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Urban agglomerations (UAs), which serve as pivotal hubs for economic and innovative convergence, play a crucial role in enhancing internal circulation and strengthening external linkages. This study utilizes the China city-level multi-regional input-output tables, incorporating the Dagum Gini coefficient and kernel density estimation methods, to perform a thorough quantitative analysis. Disparities within the national and global value chains ("dual value chains") of Chinese UAs from 2012 to 2017 were assessed. Additionally, the logarithmic mean Divisia index (LMDI) method was applied to disaggregate the drivers of both national and global intermediate inputs (NII and GII). The study's key findings include the following: (1) The national value chain (NVC) within UAs exhibits robust growth, contrasting with the decline in the global value chain (GVC). (2) The inter-UA disparity contribution rate significantly surpasses the combined rates of intra-UA contribution and super-variation density. (3) Distinct evolutionary peak trends are discerned among various UAs within the "dual value chains", highlighting diverse spatial polarization characteristics and expansiveness. (4) The growth of the NVC has transitioned from a negative to a positive impact on NII, while the decline in GVC has substantially counteracted GII growth. Economic and demographic factors notably drive positive improvements in both NII and GII, whereas the efficiency of outflows presents a negative driving effect. Based on these findings, this study offers strategic recommendations to facilitate the effective integration of UAs into the new development paradigm, thereby providing a scientific basis for related decision-making processes. [ABSTRACT FROM AUTHOR]

Designers rely on sketching to visualize and refine their initial ideas, and virtual reality (VR) tools now facilitate sketching in immersive 3D environments. However, little research has been conducted on the differences in the visual and spatial processes involved in 3D versus 2D sketching and their effects on cognition. This study investigated potential differences in spatial and visual functions related to the use of 3D versus 2D sketching media by analyzing functional magnetic resonance imaging (fMRI) data. We recruited 20 healthy, right-handed students from the Department of Horticulture and Landscape Architecture with at least three years of experience in freehand landscape drawing. Using an Oculus Quest VR headset controller and a 12.9-inch iPad Pro with an Apple Pencil, we tested participants individually with 3D and 2D sketching, respectively. When comparing 2D and 3D sketches, our fMRI results revealed significant differences in the activation of several brain regions, including the right middle temporal gyrus, both sides of the parietal lobe, and the left middle occipital gyrus. We also compared different sketching conditions, such as lines, geometrical objects (cube), and naturalistic objects (perspective view of a tree), and found significant differences in the spatial and visual recognition of brain areas that support visual recognition, composition, and spatial perception. This finding suggests that 3D sketching environments, such as VR, may activate more visual–spatial functions during sketching compared to 2D environments. The result highlights the potential of immersive sketching environments for design-related processes and spatial thinking. [ABSTRACT FROM AUTHOR]

Abrupt changes in system states and dynamical behaviors are often observed in natural systems; such phenomena, named regime shifts, are explained as transitions between alternative steady states (more generally, attractors). Various methods have been proposed to detect regime shifts from time series data, but a generic detection method with theoretical linkage to underlying dynamics is lacking. Here, we provide a novel method named Nested-Library Analysis (NLA) to retrospectively detect regime shifts using empirical dynamic modeling (EDM) rooted in theory of attractor reconstruction. Specifically, NLA determines the time of regime shift as the cutting point at which sequential reduction of the library set (i.e., the time series data used to reconstruct the attractor for forecasting) optimizes the forecast skill of EDM. We illustrate this method on a chaotic model of which changing parameters present a critical transition. Our analysis shows that NLA detects the change point in the model system and outperforms existing approaches based on statistical characteristics. In addition, NLA empirically detected a real-world regime shift event revealing an abrupt change of Pacific Decadal Oscillation index around the mid-1970s. Importantly, our method can be easily generalized to various systems because NLA is equation-free and requires only a single time series. Author summary: Abrupt shifts in system dynamics, referred to as regime shifts, are common in natural systems and pose significant challenges for system management and risk assessment. Accurately detecting the change point that separates pre- and post-regime shift periods is crucial, as the data collected after regime shift can be more informative to forecast future system states. While numerous methods have been proposed to tackle this issue, identifying change points in chaotic systems remains difficult, in which regime shift signals can be concealed by chaotic dynamics. To address this issue, we propose Nested-Library Analysis (NLA), a machine learning method rooted in a data-driven, nonparametric framework for nonlinear dynamical systems, known as Empirical Dynamic Modeling (EDM). NLA effectively identifies the change points from time series data, even when the shifts in dynamics are nearly imperceptible due to chaotic behavior, surpassing the existing change point detection methods. As such, our method offers a generic solution for revealing the timing of regime shifts in a various type of dynamical system. [ABSTRACT FROM AUTHOR]

