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Background: Parental feeding practices (PFPs) play a key role in fostering preschoolers' dietary habits and in mitigating the risk of childhood obesity. Nevertheless, parents often employ inappropriate feeding practices, leading to children's potential nutrition-related issues. Thus, research is needed to inform interventions that focus on optimizing feeding practices., Methods: This protocol describes the evaluation of a novel intervention-Empowering Parents to Optimize Feeding Practices (EPO-Feeding Program). The program will be evaluated with a two-arm feasibility randomized controlled trial (RCT) in Yangzhou, China. The program includes four weekly group-based training sessions led by healthcare professionals for parents of preschool children. The intervention incorporates sessions, group discussions, motivational interviewing, and supplementary materials (e.g., key messages and educational videos) aimed at enhancing parents' knowledge, skills, and behaviours related to feeding practices. The primary outcomes include i) implementation feasibility, primarily assessed through retention rates; and ii) program acceptability through a survey and qualitative process evaluation. Secondary outcomes encompass the potential impacts on i) PFPs, ii) parental perception of child weight (PPCW), iii) parenting sense of competence, iv) children's eating behaviours, and v) child weight status. Quantitative analyses include descriptive estimates for evaluating the feasibility and linear mixed regression analysis for testing the potential effects. Qualitative valuation will use thematic framework analysis., Discussion: If this study shows this program to be feasible to implement and acceptable to parents, it will be used to inform a fully powered trial to determine its effectiveness. The research will also help inform policy and practices in the context of child nutrition promotion, particularly regarding implementing group-based training sessions by healthcare providers in similar settings., Trial Registration: Clinicaltrials.gov, Protocol #NCT06181773, 20/11/2023., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The hotel industry is essential for tourism. With the rapid expansion of the internet, consumers only search for their desired keywords on the website when they trying to find a hotel to stay, causing the relevant hotel information would appear. To quickly respond to the changing market and consumer habits, each hotel must focus on its website information and information quality. This study proposes a novel methodology that uses rough set theory (RST), principal component analysis, t-Distributed Stochastic Neighbor Embedding (t-SNE), and attribute performance visualization to explore the relationship between hotel star ratings and hotel website information quality. The collected data are based on the star-rated hotels of the Taiwanstay website, and the checklists of hotel website services are used to obtain the relevant attributes data. The results show that there are significant differences in information quality between hotels below two stars and those above four stars. The information quality provided by the higher star hotels was more detailed than that offered by low-star hotels. Based on the attribute performance matrix, the one-star and two-star hotels have advantage attributes in their landscape, reply time, restaurant information, social media, and compensation. Furthermore, the three-five star hotels have advantage attributes in their operational support, compensation, restaurant information, traffic information, and room information. These results could be provided to the stakeholders as a reference., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Cheng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Social support for postpartum women helps mothers to recover from childbirth and fosters healthy infant development. However, the impacts of reduced interpersonal interactions inflicted by the COVID-19 outbreak on available social support for postpartum women have received little attention. Therefore, this study aimed to examine the levels of social support provided to postpartum women and associated factors in Thailand during the COVID-19 pandemic., Methods: A cross-sectional study was conducted from July to October 2021 using an anonymous online questionnaire. The responses of 840 eligible women up to six months postpartum in Thailand were obtained. The maternity social support scale was used to measure social support. Multivariate logistic regression was used to analyse the factors associated with social support among postpartum women., Results: About 57% of women reported to receive high support. Women in the high social support group were more likely to be married (aOR:2.70; 95% CI:1.57-4.66), have a university education or above (1.88; 1.35-2.64), have an intended pregnancy (2.06; 1.34-3.16), good health (2.01; 1.44-2.81), good sleep quality (1.62; 1.14-2.31), receive counsel from peers or family (1.56; 1.13-2.16), and use internet or social media to reduce stress and depression (1.51; 1.08-2.11). Meanwhile, women in the high social support group were significantly less likely to feed complementary foods to infants within 24 hours of completing the survey (0.28; 0.15-0.52)., Conclusions: The results of this study indicated that more than half of the women reported high support and illustrated the important role played by family, peers, and professionals as well as online and remote channels in providing postpartum informational and emotional support during the pandemic. Online platforms and remote support may be considered to provide social support to postpartum women during a pandemic such as COVID-19., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Antenatal corticosteroid (ACS) administration has been known as one of the most effective treatment in perinatal medicine, but the beneficial effects of ACS may vary not only gestational age, but also the quality of perinatal and neonatal care of the institution. This nationwide cohort study of the Korean Neonatal Network (KNN) data was consisted of <1,500g infants born at 23-34 weeks at 67 KNN hospitals between 2013 and 2017. The 9,142 eligible infants were assigned into two groups-group 1 and 2 <50% and ≥50% mortality rate, respectively, for 23-24 weeks' gestation-reflecting the quality of perinatal and neonatal care. Each group of infants were further stratified into 23-24, 25-26, 27-28, and 29-34 weeks of gestation age. Despite comparable ACS usage between group 1 (82%) and group 2 (81%), the benefits of ACS were only observed in group 1. In the multivariable analyses, infants of group 1 showed significant decrease in mortality and IVH at gestational age 23-24 weeks with ACS use, and the decrease was also seen in early-onset sepsis and respiratory distress syndrome at gestational age of 29-34 weeks while there were no significant decrease in group 2. In this study the overall data was congruent with the previous findings stating that ACS use decreases mortality and morbidity. These results indicate that the improved mortality of infants at 23-24 weeks' gestation reflects the quality improvement of perinatal and neonatal intensive care, which is a prerequisite to the benefits of ACS., Competing Interests: The authors have declared that no competing interests exist.

Background: Hemopericardium is a common and hazardous complication of acute type A aortic dissection (ATAAD). This retrospective study aimed to clarify the short-term and mid-term outcomes in patients who underwent surgical rescues for hemopericardium complicated by ATAAD., Methods: Between January 2007 and March 2019, 586 consecutive patients underwent ATAAD repair at our institution. According to preoperative computed tomography, hemopericardium was found in 191 patients (32.6%), 150 were stabilized with medical treatment, and 41 underwent surgical rescues for critical hemodynamics. The 41 patients were classified into groups according to their rescue procedures: emergent subxiphoid pericardiotomy (E-SXP group, n = 26, 63.4%) or emergent cardiopulmonary bypass (E-CPB group, n = 15, 36.6%). Clinical features, surgical information, postoperative complications, and 3-year survival were analyzed and compared., Results: Demographics, comorbidities and aortic repair procedures were generally homogenous between the two groups, except for sex. The average systolic blood pressure was 62.4 ± 13.3 mmHg and 67.1 ± 13.1 mmHg in the E-SXP and E-CPB groups, respectively. A total of 29.3% of patients underwent cardiopulmonary resuscitation (CPR) before surgical rescues. The in-hospital mortality was similar (30.8% versus 33.3%, P = 0.865) in the two groups. Multivariate analysis revealed that preoperative CPR was an in-hospital predictor of mortality. For patients who survived to discharge, 3-year cumulative survival rates were 87.8% ± 8.1% and 60.0% ± 19.7% in the E-SXP and E-CPB groups, respectively (P = 0.170)., Conclusions: Patients who underwent surgical rescues for ATAAD-complicated hemopericardium are at a high risk of in-hospital mortality. The two rescue procedures revealed similar short-term and mid-term outcomes., Competing Interests: The authors have declared that no competing interests exist.

With advances in technology, wireless and sensor technologies represent a method for continuously recording people's biomedical signals, which may enhance the diagnosis and treatment of users' everyday health conditions. These technologies mostly target older adults. In this study, we examine a smart clothing system targeting clinically high-risk patients, including older adults with cardiovascular disease (31 outpatients) and older adults in general (81 participants), to obtain an understanding of the patients' perception of using wearable healthcare technologies. Given that technology anxiety has been shown to affect users' resistance to using new technology and that perceived ubiquity is considered a characteristic of wearable devices and other mobile wireless technologies, we included three external variables: i.e., technology anxiety, perceived ubiquity, and resistance to change, in addition to the traditional components of the technology acceptance model (TAM). The results of the hypothesized model showed that among older adults in general, technology anxiety had a negative effect on the perceived ease of use and perceived ubiquity. The perceived ubiquity construct affects both user groups' perceived ease of use and perceived usefulness of wearing smart clothes. Most relationships among the original constructs of the TAM were validated in older adults in general. Interestingly, we found that perceived usefulness had an indirect effect on behavioral intention through attitude. These results further confirm the validity of the extended TAM in determining older users' technology acceptance behavior., Competing Interests: The authors have declared that no competing interests exist.

