit-and-reach, step test) parameters in all participants (all p < 0.05). Subgroup analyses revealed shift workers had a more significant mean reduction in body mass index than non-shift workers (adjusted p = 0.045). However, there was no significant response difference across sex, age, and weight subgroups., Conclusion: This study suggested that a multidisciplinary WHP program can improve anthropometric and PF profiles regardless of sex, age, and weight status for HCWs, and shifter workers might benefit more from the intervention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cheng, Wu, Chen, Hsu, Lin, Luo, Lee and Chuang.)

As internationalization of higher education has become more prevalent, the search for approaches to support quality learning within multicultural classrooms has become critical. In this study, we presented a blended and collaborative learning (BCL) method and discussed its potential as a viable learning approach for graduate classrooms with culturally-diverse students. We first discussed implementation of a BCL approach in a multicultural graduate course, then explored learnings gained from the BCL experience in terms of three interdependent Community of Inquiry elements: teaching, cognitive, and social presences, and in terms of its implementation in a multicultural setting., Competing Interests: The authors have declared that no competing interests exist.

Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, is overexpressed and activated in many cancer types. FAK regulates diverse cellular processes, including growth factor signaling, cell cycle progression, cell survival, cell motility, angiogenesis, and the establishment of immunosuppressive tumor microenvironments through kinase-dependent and kinase-independent scaffolding functions in the cytoplasm and nucleus. Mounting evidence has indicated that targeting FAK, either alone or in combination with other agents, may represent a promising therapeutic strategy for various cancers. In this review, we summarize the mechanisms underlying FAK-mediated signaling networks during tumor development. We also summarize the recent progress of FAK-targeted small-molecule compounds for anticancer activity from preclinical and clinical evidence.

Many patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) will not respond to platinum-containing salvage chemotherapy. Predicting treatment failure earlier could help clinicians minimize chemotherapy toxicities for non-responders in favor of other treatments. We conducted a pilot study where 2 early PET/CTs were obtained on days 4 (D4) and 21 (D21) of cycle 1 (C1) of salvage therapy for DLBCL. Twenty-five patients were enrolled and have evaluable data. Ten (40%) had an unplanned therapy change after C1 and before end-of-treatment (EOT) evaluation due to treatment failure on early PET/CT as interpreted by the treating physician. Early PET/CT response at D4 or D21 was not associated with EOT response in evaluable patients. Disease specific survival was longer for patients with a persistent response on both D4 and D21 ( p  = 0.042). Early PET/CT may predict salvage chemotherapy failure and could inform future clinical trials investigating early therapy change to non-chemotherapy treatments.

Background: The overlapping clinical presentations of limb-girdle muscular dystrophy (LGMD) and idiopathic inflammatory myopathy (IIM) make clinical diagnosis challenging. This study provides a comprehensive evaluation of the distributions and characteristics of muscle fat substitution and edema and aims to differentiate those two diseases. Methods: This retrospective study reviewed magnetic resonance imaging (MRI) of seventeen patients with pathologically proved diagnosis, comprising 11 with LGMD and 6 with IIM. The fat-only and water-only images from a Dixon sequence were used to evaluate muscle fat substitution and edema, respectively. The degrees of muscle fat substitution and edema were graded and compared using the appropriate statistical methods. Results: In LGMD, more than 50% of patients had high-grade fat substitution in the majority of muscle groups in the thigh and calf. However, <50% of IIM patients had high-grade fat substitution in all muscle groups. Moreover, LGMD patients had significantly higher grade fat substitution than IIM patients in all large muscle groups ( p < 0.05). However, there was no significant difference in edema in the majority of muscle groups, except the adductor magnus ( p = 0.012) and soleus ( p = 0.009) with higher grade edema in IIM. Additionally, all the adductor magnus muscles in LGMD (100%) showed high-grade fat substitution, but none of them showed high-grade edema. Conclusions: MRI could be a valuable tool to differentiate LGMD from IIM based on the discrepancy in muscle fat substitution, and the adductor magnus muscle could provide a biosignature to categorizing LGMD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hsu, Lin, Chuang, Yeh, Chan and Ro.)