Background: Angiotensin receptor blockers (ARBs) are considered an alternative to angiotensin-converting enzyme inhibitors (ACEIs) in patients with acute myocardial infarction (AMI), but in the era of extensive use of preventive therapies and percutaneous coronary intervention, this has not been adequately evaluated in Asians. Methods: This retrospective cohort study used data from the Taiwan National Health Insurance Research Database. In total, 52,620 patients initially hospitalized due to AMI between 2002 and 2015 were assessed. Results: After propensity score matching, 14,993 patients each were assigned to ACEI and ARB groups. Patients who received ARBs had significantly lower all-cause mortality (adjusted hazard ratio [aHR]: 0.82; 95% confidence interval [CI]: 0.75–0.90) and hospitalization for heart failure (aHR: 0.92; 95% CI: 0.85–0.99) compared with those who received ACEIs at 18 month follow-up. No significant difference was observed between the two groups in terms of major adverse cardiovascular events (aHR: 098; 95% CI: 0.90–1.07), cardiovascular death (aHR: 0.82; 95% CI: 0.68–1.00), ischemia stroke (aHR: 0.93; 95% CI: 0.77–1.11), and nonfatal myocardial infarction (aHR: 1.04; 95% CI: 0.93–1.17). ARBs showed benefits in many subgroups in terms of all-cause mortality and cardiovascular death. Conclusions: Real-world data demonstrate that ARBs might be associated with lower all-cause mortality and hospitalization for heart failure compared with ACEIs among patients with AMI. [ABSTRACT FROM AUTHOR]

Background: Sarcopenia and muscle weakness in elderly are contributed burden of public health and impact on quality of life. Weak grip strength was key role in diagnosis of sarcopenia and reported increased mortality, function declined in elderly. This study evaluated the association between GS and each common anthropometric characteristic in community-dwelling elderly. Design and method: From 2017 to 2019, we conducted a community-based health survey among the elderly in Chiayi county, Taiwan. Participants were 65 years old or older, and total of 3,739 elderly subjects (1,600 males and 2,139 females) with a mean age of 76 years (range 65–85 years old) were recruited. General demographic data and lifestyle patterns were measured using a standard questionnaire. Anthropometric characteristics such as body height, body weight, body mass index (BMI), body waist and hip circumference, and body fat were measured by standard methods. GS was measured using a digital dynamometers (TKK5101) method. Results: The mean GS was 32.8 ± 7.1 kg for males and 21.6 ± 4.8 kg for females (p < 0.001). For both sexes, elderly subjects with the same body weight but smaller body waist circumference had greater GS. The subjects with the same body waist size but heavier weight had greater GS. Furthermore, after adjusting for age, lifestyles, disease status, and potential anthropometric variable, multivariate regression analyses indicated that BMI was positively associated with GS (for males, beta = 0.310 and for females beta = 0.143, both p < 0.001) and body waist was negatively associated with GS (for males, beta = −0.108, p < 0.001; for females, beta = −0.030, p = 0.061). Conclusions: This study suggested that old adults with higher waist circumstance had weaker GS. Waist circumstance was negatively associated with GS, body weight was positively associated with GS in contrast. It may implies that central obesity was more important than overweight for GS in elderly. [ABSTRACT FROM AUTHOR]