This single-centered, retrospective cohort study investigated the timing of involution of retinopathy of prematurity (ROP) and retinal vascularization to zone III after intravitreal bevacizumab (IVB) treatment and its possible impacts on postnatal growth and neurodevelopment. Premature infants with birth weight ≤1500 g, born between 2008 to 2014 and diagnosed with ROP were enrolled. All patients with type 1 ROP underwent IVB as 1st line treatment and were recruited as the study group; those with any stage of ROP except type 1 ROP without treatment served as controls. Neurodevelopmental outcomes were assessed using the Bayley Score of Infant Development (BSID) editions II or III. The study group included 35 eyes from 18 patients; the control group included 86 patients. Twenty-three eyes (65.7%) exhibited ROP regression after a single dose of IVB. The majority of plus sign and extraretinal neovascularization regressed within two weeks. The length of time for retinal vascularization to reach zone III was significantly longer in the treatment group compared with the control (mean post-menstruation age 54.5 vs. 47.0 weeks, p<0.001). Long-term follow-up showed no significant differences in body weight and neurodevelopment between the study and control groups up to the 2-year corrected age., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To determine the effects of antenatal betamethasone and/or postnatal dexamethasone administration on hyperoxic lung and brain injuries in newborn rats., Methods: Newborn Sprague-Dawley rats were divided into five experimental groups: normoxia-vehicle-vehicle group, hyperoxia-vehicle-vehicle group, hyperoxia-betamethasone-vehicle group, hyperoxia-vehicle-dexamethasone group, and hyperoxia-betamethasone-dexamethasone group according to (i) whether rats were exposed to normoxia or hyperoxia after birth to postnatal day (P) 14, (ii) whether antenatal betamethasone (0.2mg/kg) or vehicle was administered to pregnant rats at gestation days 19 and 20, and (iii) whether three tapering doses of dexamethasone (0.5, 0.3, 0.1mg/kg per day) or vehicle were administered on P5, 6 and 7, respectively. The lungs and brains were harvested for histological and biochemical analyses at P8 and P14., Results: Postnatal dexamethasone but not antenatal betamethasone significantly enhanced hyperoxia-induced reduction in body weight gain and alveolarization and increased lung terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells both at P8 and P14, transiently increased hyperoxia-induced reductions in brain weight gain and angiogenesis, and increase in brain TUNEL-positive cells at P8 but not at P14. Co-administration of antenatal betamethasone significantly enhanced dexamethasone-induced impairments in alveolarization both at P8 and P14, transient increases in lung and brain oxidative stresses, and increases in brain TUNEL-positive cells at P8 but not at P14., Conclusion: Although postnatal dexamethasone but not antenatal betamethasone alone significantly increased hyperoxic lung and brain injuries, co-administration of antenatal betamethasone significantly enhanced the detrimental effects of postnatal dexamethasone on hyperoxic lung and brain injuries in newborn rats., Competing Interests: The authors have declared that no competing interests exist.

Background: Recent nutrition guidelines for extremely-low-birth-weight infants (ELBWIs) recommend implementation of high initial amino acid (AA) supplementation in parenteral nutrition., Objective: We sought to evaluate the influence of AA intake on refeeding syndrome-like electrolyte disturbances including hypophosphatemia in ELBWIs., Study Design: Medical records of 142 ELBWIs were reviewed. Demographic, nutritional, outcome, and electrolyte data were compared between ELBWIs with initial low (1.5 g/kg/day) and high (3 g/kg/day) AA intake. Multivariate analysis was conducted to determine the odds ratio of hypophosphatemia with high AA intake and small-for-gestational-age (SGA) ELBWIs., Results: The incidence of hypophosphatemia and severe hypophosphatemia increased from 51% and 8% in period I to 59% and 20% in period II, respectively (p = 0.36 and < 0.01). Specifically, SGA ELBWIs showed higher incidence of hypophosphatemia than appropriate-for-gestational age (AGA) ELBWIs in period II, whereas there was no difference in period I. For severe hypophosphatemia, SGA ELBWIs presented a 27% incidence versus a 2% incidence in AGA ELBWIs, even with low initial AA intake. Despite no difference in phosphate intake between infants with and without hypophosphatemia, serum phosphate level reached a nadir at the sixth postnatal day and gradually recovered over the second week in infants with hypophosphatemia. In multivariate analyses, the odds ratios for severe hypophosphatemia were 3.6 and 6.6 with high AA intake and SGA status, respectively, with the highest being 18.0 with combined high AA intake and SGA status., Conclusions: In summary, high initial AA intake significantly increased the risk of refeeding syndrome-like electrolyte dysregulations including severe hypophosphatemia in ELBWIs. In SGA ELBWIs, the risk of electrolyte disturbance was significantly higher, even with low initial AA intake. Therefore, new tailored parenteral nutrition protocols starting with lower energy intake and a gradual increase over the first week may be warranted for application in high-risk SGA ELBWIs., Competing Interests: The authors have declared that no competing interests exist.

We propose a machine learning (ML)-based model for predicting cochlear dead regions (DRs) in patients with hearing loss of various etiologies. Five hundred and fifty-five ears from 380 patients (3,770 test samples) diagnosed with sensorineural hearing loss (SNHL) were analyzed. A threshold-equalizing noise (TEN) test was applied to detect the presence of DRs. Data were collected on sex, age, side of the affected ear, hearing loss etiology, word recognition scores (WRS), and pure-tone thresholds at each frequency. According to the cause of hearing loss as diagnosed by the physician, we categorized the patients into six groups: 1) SNHL with unknown etiology; 2) sudden sensorineural hearing loss (SSNHL); 3) vestibular schwannoma (VS); 4) Meniere's disease (MD); 5) noise-induced hearing loss (NIHL); or 6) presbycusis or age-related hearing loss (ARHL). To develop a predictive model, we performed recursive partitioning and regression for classification, logistic regression, and random forest. The overall prevalence of one or more DRs in test ears was 20.36% (113 ears). Among the 3,770 test samples, the overall frequency-specific prevalence of DR was 6.7%. WRS, pure-tone thresholds at each frequency, disease type (VS or MD), and frequency information were useful for predicting DRs. Sex and age were not associated with detecting DRs. Based on these results, we suggest possible predictive factors for determining the presence of DRs. To improve the predictive power of the model, a more flexible model or more clinical features, such as the duration of hearing loss or risk factors for developing DRs, may be needed., Competing Interests: The authors have declared that no competing interests exist.

Clinical and model studies indicate that low nitric oxide (NO) bioavailability due in part to profound hypoargininemia contributes to cerebral malaria (CM) pathogenesis. Protection against CM pathogenesis may be achieved by altering the diet before infection with Plasmodium falciparum infection (nutraceutical) or by administering adjunctive therapy that decreases CM mortality (adjunctive therapy). This hypothesis was tested by administering citrulline or arginine in experimental CM (eCM). We report that citrulline injected as prophylaxis immediately post infection (PI) protected virtually all mice by ameliorating (i) hypoargininemia, (ii) urea cycle impairment, and (iii) disruption of blood brain barrier. Citrulline prophylaxis inhibited plasma arginase activity. Parasitemia was similar in citrulline- and vehicle control-groups, indicating that protection from pathogenesis was not due to decreased parasitemia. Both citrulline and arginine administered from day 1 PI in the drinking water significantly protected mice from eCM. These observations collectively indicate that increasing dietary citrulline or arginine decreases eCM mortality. Citrulline injected ip on day 4 PI with quinine-injected ip on day 6 PI partially protected mice from eCM; citrulline plus scavenging of superoxide with pegylated superoxide dismutase and pegylated catalase protected all recipients from eCM. These findings indicate that ameliorating hypoargininemia with citrulline plus superoxide scavenging decreases eCM mortality., Competing Interests: Wilson Caparros-Wanderley is employed by WCW Biostatistical Consulting. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

This study aimed to determine the natural course of patent ductus arteriosus (PDA) with noninterventional conservative management and whether the presence and/or prolonged duration of hemodynamically significant (HS) PDA increased the risk of mortality and morbidities in extremely preterm (EPT) infants. We retrospectively reviewed the medical records of EPT infants born at 23-28 weeks of gestation (n = 195) from January 2011 to June 2014, when PDA was managed with noninterventional conservative treatment. We stratified infants into three subgroups of 23-24, 25-26, and 27-28 weeks and analyzed the prevalence and natural evolution of HS PDA, defined as ventilator dependency and PDA size ≥2 mm. Multivariate regression analyses determined if the presence and/or prolonged duration of HS PDA increased the risk for mortality and/or morbidities. The overall incidence of HS PDA was 57% (111/195) at the end of the first postnatal week. In subgroup analyses, infants with 23-24 weeks of gestation had the highest incidence (93%, 50/54), with 64% (47/74) for 25-26 weeks and 21% (14/67) for 27-28 weeks. Six (5%) of 111 infants with HS PDA were discharged without ductus closure, 4 had spontaneous PDA closure on follow up, and device closure was performed for 2 infants. In the multivariate analyses, the presence or prolonged duration (per week) of HS PDA was not associated with the risk of mortality and/or morbidities. Spontaneous closure of HS PDA was mostly achieved, even in EPT infants, with a noninterventional conservative approach. In conclusion, our data showed the incidence and natural course of HS PDA in EPT infants and suggested that the presence or prolonged duration of HS PDA might not increase the rate of mortality or morbidities., Competing Interests: The authors have declared that no competing interests exist.