Parkinson's disease (PD), or paralysis agitans, is a common neurodegenerative disease characterized by dopaminergic deprivation in the basal ganglia because of neuronal loss in the substantia nigra pars compacta. Clinically, PD apparently involves both hypokinetic (e.g. akinetic rigidity) and hyperkinetic (e.g. tremor/propulsion) symptoms. The symptomatic pathogenesis, however, has remained elusive. The recent success of deep brain stimulation (DBS) therapy applied to the subthalamic nucleus (STN) or the globus pallidus pars internus indicates that there are essential electrophysiological abnormalities in PD. Consistently, dopamine-deprived STN shows excessive burst discharges. This proves to be a central pathophysiological element causally linked to the locomotor deficits in PD, as maneuvers (such as DBS of different polarities) decreasing and increasing STN burst discharges would decrease and increase the locomotor deficits, respectively. STN bursts are not so autonomous but show a "relay" feature, requiring glutamatergic synaptic inputs from the motor cortex (MC) to develop. In PD, there is an increase in overall MC activities and the corticosubthalamic input is enhanced and contributory to excessive burst discharges in STN. The increase in MC activities may be relevant to the enhanced beta power in local field potentials (LFP) as well as the deranged motor programming at the cortical level in PD. Moreover, MC could not only drive erroneous STN bursts, but also be driven by STN discharges at specific LFP frequencies (~ 4 to 6 Hz) to produce coherent tremulous muscle contractions. In essence, PD may be viewed as a disorder with deranged rhythms in the cortico-subcortical re-entrant loops, manifestly including STN, the major component of the oscillating core, and MC, the origin of the final common descending motor pathways. The configurations of the deranged rhythms may play a determinant role in the symptomatic pathogenesis of PD, and provide insight into the mechanism underlying normal motor control. Therapeutic brain stimulation for PD and relevant disorders should be adaptively exercised with in-depth pathophysiological considerations for each individual patient, and aim at a final normalization of cortical discharge patterns for the best ameliorating effect on the locomotor and even non-motor symptoms., (© 2021. The Author(s).)