Human umbilical cord Wharton's jelly derived mesenchymal stem cells (hUCMSCs), a source of cell therapy, have received a great deal of attention due to their homing or migrating ability in response to signals emanating from damaged sites. It has been found that IL-1β possesses the ability to induce the expression of matrix metalloproteinase-3 (MMP-3) in bone marrow MSCs. MMP-3 is involved in cell migration in various types of cells, including glioblastoma, vascular smooth muscle, and adult neural progenitor cells. In this study, we proposed that IL-1β influences hUCMSCs migration involving MMP-3. The expression level of MMP-3 in IL-1β-induced hUCMSCs was verified using cDNA microarray analysis, quantitative real-time PCR, ELISA and Western blot. Wound-healing and trans-well assay were used to investigate the cell migration and invasion ability of IL-1β-treated hUCMSCs. In addition, we pre-treated hUCMSCs with interleukin-1 receptor antagonist, MMP-3 inhibitors (ALX-260-165, UK 356618), or transfected with MMP-3 siRNA to confirm the role of MMP3 in IL-1β-induced cell migration. Our results showed that IL-1β induced MMP-3 expression is related to the migration of hUCMSCs. Moreover, extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) inhibitor U0126, p38 inhibitor SB205380, JNK inhibitor SP600125 and Akt inhibitor GSK 690693 decreased IL-1β-induced MMP-3 mRNA and protein expression. The migration and invasion ability analyses showed that these inhibitors attenuated the IL-1β-induced migration and invasion ability of hUCMSCs. In conclusion, we have found that IL-1β induces the expression of MMP-3 through ERK1/2, JNK, p38 MAPK and Akt signaling pathways to enhance the migration of hUCMSCs. These results provide further understanding of the mechanisms in IL-1β-induced hUCMSCs migration to injury sites. [ABSTRACT FROM AUTHOR]

Incessant antigenic evolution enables the persistence and spread of influenza virus in the human population. As the principal target of the immune response, the hemagglutinin (HA) surface antigen on influenza viruses continuously acquires and replaces N-linked glycosylation sites to shield immunogenic protein epitopes using host-derived glycans. Anti-glycan antibodies, such as 2G12, target the HIV-1 envelope protein (Env), which is even more extensively glycosylated and contains under-processed oligomannose-type clusters on its dense glycan shield. Here, we illustrate that 2G12 can also neutralize human seasonal influenza A H3N2 viruses that have evolved to present similar oligomannose-type clusters on their HAs from around 20 years after the 1968 pandemic. Using structural biology and mass spectrometric approaches, we find that two N-glycosylation sites close to the receptor binding site (RBS) on influenza hemagglutinin represent the oligomannose cluster recognized by 2G12. One of these glycan sites is highly conserved in all human H3N2 strains and the other emerged during virus evolution. These two N-glycosylation sites have also become crucial for fitness of recent H3N2 strains. These findings shed light on the evolution of the glycan shield on influenza virus and suggest 2G12-like antibodies can potentially act as broad neutralizers to target human enveloped viruses. Author summary: The isolation of broadly neutralizing antibodies from HIV-1 patients has shed light on the design of HIV-1 vaccines. Among them, one group consisting of anti-carbohydrate antibodies target N-glycans that compose the glycan shield on the Envelope surface glycoprotein (Env) of HIV-1. Similar to HIV-1, human H3N2 influenza viruses are highly glycosylated due to the accumulation of N-glycosylation sites over the past 50 years of natural evolution. Here, we demonstrate that an anti-HIV-1 antibody, namely 2G12, can neutralize human H3N2 viruses from the past 35 years. Comprehensive analyses by mass spectrometry and negative-stain electron microscopy reveal that oligomannose on two N-glycosylation sites near the receptor binding site are the targets of 2G12. Of note, the distance and disposition between the two glycans are the same as the equivalent oligomannose cluster on HIV-1 Env. Furthermore, mutational study shows that these two N-glycosylation sites are both required for survival of the recent H3N2 strains. Our data suggest that 2G12 can broadly neutralize non-HIV-1 human viruses by targeting oligomannose sugars, if of sufficient density and disposition on the viral surface. Since many viral surface antigens are highly glycosylated, it is worth evaluating 2G12-like antibodies as potential general therapeutics for human viral pathogens. [ABSTRACT FROM AUTHOR]