The aim of this study was done to determine whether dexamethasone treatment prevents posthemorrhagic hydrocephalus (PHH) development and attenuates brain damage after severe IVH in newborn rats. Severe IVH was induced by injecting; 100 μL of blood into each lateral ventricle of postnatal day 4 (P4) Sprague-Dawley rats. Dexamethasone was injected intraperitoneally into rat pups at a dose of 0.5 mg/kg, 0.3 mg/kg, and 0.1 mg/kg on P5, P6, and P7, respectively. Serial brain magnetic resonance imaging and behavioral function tests, such as the negative geotaxis test and the rotarod test, were performed. On P32, brain tissues were obtained for histological and biochemical analyses. Dexamethasone treatment significantly improved the severe IVH-induced increase in the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling-positive cells, glial fibrillary acidic protein-positive astrocytes and ED-1 positive microglia, and the decrease in myelin basic protein. IVH reduced a survival of 71%, that showed a tendency to improve to 86% with dexamethasone treatment, although the result was not statistically significant. However, dexamethasone failed to prevent the progression to PHH and did not significantly improve impaired behavioral tests. Similarly, dexamethasone did not decrease the level of inflammatory cytokines such as interleukin (IL) -1α and ß, IL-6, and tumor necrosis factor-α after severe IVH. Despite its some neuroprotective effects, dexamethasone failed to improve the progress of PHH and impaired behavioral tests after severe IVH., Competing Interests: The authors have declared that no competing interests exist.

Formyl peptide receptor 1 (FPR1) has been shown to be a key regulator of inflammation. However, its role in bronchopulmonary dysplasia (BPD) has not been delineated yet. We investigated whether FPR1 plays a pivotal role in regulating lung inflammation and injuries, and whether intratracheally transplanted mesenchymal stem cells (MSCs) attenuate hyperoxic lung inflammation and injuries by down-regulating FPR1. Newborn wild type (WT) or FPR1 knockout (FPR1-/-) C57/BL6 mice were randomly exposed to 80% oxygen or room air for 14 days. At postnatal day (P) 5, 2×10(5) MSCs were intratracheally transplanted. At P14, mice were sacrificed for histopathological and morphometric analyses. Hyperoxia significantly increased lung neutrophils, macrophages, and TUNEL-positive cells, while impairing alveolarization and angiogenesis, along with a significant increase in FPR1 mRNA levels in WT mice. The hyperoxia-induced lung inflammation and lung injuries were significantly attenuated, with the reduced mRNA level of FPR1, in WT mice with MSC transplantation and in FPR1-/- mice, irrespective of MSCs transplantation. However, only MSC transplantation, but not the FPR1 knockout, significantly attenuated the hyperoxia-induced increase in TUNEL-positive cells. Our findings indicate that FPR1 play a critical role in regulating lung inflammation and injuries in BPD, and MSCs attenuate hyperoxic lung inflammation and injuries, but not apoptosis, with down regulating, but not direct inhibiting FPR1., Competing Interests: We have the following interests: Human umbilical cord blood–derived mesenchymal stem cells (hUCB-MSCs) were supplied by MEDIPOST Co, Ltd; the sponsor had no involvement in study design, the collection, analysis, or interpretation of data; writing of the report; or the decision to submit the manuscript for publication. Samsung Medical Center and MEDIPOST Co, Ltd have piled patents for “Method of treating lung diseases using cells separated or proliferated from umbilical cord blood” under names of Yun Sil Chang, Won Soon Park and Yoon Sun Yang (not affiliated with this article) (Korean Patent No.10-0837167, US Patent No.US 9,498,497 B2, Canadian Patent No. 2,640,728, Singapore Patent No. 144446, Japanese Patent No.5112336). Also, Samsung Medical Center and Busan University issued “Role of formyl peptide receptor 1 in hyperoxic lung injury after intratracheal transplantation of hUCB-MSCs in newborn mice” under names of Yun Sil Chang, Won Soon Park, So Yoon Ahn, Dong Kyung Sung, Young Eun Kim and Jae Ho Kim (KR10-2018-0051692). In addition, Samsung Medical Center have filed “Composition for treating intraventricular hemorrhage in preterm infants comprising mesenchymal stem cells” under names of Yun Sil Chang and Won Soon Park (Korean Patent No. 10-1405620, US Patent No. 9,539,285,) and filed and issued “Composition for treating inflammatory brain disease, which includes stem cell as active ingredient under names of Yun Sil Chang and Won Soon Park (Korean Patent No 10-1654970, EU14754748.3 and US 14/768,734). Young Eun Kim and Yun Sil Chang are employed by Samsung Advanced Institute for Health Sciences and Technology (SAIHST). Won Soon Park, Ahn So Yoon, Dong Kyung Sung and Yun Sil Chang are employed by Samsung Medical Center. Won Soon Park, Dong Kyung Sung and Yun Sil Chang are employed by Samsung Biomedical Research Institute. Won Soon Park received other commercial funds not related to this article from MEDIPOST Co. Ltd. (PHO0140131, HO0133531, PHO0181901). There are no further patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Objectives: To evaluate and compare the diagnostic accuracy of high versus low attenuation thresholds for determining the solid component of ground-glass opacity nodules (GGNs) for the differential diagnosis of adenocarcinoma in situ (AIS) from minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IA)., Methods: Eighty-six pathologically confirmed GGNs < 3 cm observed in 86 patients (27 male, 59 female; mean age, 59.3 ± 11.0 years) between January 2013 and December 2015 were retrospectively included. The solid component of each GGN was defined using two different attenuation thresholds: high (-160 Hounsfield units [HU]) and low (-400 HU). According to the presence or absence of solid portions, each GGN was categorized as a pure GGN or part-solid GGN. Solid components were regarded as indicators of invasive foci, suggesting MIA or IA., Results: Among the 86 GGNs, there were 57 cases of IA, 19 of MIA, and 10 of AIS. Using the high attenuation threshold, 44 were categorized as pure GGNs and 42 as part-solid GGNs. Using the low attenuation threshold, 13 were categorized as pure GGNs and 73 as part-solid GGNs. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy for the invasive focus were 55.2%, 100%, 100%, 22.7%, and 60.4%, respectively, for the high attenuation threshold, and 93.4%, 80%, 97.2%, 61.5%, and 91.8%, respectively, for the low attenuation threshold., Conclusion: The low attenuation threshold was better than the conventional high attenuation threshold for determining the solid components of GGNs, which indicate invasive foci., Competing Interests: The authors have declared that no competing interests exist.

There is a globally increasing prevalence and incidence of diabetes mellitus (DM). Prolonged hyperglycaemia could lead to both macrovascular damage, such as carotid artery atherosclerosis, and microvascular damage, such as retinal arteriolar narrowing, and might contribute to retinal artery occlusion (RAO). Accordingly, it is important to determine whether DM is a contrubuting factor of RAO. We conducted a retrospective cohort study that included 241,196 DM patients from the Longitudinal Cohort of Diabetes Patients Database who were recruited between 2003 and 2005. An age- and sex-matched non-DM control group included the same number of patients who were selected from the Taiwan Longitudinal Health Insurance Database of 2000. Relevant data of each patient were collected from the index date until December 2013. The incidence and risk of RAO were calculated and compared between the DM and non-DM groups. The hazard ratio for RAO was calculated using Cox proportional hazards regression analysis after adjusting for confounders. The cumulative incidence rate of RAO was calculated by Kaplan-Meier analysis. In total, 317 patients with DM and 144 controls developed RAO during the follow-up period, leading to an incidence rate of RAO in DM patients that was 2.30 times (95% confidence interval [CI] = 1.89-2.80) greater than that in controls. After adjustment for potential confounders, patients with DM were 2.11 times (95% CI, 1.71-2.59) more likely to develop RAO in the total study cohort. In conclusion, DM increases the risk of RAO, which is an interdisciplinary emergency. Close collaboration between endocrinologists and ophthalmologists is important in managing RAO following DM., Competing Interests: The authors have declared that no competing interests exist.

Matrix metalloproteinase (MMP)-9 is a zinc-dependent protease associated with early immune responses to Mycobacterium tuberculosis infection, macrophage recruitment and granuloma formation. We evaluated whether adjunctive inhibition of MMP-9 could improve the response to standard TB treatment in a mouse model that develops necrotic lesions. Six weeks after an aerosol infection with M. tuberculosis, C3HeB/FeJ mice received standard TB treatment (12 weeks) comprising rifampin, isoniazid and pyrazinamide alone or in combination with either anti-MMP-9 antibody, etanercept (positive control) or isotype antibody (negative control) for 6 weeks. Anti-MMP-9 and the isotype control had comparable high serum exposures and expected terminal half-life. The relapse rate in mice receiving standard TB treatment was 46.6%. Compared to the standard TB treatment, relapse rates in animals that received adjunctive treatments with anti-MMP-9 antibody or etanercept were significantly decreased to 25.9% (P = 0.006) and 29.8% (P = 0.019) respectively, but were not different from the arm that received the isotype control antibody (25.9%). Immunostaining demonstrated localization of MMP-9 primarily in macrophages in both murine and human lung tissues infected with M. tuberculosis, suggesting the importance of MMP-9 in TB pathogenesis. These data suggest that the relapse rates in M. tuberculosis-infected mice may be non-specifically improved by administration of antibodies in conjunction with standard TB treatments. Future studies are needed to evaluate the mechanism(s) leading to improved outcomes with adjunctive antibody treatments.

[This corrects the article DOI: 10.1371/journal.pone.0181757.].