Background: Learning through a 360° virtual reality (VR) or 2D video represents an alternative way to learn a complex medical education task. However, there is currently no consensus on how best to assess the effects of different learning materials on cognitive load estimates, heart rate variability (HRV), outcomes, and experience in learning history taking and physical examination (H&P) skills., Objective: The aim of this study was to investigate how learning materials (ie, VR or 2D video) impact learning outcomes and experience through changes in cognitive load estimates and HRV for learning H&P skills., Methods: This pilot system-design study included 32 undergraduate medical students at an academic teaching hospital. The students were randomly assigned, with a 1:1 allocation, to a 360° VR video group or a 2D video group, matched by age, sex, and cognitive style. The contents of both videos were different with regard to visual angle and self-determination. Learning outcomes were evaluated using the Milestone reporting form. Subjective and objective cognitive loads were estimated using the Paas Cognitive Load Scale, the National Aeronautics and Space Administration Task Load Index, and secondary-task reaction time. Cardiac autonomic function was assessed using HRV measurements. Learning experience was assessed using the AttrakDiff2 questionnaire and qualitative feedback. Statistical significance was accepted at a two-sided P value of <.01., Results: All 32 participants received the intended intervention. The sample consisted of 20 (63%) males and 12 (38%) females, with a median age of 24 (IQR 23-25) years. The 360° VR video group seemed to have a higher Milestone level than the 2D video group (P=.04). The reaction time at the 10th minute in the 360° VR video group was significantly higher than that in the 2D video group (P<.001). Multiple logistic regression models of the overall cohort showed that the 360° VR video module was independently and positively associated with a reaction time at the 10th minute of ≥3.6 seconds (exp B=18.8, 95% CI 3.2-110.8; P=.001) and a Milestone level of ≥3 (exp B=15.0, 95% CI 2.3-99.6; P=.005). However, a reaction time at the 10th minute of ≥3.6 seconds was not related to a Milestone level of ≥3. A low-frequency to high-frequency ratio between the 5th and 10th minute of ≥1.43 seemed to be inversely associated with a hedonic stimulation score of ≥2.0 (exp B=0.14, 95% CI 0.03-0.68; P=.015) after adjusting for video module. The main qualitative feedback indicated that the 360° VR video module was fun but caused mild dizziness, whereas the 2D video module was easy to follow but tedious., Conclusions: Our preliminary results showed that 360° VR video learning may be associated with a better Milestone level than 2D video learning, and that this did not seem to be related to cognitive load estimates or HRV indexes in the novice learners. Of note, an increase in sympathovagal balance may have been associated with a lower hedonic stimulation score, which may have met the learners' needs and prompted learning through the different video modules., Trial Registration: ClinicalTrials.gov NCT03501641; https://clinicaltrials.gov/ct2/show/NCT03501641., (©Yi-Ping Chao, Hai-Hua Chuang, Li-Jen Hsin, Chung-Jan Kang, Tuan-Jen Fang, Hsueh-Yu Li, Chung-Guei Huang, Terry B J Kuo, Cheryl C H Yang, Hsin-Yih Shyu, Shu-Ling Wang, Liang-Yu Shyu, Li-Ang Lee. Originally published in JMIR Serious Games (https://games.jmir.org), 22.11.2021.)

Lung cancer is one of the most common cancers and the leading cause of death in humans worldwide. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases and is often diagnosed at a late stage. Among patients with NSCLC, 50% die within 1 year after diagnosis. Even with clinical intervention, the 5-year survival rate is only approximately 20%. Therefore, the development of an advanced therapeutic strategy or novel agent is urgently required for treating NSCLC. Berberine exerts therapeutic activity toward NSCLC; therefore, its activity as an antitumor agent needs to be explored further. In this study, three terpenylated-bromide derivatives of berberrubine were synthesized and their anti-NSCLC activities were evaluated. Each derivative had higher anti-NSCLCs activity than berberrubine and berberine. Among them, 9-O-gernylberberrubine bromide (B4) and 9-O-farnesylberberrubine bromide (B5) showed greater growth inhibition, cell-cycle regulation, in vitro tumorigenesis suppression, and tumor migration reduction. In addition, some degree of apoptosis and autophagic flux blocking was noted in the cells under B4 and B5 treatments. Our study demonstrates that the berberrubine derivatives, B4 and B5, exhibit impressive anti-NSCLC activities and have potential for use as chemotherapeutic agents against NSCLC.

Older age, obesity, and obstructive sleep apnea syndrome (OSAS) are known to increase the risk of hypertension in adults. However, data for children are scarce. This study aimed to investigate the relationships between hypertension, age, weight status, and disease severity in 396 children with OSAS. The prevalence rates of hypertension, obesity, and severe OSAS (apnea-hypopnea index ≥10) were 27.0%, 28.0%, and 42.9%, respectively. Weight z-score and apnea-hypopnea index were independently correlated with systolic blood pressure z-score, and minimal blood oxygen saturation (SpO 2 ) was independently associated with diastolic blood pressure z-score. Overall, late childhood/adolescence (odds ratio (OR) = 1.72, 95% CI = 1.05-2.81), obesity (OR, 2.58, 95% CI = 1.58-4.22), and severe OSAS (OR = 2.38, 95% CI = 1.48-3.81) were independent predictors of pediatric hypertension. Furthermore, late childhood/adolescence (OR = 2.50, 95% CI = 1.10-5.71) and abnormal SpO 2 (mean SpO 2 < 95%; OR = 4.91, 95% CI = 1.81-13.27) independently predicted hypertension in obese children, and severe OSAS (OR = 2.28, 95% CI = 1.27-4.10) independently predicted hypertension in non-obese children. In conclusion, obesity, OSAS severity, and abnormal SpO 2 are potentially modifiable targets to improve hypertension while treating children with OSAS.