Finding suitable habitats for specific functions such as breeding provides examples of key biotic adaptation. The adult marine midge Pontomyia oceana requires an extremely specific habitat, i.e., hard substrates above water in shallow water, to deposit fertilized eggs. We investigated how these sea surface-skimming insects accomplished this with a stringent time constraint of 1–2 h of the adult life span in the evenings. We observed that in artificial containers, midges aggregated at bright spots only if the light was not in the direction of the sea. This behavior could potentially attract midges toward the shore and away from the open water. Experiments were performed in the intertidal zone in southern Taiwan to test three hypotheses explaining such behavior: gradients of temperature and CO2, and soundscape. No differences were observed in moving directions or aggregation of midges under artificial temperature and CO2 gradients. However, midges preferred sounds at 75 Hz compared with other frequencies (all ≤300 Hz) as observed in a field experiment involving floating traps with loudspeakers. Moreover, when background noise was experimentally masked using white noise of all frequencies, midges were significantly more likely to aggregate at bright spots in the direction of the sea than in the absence of white noise. These results establish that sound is used by midges to navigate in dark seas and move toward the shore where exposed hard substrates are in abundance. Marine mammals present well-known cases of sound pollution at sea; here the finding in the insignificant marine midge is just the harbinger of the potential effects noise at shore may have to affect critical reproductive stages of marine organisms. [ABSTRACT FROM AUTHOR]

Introduction: Known to have pleiotropic functions, high-density lipoprotein (HDL) helps to regulate systemic inflammation during sepsis. As preserving HDL-C level is a promising therapeutic strategy for sepsis, the interaction between HDL and sepsis worth further investigation. This study aimed to determine the impact of sepsis on HDL's anti-inflammatory capacity and explore its correlations with disease severity and laboratory parameters. Methods and materials: We enrolled 80 septic subjects admitted to the intensive care unit and 50 controls admitted for scheduled coronary angiography in this cross-sectional study. We used apolipoprotein-B depleted (apoB-depleted) plasma to measure the anti-inflammatory capacity of HDL-C. ApoB-depleted plasma's anti-inflammatory capacity is defined as its ability to suppress tumor necrosis factor-α–induced vascular cell adhesion molecule-1 (VCAM-1) expression in human umbilical-vein endothelial cells. A subgroup analysis was conducted to investigate in septic subjects according to disease severity. Results: ApoB-depleted plasma's anti-inflammatory capacity was reduced in septic subjects relative to controls (VCAM-1 mRNA fold change: 50.1% vs. 35.5%; p < 0.0001). The impairment was more pronounced in septic subjects with than in those without septic shock (55.8% vs. 45.3%, p = 0.0022). Both associations were rendered non-significant with the adjustment for the HDL-C level. In sepsis patients, VCAM-1 mRNA fold change correlated with the SOFA score (Spearman's r = 0.231, p = 0.039), lactate level (r = 0.297, p = 0.0074), HDL-C level (r = –0.370, p = 0.0007), and inflammatory markers (C-reactive protein level: r = 0.441, p <0.0001; white blood cell: r = 0.353, p = 0.0013). Conclusion: ApoB-depleted plasma's anti-inflammatory capacity is reduced in sepsis patients and this association depends of HDL-C concentration. In sepsis patients, this capacity correlates with disease severity and inflammatory markers. These findings explain the prognostic role of the HDL-C level in sepsis and indirectly support the rationale for targeting HDL-C as sepsis treatment. [ABSTRACT FROM AUTHOR]

We present a two-tiered microchip system to capture and retrieve rare cells from blood samples with high purity. The first module of the system is a high throughput microfluidic interface that is used to immunomagnetically isolate targeted rare cells from whole blood, and discard > 99.999% of the unwanted leukocytes. The second module is a microwell array that furthers the purification by magnetically guiding each cell into a separate well concurrently, and allows individual retrieval of each cell. We demonstrate the design of the system as well as its characterization by experiments using model cell lines that represent circulating fetal trophoblasts. Our results show that single cells can be retrieved with efficiencies and purities as high as 100% within 145 mins. [ABSTRACT FROM AUTHOR]