We explored GA, BW, Apgar score, CRIB II score, and serum albumin levels as univariate predictors of mortality in extremely low birth weight infants. Medical records of 564 extremely low birth weight infants were reviewed retrospectively. The infants were grouped as survivors (group I), expired ≤ 7th postnatal day (group II), and expired > 7th postnatal day (group III). The predictive value for mortality of gestational age, birth weight, Apgar scores at 1 and 5 min, clinical risk index for babies II score, and first and lowest serum albumin levels was assessed by calculating the associated area under the curve (AUC) in receiver operating characteristic (ROC) curves. The overall survival and mortality rates of groups I, II, and III were 81.0% (457/564), 7.6% (43/564), and 11.4% (64/564), respectively. Birth weight, Apgar scores at 1 and 5 min, and first serum albumin levels were significantly higher, while the clinical risk index for babies II score was significantly lower in group I when compared to groups II and III. Gestational age and lowest serum albumin level in group I were significantly higher than group III, but not group II. However, gestational age, birth weight, and clinical risk index for babies II score showed gestational age dependent variations regardless of survival or mortality. Apgar score at 5 min (0.756) and lowest serum albumin level (0.771) demonstrated the highest AUC of the ROC curve in predicting mortality in group II and III, respectively. In conclusion, Apgar score at 5 min and lowest serum albumin level were the most effective predictors for mortality in extremely low birth weight infants during ≤ 7th and > 7th postnatal days, respectively.

We investigated the aftereffects of confirmatory QuantiFERON testing (QFT) added to a positive tuberculin skin test (TST). We reviewed the pre and post course of sequential tuberculosis (TB) outbreaks in a high school where massive 43 active TB cases had been found within one year before delayed contact investigation. And we investigated the TB development in relation to initial TST and QFT during mean follow-up of 3.9 ± 0.9 years. After delayed contact investigation for two subsequent TB outbreaks, 925 contacts were divided into the following 3 groups: TST- (n = 632), TST+/QFT+ (n = 24), TST+/QFT- (n = 258). QFT- was more prevalent than QFT+ in contacts with 10mm ≤ TST <15mm (158, 61.2%) compared with TST ≥15mm (100, 38.8%) among the TST+ reactors (P < 0.001). Among the 258 TST+/QFT- subjects, 256 received no latent TB infection (LTBI) treatment, but 7 contacts developed TB during follow-up. Among these 7 patients, 4 had initial TST ≥15mm and 3 had 10mm ≤ TST <15mm. In conclusion, the delayed contact investigation for LTBI in a high school resulted in continued TB developments. False-negative QFT performed late among the TST+ reactors should not be considered criteria for LTBI treatment. Additionally, the contacts only with TST ≥15mm should be considered for LTBI treatment in congregate settings of intermediate-burden countries.

Purpose: Paranasal sinusitis is widespread and can lead to orbital complications, blindness, and death. However, the correlation between ophthalmological findings and disease staging remains unclear. This study aimed to investigate the staging, acute ophthalmological manifestations, diagnosis, management, and outcomes of orbital complications of paranasal sinusitis during a 27-year period., Methods: We retrospectively reviewed the medical records of all patients with orbital complications of paranasal sinusitis hospitalized at the National Cheng Kung University Hospital, a medical center in Taiwan during 1988-2015. Sex, age, symptoms, history, ophthalmological findings, laboratory and imaging findings, treatments, and outcomes were analyzed by staging., Results: Eighty-three patients aged 9 days to 80 years had stage I (preseptal cellulitis, n = 39 patients), II (postseptal orbital cellulitis, n = 8), III (subperiosteal abscess, n = 16), IV (orbital abscess, n = 8), or V (intracranial involvement, n = 12) complications. Peak incidences occurred in patients aged 0-19 and 60-69 years. Chronic sinusitis and diabetes mellitus were common preexisting diseases. Extraocular movement limitation and proptosis predicted postseptal (stage II or more) involvement. The likelihood of elevated intraocular pressure increased with stage. Reduced visual acuity and presence of relative afferent pupillary defect indicated consideration of magnetic resonance imaging to investigate possible intracranial extension. Ipsilateral maxillary (81.7%) and ethmoidal (75.6%) sinuses were the most common sources of infection, and the most frequently implicated pathogens were coagulase-negative Staphylococcus spp. (25.3%) and Staphylococcus aureus (20.5%). All patients received intravenous antimicrobial therapy (multi-drug therapy in 88.0%), and 55.4% underwent surgery, most commonly endoscopic sinus surgery. One (1.2%) diabetic man with stage V complications died of fungal sinusitis with intracranial invasion. Five (6.0%) patients, all stage V, lost vision despite intensive treatment. The average length of hospital stay was 13.8 days (range 2-72 days), and significantly longer stays were associated with stages II-V as compared to stage I., Conclusions: Orbital infection originating from paranasal sinusitis can cause vision loss and death due to intracranial extension. Acute ophthalmological findings predict staging and prognosis. Cooperative consultation between ophthalmologists, otorhinolaryngologists, and neurologists is essential. Urgent diagnostic studies and aggressive antimicrobial therapy are indicated, and surgery should be considered.

The use of the Internet and social applications has many benefits for the elderly, but numerous investigations have shown that the elderly do not perceive online social networks as a friendly social environment. Therefore, TreeIt, a social application specifically designed for the elderly, was developed for this study. In the TreeIt application, seven mechanisms promoting social interaction were designed to allow older adults to use social networking sites (SNSs) to increase social connection, maintain the intensity of social connections and strengthen social experience. This study's main objective was to investigate how user interface design affects older people's intention and attitude related to using SNSs. Fourteen user interface evaluation heuristics proposed by Zhang et al. were adopted as the criteria to assess user interface usability and further grouped into three categories: system support, user interface design and navigation. The technology acceptance model was adopted to assess older people's intention and attitude related to using SNSs. One hundred and one elderly persons were enrolled in this study as subjects, and the results showed that all of the hypotheses proposed in this study were valid: system support and perceived usefulness had a significant effect on behavioral intention; user interface design and perceived ease of use were positively correlated with perceived usefulness; and navigation exerted an influence on perceived ease of use. The results of this study are valuable for the future development of social applications for the elderly.

In this study, we examined the repeatability of computed tomography (CT) lung volume measurements in healthy individuals and patients with obstructive and restrictive lung diseases. To do this, we retrospectively enrolled 200 healthy individuals (group 1), 100 patients with obstructive lung disease (group 2), and 100 patients with restrictive lung disease (group 3) who underwent two consecutive chest CT scans within a 1-year period. The CT lung volume was measured using a threshold-based, three-dimensional auto-segmentation technique at a default range from -200 to -1024 HU. The within-subject standard deviation, repeatability coefficient, within-subject coefficient variability, and intraclass correlation coefficient were evaluated. No significant differences were identified between the two consecutive CT lung volume measurements in any of the groups (p> 0.05). The within-subject standard deviations for groups 1, 2, and 3 were 441.1, 387.0, and 288.6, respectively, while the repeatability coefficients were 1222.6, 1072.6, and 800.1, respectively. The within-subject coefficient variabilities for groups 1, 2, and 3 were 0.097, 0.083, and 0.090, respectively, while the intraclass correlation coefficients were 0.818, 0.881, and 0.910, respectively. The two CT lung volume measurements showed excellent agreement in healthy individuals and patients with obstructive or restrictive lung disease. However, the repeatability was lower in healthy individuals than it was in patients with lung diseases.

The aim of this study was to assess any potential additive effects of a treatment combining aliskiren with paricalcitol on reducing renal fibrosis. C57BL/6J mice were treated individually with aliskiren and/or paricalcitol until 7 days after initiation of unilateral ureteral obstruction (UUO).In obstructed kidneys of UUO mice, monotherapy with aliskiren or paricalcitol significantly attenuated interstitial fibrosis, collagen IV accumulation, and α-smooth muscle actin- and terminal deoxynucleotidyl transferase-mediated biotin nick end-labeling-positive cells. The combination treatment showed additive efficacy in inhibition of these parameters. Renal NADPH oxidase (Nox)1 and Nox2 were significantly decreased by aliskiren or paricalcitol alone or in combination, while renal Nox4 expression was significantly reduced by paricalcitol mono- or combination treatment. Increased levels of p-Erk and p-p38 MAPK, and NF-κB in UUO kidneys were also significantly reduced by either aliskiren or paricalcitol treatment alone or in combination. Aliskiren or paricalcitol monotherapy significantly reduced the expression of (pro)renin receptor in UUO kidneys. In addition, aliskiren tended to augment renin expression in UUO kidneys, but paricalcitol reduced its expression level. The combination treatment effectively blocked both (pro)renin receptor and renin expression induced by aliskiren, and resulted in a further reduction of the renal expression of angiotensin II AT1 receptor. Aliskiren failed to increase the expression of vitamin D receptor in UUO kidneys, but the combination treatment restored its expression level. Taken together, a treatment combining aliskiren with paricalcitol better inhibits UUO-induced renal injury. The mechanism of this synergy may involve more profound inhibition of the intrarenal renin-angiotensin system.