Efficient screening for severe obstructive sleep apnea (OSA) is important for children with snoring before time-consuming standard polysomnography. This retrospective cross-sectional study aimed to compare clinical variables, home snoring sound analysis, and home sleep pulse oximetry on their predictive performance in screening severe OSA among children who habitually snored. Study 1 included 9 (23%) girls and 30 (77%) boys (median age of 9 years). Using univariate logistic regression models, 3% oxygen desaturation index (ODI3) ≥ 6.0 events/h, adenoidal-nasopharyngeal ratio (ANR) ≥ 0.78, tonsil size = 4, and snoring sound energy of 801-1000 Hz ≥ 22.0 dB significantly predicted severe OSA in descending order of odds ratio. Multivariate analysis showed that ODI3 ≥ 6.0 events/h independently predicted severe pediatric OSA. Among several predictive models, the combination of ODI3, tonsil size, and ANR more optimally screened for severe OSA with a sensitivity of 91% and a specificity of 94%. In Study 2 (27 (27%) girls and 73 (73%) boys; median age, 7 years), this model was externally validated to predict severe OSA with an accuracy of 76%. Our results suggested that home sleep pulse oximetry, combined with ANR, can screen for severe OSA more optimally than ANR and tonsil size among children with snoring.

Physical fitness (PF) is closely related to various health outcomes and quality of life among children. However, the associations between anthropometry, body composition (BC), and PF are not fully elucidated. This cross-sectional study aimed to investigate the associations between demographic metrics (age, sex), anthropometric measures (body mass index z-score (BMI z-score) waist/height ratio (WHtR)), BC parameters (body-fat percentage (BF%), muscle weight), and PF levels (800-m run, sit-and-reach, 1-min sit-ups, standing long jump) in school-aged children. Continuous variables were dichotomized by median splits. The results of 180 girls and 180 boys (mean age: 10.0 ± 0.7 years; mean BMI z-score: 0.366 ± 1.216) were analyzed. Multivariable linear regressions revealed that BF% (regression coefficient (B) = 3.4, 95% confidence interval (CI) = 2.5-4.3) was independently correlated with the 800-m run. Sex (B = 4.6, 95% CI = 3.0-6.3), age (B = 3.1, 95% CI = 1.9-4.3), and BMI z-score (B = -0.7, 95% CI = -1.4--0.1) were independently related to sit-and-reach. Age (B = 3.3, 95% CI = 2.0-4.7), BF% (B = -0.3, 95% CI = -0.4--0.2), and muscle weight (B = 0.7, 95% CI = 0.2-1.2) were independently associated with 1-min sit-ups. In addition to demography, anthropometry and BC provided additional information concerning some PF levels in school-aged children. Weight management and PF promotion should be addressed simultaneously in terms of preventive medicine and health promotion for children.

The tonsil microbiome is associated with chronic tonsillitis and obstructive sleep apnea (OSA) in children, and the gut microbiome is associated with host weight status. In this study, we hypothesized that weight status may be associated with clinical profiles and the tonsil microbiome in children with OSA. We prospectively enrolled 33 non-healthy-weight (cases) and 33 healthy-weight (controls) pediatric OSA patients matched by the proportion of chronic tonsillitis. Differences in the tonsil microbiome between the non-healthy-weight and healthy-weight subgroups and relationships between the tonsil microbiome and clinical variables were investigated. Non-healthy weight was associated with significant intermittent hypoxemia (oxygen desaturation index, mean blood saturation (SpO 2 ), and minimal SpO 2 ) and higher systolic blood pressure percentile, but was not related to the tonsil microbiome. However, chronic tonsillitis was related to Acidobacteria in the non-healthy-weight subgroup, and oxygen desaturation index was associated with Bacteroidetes in the healthy-weight subgroup. In post hoc analysis, the children with mean SpO 2 ≤ 97% had reduced α and β diversities and a higher abundance of Bacteroidetes than those with mean SpO 2 > 97%. These preliminary findings are novel and provide insights into future research to understand the pathogenesis of the disease and develop personalized treatments for pediatric OSA.