The aim of this retrospective, nationwide, matched cohort study was to investigate the association of serous retinal detachment with having end-stage renal disease (ESRD) while on dialysis. The cohort study included 94,024 patients with ESRD on dialysis registered between January 2000 to December 2009 in the Taiwan National Health Insurance Research Database. An age- and sex-matched control group comprised 94,024 patients selected from the Taiwan Longitudinal Health Insurance Database 2000. Information for each patient was collected from the index date until December 2011. Twenty-seven ESRD patients and 11 controls developed serous retinal detachment (P < 0.001) during follow-up, demonstrating a significantly increased risk of serous retinal detachment in patients with ESRD on dialysis compared with controls (incidence rate ratio = 3.39, 95% confidence interval [CI] = 1.68-6.83). After adjustment for potential confounders, patients were 3.86 times more likely to develop serous retinal detachment than the full cohort (adjusted HR = 3.86, 95% CI = 1.15-12.96). In conclusion, patients with ESRD on dialysis demonstrate an increased risk of serous retinal detachment. Interdisciplinary collaboration between nephrologists and ophthalmologists is important to deal with serous retinal detachment in patients with ESRD on dialysis and prevent impairments of visual acuity.

Rhodostomin (Rho) is a medium disintegrin containing a 48PRGDMP motif. We here showed that Rho proteins with P48A, M52W, and P53N mutations can selectively inhibit integrin αIIbβ3. To study the roles of the RGD loop and C-terminal region in disintegrins, we expressed Rho 48PRGDMP and 48ARGDWN mutants in Pichia pastoris containing 65P, 65PR, 65PRYH, 65PRNGLYG, and 65PRNPWNG C-terminal sequences. The effect of C-terminal region on their integrin binding affinities was αIIbβ3 > αvβ3 ≥ α5β1, and the 48ARGDWN-65PRNPWNG protein was the most selective integrin αIIbβ3 mutant. The 48ARGDWN-65PRYH, 48ARGDWN-65PRNGLYG, and 48ARGDWN-65PRNPWNG mutants had similar activities in inhibiting platelet aggregation and the binding of fibrinogen to platelet. In contrast, 48ARGDWN-65PRYH and 48ARGDWN-65PRNGLYG exhibited 2.9- and 3.0-fold decreases in inhibiting cell adhesion in comparison with that of 48ARGDWN-65PRNPWNG. Based on the results of cell adhesion, platelet aggregation and the binding of fibrinogen to platelet inhibited by ARGDWN mutants, integrin αIIbβ3 bound differently to immobilized and soluble fibrinogen. NMR structural analyses of 48ARGDWN-65PRYH, 48ARGDWN-65PRNGLYG, and 48ARGDWN-65PRNPWNG mutants demonstrated that their C-terminal regions interacted with the RGD loop. In particular, the W52 sidechain of 48ARGDWN interacted with H68 of 65PRYH, L69 of 65PRNGLYG, and N70 of 65PRNPWNG, respectively. The docking of the 48ARGDWN-65PRNPWNG mutant into integrin αIIbβ3 showed that the N70 residue formed hydrogen bonds with the αIIb D159 residue, and the W69 residue formed cation-π interaction with the β3 K125 residue. These results provide the first structural evidence that the interactions between the RGD loop and C-terminus of medium disintegrins depend on their amino acid sequences, resulting in their functional differences in the binding and selectivity of integrins.

Background: Sleep disordered breathing (SDB) and sleep disturbances have been reported to be associated with allergic rhinitis and asthma. However, population-based studies of this issue in the elderly are rare., Objective: To investigate the impact of self-reported rhinitis and asthma on sleep apnea and sleep quality using polysomnography in an elderly Korean population., Methods: A total of 348 elderly subjects who underwent one-night polysomnography study among a randomly selected sample were enrolled. Study subjects underwent anthropometric and clinical evaluations. Simultaneously, the prevalence and co-morbid status of asthma and allergic rhinitis, and subjective sleep quality were evaluated using a self-reported questionnaire., Results: Ever-diagnosis of allergic rhinitis was significantly more prevalent in subjects with SDB compared with those without SDB. Subjects with an ever-diagnosis of allergic rhinitis showed a higher O2 desaturation index and mean apnea duration. Indices regarding sleep efficiency were affected in subjects with a recent treatment of allergic rhinitis or asthma. Waking after sleep onset was longer and sleep efficiency was lower in subjects who had received allergic rhinitis treatment within the past 12 months. Subjects who had received asthma treatment within the past 12 months showed significantly lower sleep efficiency than others., Conclusion: Our study indicates that a history of allergic rhinitis is associated with increased risk of SDB in the elderly. Sleep disturbance and impaired sleep efficiency were found in the subjects who had received recent treatment of allergic rhinitis or asthma. Physicians should be aware of the high risk of sleep disorders in older patients with respiratory allergic diseases.

5-[18F]F-pyrazinamide (5-[18F]F-PZA), a radiotracer analog of the first-line tuberculosis drug pyrazinamide (PZA), was employed to determine the biodistribution of PZA using PET imaging and ex vivo analysis. 5-[18F]F-PZA was synthesized in 60 min using a halide exchange reaction. The overall decay-corrected yield of the reaction was 25% and average specific activity was 2.6 × 106 kBq (70 mCi)/μmol. The biodistribution of 5-[18F]F-PZA was examined in a pulmonary Mycobacterium tuberculosis mouse model, where rapid distribution of the tracer to the lung, heart, liver, kidney, muscle, and brain was observed. The concentration of 5-[18F]F-PZA was not significantly different between infected and uninfected lung tissue. Biochemical and microbiological studies revealed substantial differences between 5-F-PZA and PZA. 5-F-PZA was not a substrate for pyrazinamidase, the bacterial enzyme that activates PZA, and the minimum inhibitory concentration for 5-F-PZA against M. tuberculosis was more than 100-fold higher than that for PZA., Competing Interests: The authors have declared that no competing interests exist.

Objective: To investigate the trends in mortality, as well as in the timing and cause of death, among extremely preterm infants at the limit of viability, and thus to identify the clinical factors that contribute to decreased mortality., Methods: We retrospectively reviewed the medical records of 382 infants born at 23-26 weeks' gestation; 124 of the infants were born between 2001 and 2005 (period I) and 258 were born between 2006 and 2011 (period II). We stratified the infants into two subgroups-"23-24 weeks" and "25-26 weeks"-and retrospectively analyzed the clinical characteristics and mortality in each group, as well as the timing and cause of death. Univariate and multivariate logistic regression analyses were done to identify the clinical factors associated with mortality., Results: The overall mortality rate in period II was 16.7% (43/258), which was significantly lower than that in period I (30.6%; 38/124). For overall cause of death, there were significantly fewer deaths due to sepsis (2.4% [6/258] vs. 8.1% [10/124], respectively) and air-leak syndrome (0.8% [2/258] vs. 4.8% (6/124), respectively) during period II than during period I. Among the clinical factors of time period, 1-and 5-min Apgar score, antenatal steroid identified significant by univariate analyses. 5-min Apgar score and antenatal steroid use were significantly associated with mortality in multivariate analyses., Conclusion: Improved mortality rate attributable to fewer deaths due to sepsis and air leak syndrome in the infants with 23-26 weeks' gestation was associated with higher 5-minute Apgar score and more antenatal steroid use., Competing Interests: The authors have declared that no competing interests exist.

This study aimed to evaluate the association between rheumatoid arthritis (RA) and hearing impairment in the Korean adult population. Audiometric and laboratory test data from the 2010-2012 Korean National Health and Nutrition Examination Survey (KNHANES) were used for analysis. The relationship between RA and hearing impairment was analyzed, adjusting for various known risk factors associated with hearing impairment. RA was defined in the questionnaire as "RA diagnosed by a physician (yes/no) through a standardized interview." We defined hearing impairment according to 2 categories of frequency (low/mid and high) as follows (average values in kHz): low/mid frequency, 0.5, 1.0, and 2.0, and high frequency, 3.0, 4.0, and 6.0. Of the subjects, 15,158 (weighted n = 32,035,996) completed the audiometric tests. The overall weighted prevalence of RA was 1.5%. The prevalence of hearing impairment was higher in the subjects with RA than in those without RA, in both, the low/mid- and high-frequency categories (21.1% vs 7.5%, p < 0.001 and 43.3% vs. 26.2%, p < 0.001, respectively). In the multivariable logistic analysis, RA (odds ratios [OR] 1.47, 95% confidence interval [CI] 1.05-2.06, p = 0.025) was an independent risk factor of low/mid-frequency hearing impairment along with age (OR 1.12, 95% CI 1.12-1.13, p < 0.001), current smoking (OR 1.27, 95% CI 1.03-1.56, p = 0.026), and college graduation (OR 0.53, 95% CI 0.39-0.72, p < 0.001). In the multivariable analysis of high-frequency hearing impairment, RA did not show any association with hearing impairment. This study suggests that RA is associated with low/mid-frequency hearing impairment after adjustment for various known risk factors. Further study is needed to verify the hearing impairment in RA., Competing Interests: The authors have declared that no competing interests exist.

The multi-subunit mammalian Mediator complex acts as an integrator of transcriptional regulation by RNA Polymerase II, and has emerged as a master coordinator of development and cell fate determination. We previously identified the Mediator subunit, MED28, as a cytosolic binding partner of merlin, the Neurofibromatosis 2 (NF2) tumor suppressor, and thus MED28 is distinct in having a cytosolic role as an NF2 interacting protein as well as a nuclear role as a Mediator complex subunit. Although limited in vitro studies have been performed on MED28, its in vivo function remains unknown. Employing a knockout mouse model, we describe for the first time the requirement for Med28 in the developing mouse embryo. Med28-deficiency causes peri-implantation lethality resulting from the loss of pluripotency of the inner cell mass accompanied by reduced expression of key pluripotency transcription factors Oct4 and Nanog. Further, overexpression of Med28 in mouse embryonic fibroblasts enhances the efficiency of their reprogramming to pluripotency. Cre-mediated inactivation of Med28 in induced pluripotent stem cells shows that Med28 is required for their survival. Intriguingly, heterozygous loss of Med28 results in differentiation of induced pluripotent stem cells into extraembryonic trophectoderm and primitive endoderm lineages. Our findings document the essential role of Med28 in the developing embryo as well as in acquisition and maintenance of pluripotency during reprogramming.

The aim of this study was to determine the optimal route of mesenchymal stem cell (MSC) transplantation. To this end, gene expression profiling was performed to compare the effects of intratracheal (i.t.) versus intravenous (i.v.) MSC administration. Furthermore, the therapeutic efficacy of each route to protect against neonatal hyperoxic lung injury was also determined. Newborn Sprague-Dawley rats were exposed to hyperoxia (90% oxygen) from birth for 14 days. Human umbilical cord blood-derived MSCs labeling with PKH26 were transplanted through either the i.t. (5×10(5)) or i.v. (2×10(6)) route at postnatal day (P) 5. At P14, lungs were harvested for histological, biochemical and microarray analyses. Hyperoxic conditions induced an increase in the mean linear intercept and mean alveolar volume (MAV), indicative of impaired alveolarization. The number of ED-1 positive cells was significantly decreased by both i.t. and i.v. transplantations. However, i.t. administration of MSCs resulted in a greater decrease in MAV and ED-1 positive cells compared to i.v. administration. Moreover, the number of TUNEL-positive cells was significantly decreased in the i.t. group, but not in the i.v. group. Although the i.t. group received only one fourth of the number of MSCs that the i.v. group did, a significantly higher number of donor cell-derived red PKH 26 positivity were recovered in the i.t. group. Hyperoxic conditions induced the up regulation of genes associated with the inflammatory response, such as macrophage inflammatory protein-1 α, tumor necrosis factor-α and inter leukin-6; genes associated with cell death, such as p53 and caspases; and genes associated with fibrosis, such as connective tissue growth factor. In contrast, hyperoxic conditions induced the dwon-regulation of vascular endothelial growth factor and hepatocyte growth factor. These hyperoxia-induced changes in gene expression were decreased in the i.t. group, but not in the i.v. group. Thus, local i.t. MSC transplantation was more effective than systemic i.v. MSC administration in protecting against neonatal hyperoxic lung injury.

The study was conducted to determine whether patients with rheumatoid arthritis (RA) are at increased risk of acute pancreatitis compared with those without RA and to determine if the risk of acute pancreatitis varied by anti-RA drug use. We used the large population-based dataset from the National Health Insurance (NHI) program in Taiwan to conduct a retrospective cohort study. Patients newly diagnosed with RA between 2000 and 2011 were referred to as the RA group. The comparator non-RA group was matched with propensity score, using age and sex, in the same time period. We presented the incidence density by 100,000 person-years. The propensity score and all variables were analyzed in fully adjusted Cox proportional hazard regression. The cumulative incidence of acute pancreatitis was assessed by Kaplan-Meier analysis, with significance based on the log-rank test. From claims data of one million enrollees randomly sampled from the Taiwan NHI database, 29,755 adults with RA were identified and 119,020 non-RA persons were matched as a comparison group. The RA cohort had higher incidence density of acute pancreatitis (185.7 versus 119.0 per 100,000 person-years) than the non-RA cohort. The adjusted hazard ratio (HR) was 1.62 (95% CI [confidence interval] 1.43-1.83) for patients with RA to develop acute pancreatitis. Oral corticosteroid use decreased the risk of acute pancreatitis (adjusted HR 0.83, 95% CI 0.73-0.94) but without a dose-dependent effect. Current use of disease modifying anti-rheumatic drugs or tumor necrosis factor blockers did not decrease the risk of acute pancreatitis. In conclusion, patients with RA are at an elevated risk of acute pancreatitis. Use of oral corticosteroids may reduce the risk of acute pancreatitis.

Recently, we showed that intracerebroventricular (IC) transplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) significantly attenuates posthemorrhagic hydrocephalus (PHH) and brain damage after severe IVH in newborn rats. This study was performed to determine the optimal route for transplanting MSCs for severe IVH by comparing IC transplantation, intravenous (IV) transplantation, and IV transplantation plus mannitol infusion. Severe IVH was induced by injecting 100 uL of blood into each ventricle of Sprague-Dawley rats on postnatal day 4 (P4). After confirming severe IVH with brain magnetic resonance imaging (MRI) at P5, human UCB-derived MSCs were transplanted at P6 by an IC route (1×105), an IV route (5×105), or an IV route with mannitol infused. Follow-up brain MRIs and rotarod tests were performed. At P32, brain tissue samples were obtained for biochemical and histological analyses. Although more MSCs localized to the brain after IC than after IV delivery, both methods were equally effective in preventing PHH; attenuating impaired rotarod test; increasing the number of TUNEL-positive cells, inflammatory cytokines, and astrogliosis; and reducing corpus callosal thickness and myelin basic protein expression after severe IVH regardless of mannitol co-infusion. Despite the superior delivery efficacy with IC than with the IV route, both IC and IV transplantation of MSCs had equal therapeutic efficacy in protecting against severe IVH. These findings suggest that the less invasive IV route might be a good alternative for clinically unstable, very preterm infants that cannot tolerate a more invasive IC delivery of MSCs.

Diffusion tensor imaging (DTI) studies of human brain development have consistently shown widespread, but nonlinear increases in white matter anisotropy through childhood, adolescence, and into adulthood. However, despite its sensitivity to changes in tissue microstructure, DTI lacks the specificity to disentangle distinct microstructural features of white and gray matter. Neurite orientation dispersion and density imaging (NODDI) is a recently proposed multi-compartment biophysical model of brain microstructure that can estimate non-collinear properties of white matter, such as neurite orientation dispersion index (ODI) and neurite density index (NDI). In this study, we apply NODDI to 66 healthy controls aged 7-63 years to investigate changes of ODI and NDI with brain maturation, with comparison to standard DTI metrics. Using both region-of-interest and voxel-wise analyses, we find that NDI exhibits striking increases over the studied age range following a logarithmic growth pattern, while ODI rises following an exponential growth pattern. This novel finding is consistent with well-established age-related changes of FA over the lifespan that show growth during childhood and adolescence, plateau during early adulthood, and accelerating decay after the fourth decade of life. Our results suggest that the rise of FA during the first two decades of life is dominated by increasing NDI, while the fall in FA after the fourth decade is driven by the exponential rise of ODI that overcomes the slower increases of NDI. Using partial least squares regression, we further demonstrate that NODDI better predicts chronological age than DTI. Finally, we show excellent test-retest reliability of NODDI metrics, with coefficients of variation below 5% in all measured regions of interest. Our results support the conclusion that NODDI reveals biologically specific characteristics of brain development that are more closely linked to the microstructural features of white matter than are the empirical metrics provided by DTI.

Background: Thalidomide is known to have anti-inflammatory and immunomodulatory actions. However, the effect and the anti-asthmatic mechanism of thalidomide in the pathogenesis of asthmatic airways are not fully understood., Objective: This study is designed to determine the effect and the potential mechanism of thalidomide in the pathogenesis of asthmatic airways using animal model of allergic asthma., Methods: Six-week-old female BALB/C mice were sensitized with alum plus ovalbumin (OVA) and were exposed to OVA via intranasal route for 3 days for challenge. Thalidomide 200 mg/kg was given via gavage twice a day from a day before the challenge and airway hyperresponsivenss (AHR), airway inflammatory cells, and cytokines in bronchoalveolar lavage fluids (BALF) were evaluated. The expression levels of pro-inflammatory cytokines and other mediators were evaluated using ELISA, real time (RT)-qPCR, and flow cytometry. CRL-2456, alveolar macrophage cell line, was used to test the direct effect of thalidomide on the activation of macrophages in vitro., Results: The mice with thalidomide treatment showed significantly reduced levels of allergen-induced BALF and lung inflammation, AHR, and the expression of a number of pro-inflammatory cytokines and mediators including Th2 related, IL-17 cytokines, and altered levels of allergen-specific IgG1/IgG2a. Of interesting note, thalidomide treatment significantly reduced expression levels of allergen- or Th2 cytokine-stimulated alternative activation of macrophages in vivo and in vitro., Conclusion: These studies highlight a potential use of thalidomide in the treatment of allergic diseases including asthma. This study further identified a novel inhibitory effect of thalidomide on alternative activation of macrophages as a potential mechanism of anti-asthmatic effect of thalidomide.