Helicobacter pylori ( H. pylori ) infection involves the development of gastric cancer and may be associated with laryngeal cancer. However, laryngeal H. pylori infection in Taiwanese patients with newly diagnosed laryngeal cancer has not been reported. This study was aimed to investigate the possible association between laryngeal H. pylori infection and laryngeal cancer in Taiwan and perform a systematic review of previous reports in other countries. An analysis of 105 patients with laryngeal lesions found the positive rates of H. pylori DNA (determined by polymerase chain reaction) and antigen (determined by immunohistochemistry) of the laryngeal lesions were relatively low (vocal polyps: 3% and 3%; vocal fold leukoplakia: 0% and 0%; laryngeal cancers: 0% and 2%). Furthermore, H. pylori -associated laryngopharyngeal reflux and the expression of E-cadherin and CD1d (determined by immunohistochemistry) were comparable among the three subgroups. Fifteen studies were involved in the systematic review of the digital literature database, distributed to February 2021. The data of patients with laryngeal cancer and controls showed that the laryngeal H. pylori infection rates were 29.4% and 16.7%, respectively. Although current evidence supported that laryngeal H. pylori infection was associated with laryngeal cancer globally, it might not play a role in the development of laryngeal cancer in Taiwan.

Background: Coronavirus disease 2019 (COVID-19) has no confirmed specific treatments. However, there might be in vitro and early clinical data as well as evidence from severe acute respiratory syndrome and Middle Eastern respiratory syndrome that could inform clinicians and researchers. This systematic review aims to create priorities for future research of drugs repurposed for COVID-19., Methods: This systematic review will include in vitro, animal, and clinical studies evaluating the efficacy of a list of 34 specific compounds and 4 groups of drugs identified in a previous scoping review. Studies will be identified both from traditional literature databases and pre-print servers. Outcomes assessed will include time to clinical improvement, time to viral clearance, mortality, length of hospital stay, and proportions transferred to the intensive care unit and intubated, respectively. We will use the GRADE methodology to assess the quality of the evidence., Discussion: The challenge posed by COVID-19 requires not just a rapid review of drugs that can be repurposed but also a sustained effort to integrate new evidence into a living systematic review., Trial Registration: PROSPERO 2020 CRD42020175648.