Though hypothermia is the only clinically available treatment for neonatal hypoxic-ischemic encephalopathy (HIE), it is not completely effective in severe cases. We hypothesized that combined treatment with hypothermia and transplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) would synergistically attenuate severe HIE compared to stand-alone therapy. To induce hypoxia-ischemia (HI), male Sprague-Dawley rats were subjected to 8% oxygen for 120 min after unilateral carotid artery ligation on postnatal day (P) 7. After confirmation of severe HIE involving >50% of the ipsilateral hemisphere volume as determined by diffusion-weighted brain magnetic resonance imaging (MRI) within 2 h after HI, intraventricular MSC transplantation (1 × 105 cells) and/or hypothermia with target temperature at 32°C for 24 h were administered 6 h after induction of HI. Follow-up brain MRI at P12 and P42, sensorimotor function tests at P40-42, evaluation of cytokines in the cerebrospinal fluid (CSF) at P42, and histologic analysis of peri-infarct tissues at P42 were performed. Severe HI resulted in progressively increased brain infarction over time as assessed by serial MRI, increased number of cells positive for terminal deoxynucleotidyl transferase nick-end labeling, microgliosis and astrocytosis, increased CSF cytokine levels, and impaired function in behavioral tests such as rotarod and cylinder tests. All of the abnormalities observed in severe HIE showed greater improvement after combined treatment with hypothermia and MSC transplantation than with either therapy alone. Overall, these findings suggest that combined treatment with hypothermia and human UCB-derived MSC transplantation might be a novel therapeutic modality to improve the prognosis of severe HIE, an intractable disease that currently has no effective treatment.

Background: Though insurance claims data are useful for researching asthma, they have important limitations, such as a diagnostic inaccuracy and a lack of clinical information. To overcome these drawbacks, we used the novel method by merging the clinical data from our asthma cohort with the National Health Insurance (NHI) claims data., Methods and Results: Longitudinal analysis of asthma-related healthcare use from the NHI claims database, merged with data of 736 patients registered in a Korean asthma cohort, was conducted for three consecutive years from registration of the cohort. Asthma-related asthma healthcare referred to outpatient and emergency department visits, hospitalizations, and the use of systemic corticosteroids. Univariate and multivariate logistic regression analysis was used to evaluate risk factors for asthma-related healthcare. Over three years after enrollment, many patients changed from tertiary to primary/secondary hospitals with a lack of maintenance of inhaled corticosteroid-based controllers. An independent risk factor for emergency visits was a previous history of asthma exacerbation. In hospitalizations, old age and Asthma Control Test (ACT) score variability were independent risk factors. An independent risk factor for per person cumulative duration of systemic corticosteroids was the FEV1 (Forced expiratory volume in one second)%. The use of systemic corticosteroids was independently associated with being female, the FEV1%, and ACT score variability., Conclusion: We found that old age, being female, long-standing asthma, a low FEV1%, asthma brittleness, asthma drug compliance, and a history of asthma exacerbation were independent risk factors for increased asthma-related healthcare use in Korea.

Over 90% of children with Autism Spectrum Disorders (ASD) demonstrate atypical sensory behaviors. In fact, hyper- or hyporeactivity to sensory input or unusual interest in sensory aspects of the environment is now included in the DSM-5 diagnostic criteria. However, there are children with sensory processing differences who do not meet an ASD diagnosis but do show atypical sensory behaviors to the same or greater degree as ASD children. We previously demonstrated that children with Sensory Processing Disorders (SPD) have impaired white matter microstructure, and that this white matter microstructural pathology correlates with atypical sensory behavior. In this study, we use diffusion tensor imaging (DTI) fiber tractography to evaluate the structural connectivity of specific white matter tracts in boys with ASD (n = 15) and boys with SPD (n = 16), relative to typically developing children (n = 23). We define white matter tracts using probabilistic streamline tractography and assess the strength of tract connectivity using mean fractional anisotropy. Both the SPD and ASD cohorts demonstrate decreased connectivity relative to controls in parieto-occipital tracts involved in sensory perception and multisensory integration. However, the ASD group alone shows impaired connectivity, relative to controls, in temporal tracts thought to subserve social-emotional processing. In addition to these group difference analyses, we take a dimensional approach to assessing the relationship between white matter connectivity and participant function. These correlational analyses reveal significant associations of white matter connectivity with auditory processing, working memory, social skills, and inattention across our three study groups. These findings help elucidate the roles of specific neural circuits in neurodevelopmental disorders, and begin to explore the dimensional relationship between critical cognitive functions and structural connectivity across affected and unaffected children.

Cancer stem cells (CSCs) represent a unique sub-population of tumor cells with the ability to initiate tumor growth and sustain self-renewal. Although CSC biomarkers have been described for various tumors, only a few markers have been identified for nasopharyngeal carcinoma (NPC). In this study, we show that CD24+ cells isolated from human NPC cell lines express stem cell genes (Sox2, Oct4, Nanog, Bmi-1, and Rex-1), and show activation of the Wnt/β-catenin signaling pathway. CD24+ cells possess typical CSC characteristics that include enhanced cell proliferation, increased colony and sphere formation, maintenance of cell differentiation potential in prolonged culture, and enhanced resistance to chemotherapeutic drugs. Notably, CD24+ cells produce tumors following inoculation of as few as 500 cells in immunodeficient NOD/SCID mice. CD24+ cells further show increased invasion ability in vitro, which correlates with enhanced expression of matrix metalloproteinase 2 and 9. In summary, our results suggest that CD24 represents a novel CSC biomarker in NPC.

Peroxisome proliferator-activated receptor (PPAR)-α, a lipid-sensing transcriptional factor, serves an important role in lipotoxicity. We evaluated whether fenofibrate has a renoprotective effect by ameliorating lipotoxicity in the kidney. Eight-week-old male C57BLKS/J db/m control and db/db mice, divided into four groups, received fenofibrate for 12 weeks. In db/db mice, fenofibrate ameliorated albuminuria, mesangial area expansion and inflammatory cell infiltration. Fenofibrate inhibited accumulation of intra-renal free fatty acids and triglycerides related to increases in PPARα expression, phosphorylation of AMP-activated protein kinase (AMPK), and activation of Peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)-estrogen-related receptor (ERR)-1α-phosphorylated acetyl-CoA carboxylase (pACC), and suppression of sterol regulatory element-binding protein (SREBP)-1 and carbohydrate regulatory element-binding protein (ChREBP)-1, key downstream effectors of lipid metabolism. Fenofibrate decreased the activity of phosphatidylinositol-3 kinase (PI3K)-Akt phosphorylation and FoxO3a phosphorylation in kidneys, increasing the B cell leukaemia/lymphoma 2 (BCL-2)/BCL-2-associated X protein (BAX) ratio and superoxide dismutase (SOD) 1 levels. Consequently, fenofibrate recovered from renal apoptosis and oxidative stress, as reflected by 24 hr urinary 8-isoprostane. In cultured mesangial cells, fenofibrate prevented high glucose-induced apoptosis and oxidative stress through phosphorylation of AMPK, activation of PGC-1α-ERR-1α, and suppression of SREBP-1 and ChREBP-1. Our results suggest that fenofibrate improves lipotoxicity via activation of AMPK-PGC-1α-ERR-1α-FoxO3a signaling, showing its potential as a therapeutic modality for diabetic nephropathy.

The manipulation of vascular endothelial growth factor (VEGF)-receptors (VEGFRs) in diabetic nephropathy is as controversial as issue as ever. It is known to be VEGF-A and VEGFR2 that regulate most of the cellular actions of VEGF in experimental diabetic nephropathy. On the other hand, such factors as VEGF-A, -B and placenta growth factor bind to VEGFR1 with high affinity. Such notion instigated us to investigate on whether selective VEGFR1 inhibition with GNQWFI hexamer aggravates the progression of diabetic nephropathy in db/db mice. While diabetes suppressed VEGFR1, it did increase VEGFR2 expressions in the glomerulus. Db/db mice with VEGFR1 inhibition showed more prominent features with respect to, albuminuria, mesangial matrix expansion, inflammatory cell infiltration and greater numbers of apoptotic cells in the glomerulus, and oxidative stress than that of control db/db mice. All these changes were related to the suppression of diabetes-induced increases in PI3K activity and Akt phosphorylation as well as the aggravation of endothelial dysfunction associated with the inactivation of FoxO3a and eNOS-NOx. In cultured human glomerular endothelial cells (HGECs), high-glucose media with VEGFR1 inhibition induced more apoptotic cells and oxidative stress than did high-glucose media alone, which were associated with the suppression of PI3K-Akt phosphorylation, independently of the activation of AMP-activated protein kinase, and inactivation of FoxO3a and eNOS-NOx pathway. In addition, transfection with VEGFR1 siRNA in HGECs also suppressed PI3K-Akt-eNOS signaling. In conclusion, the specific blockade of VEGFR1 with GNQWFI caused severe renal injury related to profound suppression of the PI3K-Akt, FoxO3a and eNOS-NOx pathway, giving rise to the oxidative stress-induced apoptosis of glomerular cells in type 2 diabetic nephropathy.