Parkinson's disease is characterized by both hypokinetic and hyperkinetic symptoms. While increased subthalamic burst discharges have a direct causal relationship with the hypokinetic manifestations (e.g., rigidity and bradykinesia), the origin of the hyperkinetic symptoms (e.g., resting tremor and propulsive gait) has remained obscure. Neuronal burst discharges are presumed to be autonomous or less responsive to synaptic input, thereby interrupting the information flow. We, however, demonstrate that subthalamic burst discharges are dependent on cortical glutamatergic synaptic input, which is enhanced by A-type K + channel inhibition. Excessive top-down-triggered subthalamic burst discharges then drive highly correlative activities bottom-up in the motor cortices and skeletal muscles. This leads to hyperkinetic behaviors such as tremors, which are effectively ameliorated by inhibition of cortico-subthalamic AMPAergic synaptic transmission. We conclude that subthalamic burst discharges play an imperative role in cortico-subcortical information relay, and they critically contribute to the pathogenesis of both hypokinetic and hyperkinetic parkinsonian symptoms., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Mounting molecular evidence supports Epstein-Barr virus (EBV) involvement in the pathogenesis of laryngeal squamous cell carcinoma (LSCC); however, the epidemiological data are inconsistent. In this retrospective case-control study, we aimed to determine whether EBV infection underlies the risk and prognosis of LSCC. The prevalence of EBV infection, as analyzed using an EBV DNA polymerase chain reaction assay, was significantly higher in 42 Taiwanese patients with newly diagnosed primary LSCC, compared to 39 age- and sex-matched control patients without cancer (48% vs. 19%). Furthermore, most of the EBER signals detected using in situ hybridization were localized to the nuclei of tumor-infiltrating lymphocytes. In multivariate analysis, EBV DNA positivity, age ≥ 55 years, cigarette smoking, and high BCL-2 , B2M , and CD161 expression (assessed using immunohistochemistry) were identified as independent risk factors for LSCC. Furthermore, five-year local recurrence and disease-free survival rates were 34% and 58%, respectively, with a high EBER signal and low CD3 expression independently predicting five-year local recurrence and disease-free survival. Our comprehensive profiling data accurately identified patients at risk for LSCC development, local recurrence, or disease-free survival. The information obtained in this study improves our understanding of EBV infection in LSCC, and may guide precision medicine for patients with LSCC.

The mechanisms by which tumors metastasize to bone are complex. Upon the successful establishment of metastatic deposits in the skeleton, detection of the disease becomes essential for therapeutic planning. The roles of CT, skeletal scintigraphy, SPECT/CT, MRI, PET/CT and PET/MRI will be reviewed. Therapeutic response criteria specifically designed to evaluate bone metastases (MD Anderson/MDA criteria) can guide image interpretation. Knowledge of therapeutic strategies such as systemic therapy with bisphosphonates or radiopharmaceuticals, radiation therapy, surgery, and percutaneous interventions such as vertebroplasty and radiofrequency ablation can help the radiologist produce reports that will provide maximum benefit to clinicians and patients., (Published by Elsevier Inc.)

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) specifically binds and isomerizes the phosphorylated serine/threonine-proline (pSer/Thr-Pro) motif, which leads to changes in protein conformation and function. Pin1 is widely overexpressed in cancers and plays an important role in tumorigenesis. Mounting evidence has revealed that targeting Pin1 is a potential therapeutic approach for various cancers by inhibiting cell proliferation, reducing metastasis, and maintaining genome stability. In this review, we summarize the underlying mechanisms of Pin1-mediated upregulation of oncogenes and downregulation of tumor suppressors in cancer development. Furthermore, we also discuss the multiple roles of Pin1 in cancer hallmarks and examine Pin1 as a desirable pharmaceutical target for cancer therapy. We also summarize the recent progress of Pin1-targeted small-molecule compounds for anticancer activity.

The majority of patients with classical Hodgkin lymphoma (cHL) may be cured, but for patients with relapsed or refractory (R/R) cHL, the prognosis is unfavorable. Immune dysfunction is a significant contributor of relapse and a hallmark of cHL; in particular, the immune system is unable to eradicate lymphoma cells that overexpress immune checkpoint proteins. The blocking of this mechanism used by lymphoma cells to evade the immune system has resulted in clinical benefits. Use of checkpoint inhibitors (CPIs) in R/R cHL is associated with high response rates and an acceptable adverse effects profile. There is growing interest in combining chemotherapy with CPIs in frontline therapy of cHL treatment to improve relapse rates without significant additive toxicity. In this review, we discuss the current evidence supporting CPI use in R/R cHL and maintenance therapy. We present emerging CPI data in frontline adult cHL and assess its role in the elderly. In addition, we discuss critical immune-related toxicities and their management, and elaborate on the challenges of monitoring response and minimal residual disease as tools for maximizing efficacy by limiting toxicity., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Postchemotherapy histiocyte-rich pseudotumor is a rare event in lymphoma patients and can cause elevated metabolic activity on positron emission tomography-computed tomography scan mimicking residual tumor. Here, we reported 11 lymphoma cases showing mass-like lesions with increased fluorodeoxyglucose uptake after chemotherapy. These postchemotherapy lesions occurred in various anatomic sites including spleen, mediastinum, lymph node, and other tissue locations, concerning for refractory or residual lymphoma. Their median size was 2.7 cm (range, 1.4 to 7.7 cm) and the median standardized uptake value on positron emission tomography-computed tomography was 10.6 (range, 5.2 to 13.8). Histologic examination of these lesions demonstrated reactive changes mainly composed of histiocyte-rich proliferation without viable lymphoma. Fat necrosis, cholesterol cleft, and calcium deposit were also commonly observed. After biopsies, 3 patients received additional chemotherapy, 2 had stem cell transplant with adjuvant chemotherapy or radiation, 1 had surgical excision, and the remaining 5 patients did not receive any further treatment. Follow-up imaging studies showed the resolved or decreased fluorodeoxyglucose activities in all patients including those without additional treatments, consistent with benign/reactive nature of these pseudotumor lesions. This study illustrates postchemotherapy mass-like lesions with elevated metabolic activity do not always represent residual disease and provides awareness of correlation between radiologic and histologic features of these lesions to avoid misinterpretation and overtreatment of lymphoma patients after chemotherapy., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Kidney failure is a possible but rare complication in lung cancer patients that may be caused by massive tumor lysis or a paraneoplastic effect. Clinical case reports have documented pathological characteristics of paraneoplastic syndrome in glomeruli, but are short of molecular details. When Lewis lung carcinoma 1 (LLC1) cells were implanted in mice lungs to establish lung cancer, renal failure was frequently observed two weeks post orthotopic xenograft. The high urinary albumin-to-creatinine ratio (ACR) was diagnosed as paraneoplastic nephrotic syndrome in those lung cancer mice. Profiling the secretome of the lung cancer cells revealed that the secretory proteins were potentially nephrotoxic. The nephrotoxicity of lung cancer-derived secretory proteins was tested by examining the pathogenic effects of 1 × 10 6 , 2 × 10 6 , and 5 × 10 6 LLC1 cell xenografts on the pathogenic progression in kidneys. Severe albuminuria was present in the mice that received 5 × 10 6 LLC1 cells implantation, whereas 10 6 cell and 2 × 10 6 cell-implanted mice have slightly increased albuminuria. Pathological examinations revealed that the glomeruli had capillary loop collapse, tumor antigen deposition in glomeruli, and renal intratubular casts. Since IL-6 and MCP-1 are pathologic markers of glomerulopathy, their distributions were examined in the kidneys of the lung cancer mice. Moderate to severe inflammation in the kidneys was correlated with increases in the number of cells implanted in the mice, which was reflected by renal IL-6 and MCP-1 levels, and urine ACR. TGF-β signaling-engaged renal fibrosis was validated in the lung cancer mice. These results indicated that lung cancer cells could provoke inflammation and activate renal fibrosis.

Histone deacetylase 6 (HDAC6) controls many cellular processes via its catalyzing deacetylation of downstream substrates or interacting with its partner proteins. Dysregulation of HDAC6 signaling links to many diseases. Our previous study has been reported peptidyl-prolyl cis/trans isomerase, and NIMA-interacting 1 (Pin1) involving in HDAC6-mediated cell motility. To gain insight into precisely coordination of HDAC6 and Pin1 in cell migration, shRNA-mediated gene silencing and ectopic expression were applied to manipulate protein expression level to evaluate relationship between HDAC6 and Pin1 expression. Quantitative RT-PCR and the cycloheximide (CHX) chase assay resulted in HDAC6 expression is correlated with Pin1 level in H1299 cells. It hints that the Pin1 increases HDAC6 expression through increased transcripts and posttranslational stabilization. Furthermore, wound healing assay and transwell invasion assay evidenced the contribution of Pin1 on cell motility in H1299 cells. Our data suggest that Pin1 acts as an important regulator to manage HDAC6 expression for cell motility in lung cancer cells., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