White spot syndrome virus (WSSV) is a large enveloped virus. The WSSV viral particle consists of three structural layers that surround its core DNA: an outer envelope, a tegument and a nucleocapsid. Here we characterize the WSSV structural protein VP11 (WSSV394, GenBank accession number AF440570), and use an interactome approach to analyze the possible associations between this protein and an array of other WSSV and host proteins. Temporal transcription analysis showed that vp11 is an early gene. Western blot hybridization of the intact viral particles and fractionation of the viral components, and immunoelectron microscopy showed that VP11 is an envelope protein. Membrane topology software predicted VP11 to be a type of transmembrane protein with a highly hydrophobic transmembrane domain at its N-terminal. Based on an immunofluorescence assay performed on VP11-transfected Sf9 cells and a trypsin digestion analysis of the virion, we conclude that, contrary to topology software prediction, the C-terminal of this protein is in fact inside the virion. Yeast two-hybrid screening combined with co-immunoprecipitation assays found that VP11 directly interacted with at least 12 other WSSV structural proteins as well as itself. An oligomerization assay further showed that VP11 could form dimers. VP11 is also the first reported WSSV structural protein to interact with the major nucleocapsid protein VP664.

Neural vascular insufficiency plays an important role in diabetic peripheral neuropathy (DPN). Peroxisome proliferative-activated receptor (PPAR)α has an endothelial protective effect related to activation of PPARγ coactivator (PGC)-1α and vascular endothelial growth factor (VEGF), but its role in DPN is unknown. We investigated whether fenofibrate would improve DPN associated with endothelial survival through AMPK-PGC-1α-eNOS pathway. Fenofibrate was given to db/db mice in combination with anti-flt-1 hexamer and anti-flk-1 heptamer (VEGFR inhibition) for 12 weeks. The db/db mice displayed sensory-motor impairment, nerve fibrosis and inflammation, increased apoptotic cells, disorganized myelin with axonal shrinkage and degeneration, fewer unmyelinated fibers, and endoneural vascular rarefaction in the sciatic nerve compared to db/m mice. These findings were exacerbated with VEGFR inhibition in db/db mice. Increased apoptotic cell death and endothelial dysfunction via inactivation of the PPARα-AMPK-PGC-1α pathway and their downstream PI3K-Akt-eNOS-NO pathway were noted in db/db mice, human umbilical vein endothelial cells (HUVECs) and human Schwann cells (HSCs) in high-glucose media. The effects were more prominent in response to VEGFR inhibition. In contrast, fenofibrate treatment ameliorated neural and endothelial damage by activating the PPARα-AMPK-PGC-1α-eNOS pathway in db/db mice, HUVECs and HSCs. Fenofibrate could be a promising therapy to prevent DPN by protecting endothelial cells through VEGF-independent activation of the PPARα-AMPK-PGC-1α-eNOS-NO pathway.

Background: We have previously identified four distinct groups of asthma patients in KOREAN cohorts using cluster analysis: (A) smoking asthma, (B) severe obstructive asthma, (C) early-onset atopic asthma, and (D) late-onset mild asthma., Methods and Results: A longitudinal analysis of each cluster in a Korean adult asthma cohort was performed to investigate the clinical significance of asthma clusters over 12 months. Cluster A showed relatively high asthma control test (ACT) scores but relatively low FEV1 scores, despite a high percentage of systemic corticosteroid use. Cluster B had the lowest mean FEV1, ACT, and the quality of life questionnaire for adult Korean asthmatics (QLQAKA) scores throughout the year, even though the percentage of systemic corticosteroid use was the highest among the four clusters. Cluster C was ranked second in terms of FEV1, with the second lowest percentage of systemic corticosteroid use, and showed a marked improvement in subjective symptoms over time. Cluster D consistently showed the highest FEV1, the lowest systemic corticosteroid use, and had high ACT and QLQAKA scores., Conclusion: Our asthma clusters had clinical significance with consistency among clusters over 12 months. These distinctive phenotypes may be useful in classifying asthma in real practice.

This study is the first to use genome-wide association study (GWAS) data to evaluate the multidimensional genetic architecture underlying nasopharyngeal cancer. Since analysis of data from GWAS confirms a close and consistent association between elevated risk for nasopharyngeal carcinoma (NPC) and major histocompatibility complex class 1 genes, our goal here was to explore lesser effects of gene-gene interactions. We conducted an exhaustive genome-wide analysis of GWAS data of NPC, revealing two-locus interactions occurring between single nucleotide polymorphisms (SNPs), and identified a number of suggestive interaction loci which were missed by traditional GWAS analyses. Although none of the interaction pairs we identified passed the genome-wide Bonferroni-adjusted threshold for significance, using independent GWAS data from the same population (Stage 2), we selected 66 SNP pairs in 39 clusters with P<0.01. We identified that in several chromosome regions, multiple suggestive interactions group to form a block-like signal, effectively reducing the rate of false discovery. The strongest cluster of interactions involved the CREB5 gene and a SNP rs1607979 on chromosome 17q22 (P = 9.86×10(-11)) which also show trans-expression quantitative loci (eQTL) association in Chinese population. We then detected a complicated cis-interaction pattern around the NPC-associated HLA-B locus, which is immediately adjacent to copy-number variations implicated in male susceptibility for NPC. While it remains to be seen exactly how and to what degree SNP-SNP interactions such as these affect susceptibility for nasopharyngeal cancer, future research on these questions holds great promise for increasing our understanding of this disease's genetic etiology, and possibly also that of other gene-related cancers.

Objectives: The aim of this cohort study was to examine the role of the chemokine (C-X-C motif) ligand 9 (CXCL9) on nasopharyngeal carcinoma (NPC)., Materials & Methods: Sera from 205 NPC patients and 231 healthy individuals, and 86 NPC tumor samples were enrolled. CXCL9 expression in tissue samples was analyzed by quantitative real-time PCR and immunohistochemistry. CXCL9 serum concentrations were measured by enzyme-linked immunosorbent assay., Results: CXCL9 expression was significantly higher in tumors than in normal epithelium. CXCL9 serum concentrations were also significantly higher in NPC patients compared to those in healthy individuals (516.8±617.6 vs. 170.7±375.0 pg/mL, P<0.0001). Serum CXCL9 levels were significantly higher in NPC patients with higher tumor stages, nodal stages, and overall stages (P<0.001, P = 0.001, and P<0.001, respectively). We found a statistically significant correlation between the concentrations of CXCL9 and EBV DNA load in the NPC patients (Spearman's correlation analysis; r = 0.473, P<0.001; 95% confidence interval, 0.346-0.582). Moreover, NPC patients with higher CXCL9 levels (>290 pg/mL, median) before treatment had worse prognoses for overall survival and disease-free survival (P = 0.045 and P = 0.008, respectively). Multivariate logistic regression analyses also indicated that higher CXCL9 serum levels were an independent prognostic factor for disease-free survival (P = 0.015)., Conclusion: Our study demonstrated that CXCL9 is associated with tumor burden and aggressiveness of NPC tumors and the serum level of this ligand may be useful as a prognostic indicator.

Background: Bupropion, which is widely used in patients with depressive disorder, may cause allergic reactions. However, the real prevalence of these side effects may be overlooked and underreported due to the delayed onset phenomenon., Objective: This study aimed to estimate the real incidence of bupropion-induced urticaria and clarify the delayed onset phenomenon., Methods: We conducted a nationwide cohort study between 2000 and 2009 using Taiwan's National Health Insurance Dataset. Among 65,988 patients with depressive disorders, we identified new users of bupropion with depressive disorders (bupropion cohort, n = 2,839) and matched them at a ratio of 1:4 regarding age and sex (non-bupropion matched cohort, n = 11,356). The risk of urticaria was compared between the two cohorts., Results: The risk of urticaria occurrence was higher in bupropion users than in matched controls within 4 weeks of starting the medication (risk ratio 1.81; 95% confidence interval 1.28-2.54; p = 0.001). The occurrence of urticaria in the bupropion cohort were more frequent on Days 15-28 than Day 1-14 (p = 0.002). Cox proportional hazards model showed that a history of urticaria was an independent risk factor for developing bupropion-induced urticaria., Conclusions: Of the antidepressants, bupropion may pose a higher risk of drug-induced urticaria, and this condition might be ignored due to the delayed onset phenomenon. Depressive patients with a history of urticaria are at higher risk of the adverse drug reaction. This study emphasizes the need for increased clinical awareness of this adverse outcome to bupropion use.

Background: The epidemiology of cough in the elderly population has not been studied comprehensively. The present study aimed to investigate the epidemiology of cough in a community elderly population, particularly in relation with their comorbidity., Methods: A cross-sectional analysis was performed using a baseline dataset from the Korean Longitudinal Study on Health and Aging, a community-based elderly population cohort study. Three types of cough (frequent cough, chronic persistent cough, and nocturnal cough) were defined using questionnaires. Comorbidity was examined using a structured questionnaire. Health-related quality of life was assessed using the Short Form 36 questionnaire., Results: The prevalence was 9.3% for frequent cough, 4.6% for chronic persistent cough, and 7.3% for nocturnal cough. In multivariate logistic regression analyses, smoking, asthma and allergic rhinitis were found to be risk factors for cough in the elderly. Interestingly, among comorbidities, constipation and uncontrolled diabetes mellitus (HbA1c ≥ 8%) were also found to have positive associations with elderly cough. In the Short Form 36 scores, chronic persistent cough was independently related to impairment of quality of life, predominantly in the mental component., Conclusions: Cough has a high prevalence and is detrimental to quality of life in the elderly. Associations with smoking, asthma and rhinitis confirmed previous findings in younger populations. Previously unrecognised relationships with constipation and uncontrolled diabetes mellitus suggested the multi-faceted nature of cough in the elderly.