This cross-sectional study aimed to investigate the associations between high-sensitivity C-reactive protein (hs-CRP) and renal impairment (RI) among middle-aged and elderly people. We collected and analyzed demographic, anthropometric, metabolic, and renal function data in a community-based population in Northern Taiwan. We excluded subjects with acute inflammation from this study and defined RI as the presence of urinary albumin-creatinine ratio 30-300 mg/g or an estimated glomerular filtration rate of <60 mL/min/1.73 m 2 . There were 131, 125, and 125 participants in the low (≤0.80 mg/L), middle (0.81-1.76 mg/L), and high (>1.77 mg/L) hs-CRP tertiles, respectively. hs-CRP exhibited significantly positive correlations with body mass index, waist circumference, systolic blood pressure, triglyceride, and fasting plasma glucose, and a negative correlation with high-density lipoprotein. The prevalence and odds ratio of RI significantly increased across hs-CRP tertiles from low to high, and this trend remained significant after adjusting for the conventional cardiometabolic risk factors. hs-CRP ≥ 1.61 mg/L in the total group and ≥2.03 mg/L in the elderly group accurately predicted RI ( p = 0.01 and 0.03, respectively). These findings suggest that we should carefully evaluate the renal function for at-risk individuals with hs-CRP elevation.

Body composition (BC) parameters are associated with cardiometabolic diseases in children; however, the importance of BC parameters for predicting pediatric hypertension is inconclusive. This cross-sectional study aimed to compare the difference in predictive values of BC parameters and conventional anthropometric measures for pediatric hypertension in school-aged children. A total of 340 children (177 girls and 163 boys) with a mean age of 8.8 ± 1.7 years and mean body mass index (BMI) z-score of 0.50 ± 1.24 were enrolled (102 hypertensive children and 238 normotensive children). Significantly higher values of anthropometric measures (BMI, BMI z-score, BMI percentile, waist-to-height ratio) and BC parameters (body-fat percentage, muscle weight, fat mass, fat-free mass) were observed among the hypertensive subgroup compared to their normotensive counterparts. A prediction model combining fat mass ≥ 3.65 kg and fat-free mass ≥ 34.65 kg (area under the receiver operating characteristic curve = 0.688; sensitivity = 66.7%; specificity = 89.9%) performed better than BMI alone (area under the receiver operating characteristic curve = 0.649; sensitivity = 55.9%; specificity = 73.9%) in predicting hypertension. In conclusion, BC parameters are better than anthropometric measures in predicting pediatric hypertension. BC measuring is a reasonable approach for risk stratification in pediatric hypertension.

This report summarizes published data on parathyroid cancer, with the inclusion of topics discussed at MEN2019: 16th International Workshop on Multiple Endocrine Neoplasia, 27-29 March 2019, Houston, TX, USA. An expert panel on parathyroid cancer was constituted by the Steering Committee to address key questions in the field. The objectives were to recap open forum discussion of interested parties from multiple disciplines. The expert panel met in a closed session to consult on the data to be highlighted on the evidence-based results and on the future directions. Preceding the Conference, members of the expert panel conducted an extensive literature search. All presentations were based upon the best peer-reviewed information taking into account the historical and current literature. Questions were developed by the expert panel on parathyroid carcinoma. A comprehensive literature search for relevant studies was undertaken. This report represents the expert panel's synthesis of the conference material placed in a context designed to be relevant to clinicians and those engaged in cutting-edge studies of parathyroid carcinoma. This document not only provides a summary of our current knowledge but also places recent advances in its management into a context that should enhance future advances in our understanding of parathyroid carcinoma.