Background: Learning self-efficacy, defined as learners’ confidence in their capability to learn specific subjects, is crucial for the enhancement of academic progress, because it is positively correlated with academic achievements and effective learning strategy use. In this study, we developed a universal scale called the Learning Self-Efficacy Scale (L-SES) for Clinical Skills for undergraduate medical students and validated it through item analysis and content validity index (CVI) calculation. Design: The L-SES was developed based on the framework of Bloom’s taxonomy, and the questions were generated through expert consensus and CVI calculation. A pilot version of the L-SES was administered to 235 medical students attending a basic clinical skills course. The collected data were then examined through item analysis. Results: The first draft of the L-SES comprised 15 questions. After expert consensus and CVI calculation, 3 questions were eliminated; hence, the pilot version comprised 12 questions. The CVI values of the 12 questions were between .88 and 1, indicating high content validity. Moreover, the item analysis indicated that the quality of L-SES reached the qualified threshold. The results showed that the L-SES scores were unaffected by gender (t = −0.049; 95% confidence interval [−.115, .109], p > .05). Conclusion: The L-SES is a short, well-developed scale that can serve as a generic assessment tool for measuring medical students’ learning self-efficacy for clinical skills. Moreover, the L-SES is unaffected by gender differences. However, additional analyses in relevant educational settings are needed. [ABSTRACT FROM AUTHOR]

Hyperlipidemia is a risk factor of arteriosclerosis, stroke, and other coronary heart disease, which has been shown to correlate with single nucleotide polymorphisms of genes essential for lipid metabolism, such as lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5). In this study, the effect of magnolol, the main active component extracted from Magnolia officinalis, on LPL activity was investigated. A dose-dependent up-regulation of LPL activity, possibly through increasing LPL mRNA transcription, was observed in mouse 3T3-L1 pre-adipocytes cultured in the presence of magnolol for 6 days. Subsequently, a transgenic knock-in mice carrying APOA5 c.553G>T variant was established and then fed with corn oil with or without magnolol for four days. The baseline plasma triglyceride levels in transgenic knock-in mice were higher than those in wild-type mice, with the highest increase occurred in homozygous transgenic mice (106 mg/dL vs 51 mg/dL, p<0.01). After the induction of hyperglyceridemia along with the administration of magnolol, the plasma triglyceride level in heterozygous transgenic mice was significantly reduced by half. In summary, magnolol could effectively lower the plasma triglyceride levels in APOA5 c.553G>T variant carrier mice and facilitate the triglyceride metabolism in postprandial hypertriglyceridemia. [ABSTRACT FROM AUTHOR]

Background: Studies have shown a higher risk of depressive disorders in children with sleep apnea than in those without sleep apnea. However, the association between sleep apnea and subsequent depressive disorders in the pediatric population remains undetermined. Thus, this study investigated the risk of depressive disorders among pediatric patients with sleep apnea. Methods: In this study, the population-based National Health Insurance Research Database of Taiwan was used to identify patients who had first been diagnosed with sleep apnea between 1999 and 2013. Patients with sleep apnea who were younger than 18 years were included in the sleep apnea group. Controls (those without sleep apnea) were matched to patients with sleep apnea at a 1:10 ratio by age, sex, and index year. Patients who had baseline or inherited depressive disorders before the enrollment date were excluded. The two groups were followed up until December 31, 2013. The primary endpoint was the occurrence of one or more depressive disorders. Results: At the end of this study, 6,237 children had been enrolled, comprising 567 children with sleep apnea and 5,670 children without sleep apnea. During the mean follow-up period of 5.87 years, a total of 77 children (1.23%) developed one or more depressive disorders; 14 (2.46%) from the sleep apnea group and 63 (1.11%) from the control group. Kaplan–Meier analysis showed that children with sleep apnea had a significantly higher risk of depressive disorders (log-rank test, p = 0.002). After adjusting for covariates, the risk of subsequent depressive disorders among children with sleep apnea was still significantly higher (hazard ratio [HR] = 2.25; 95% confidence interval [CI] = 1.25–4.05; p = 0.006). Moreover, boys with sleep apnea had a significantly higher risk than those without sleep apnea (adjusted HR = 3.77; 95% CI, 1.82–7.54; p < 0.001). Furthermore, in sleep apnea group, children older than 12 years of age had more risk to depression (hazard ratio (HR) = 7.1833, 95% confidence interval (CI), 2.3734 to 21.7411; p = 0.0004). Conclusions: This study found a significantly higher subsequent risk of depressive disorders in children with sleep apnea, particularly boys and those older than 12 years of age. The study findings strongly suggest that clinicians should provide psychological evaluation and supportive care for children with sleep apnea, in addition to medical treatment. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) is a species-specific pathogenic virus that infects only humans and chimpanzees. Previous studies have indicated that interactions between the HCV E2 protein and CD81 on host cells are required for HCV infection. To determine the crucial factors for species-specific interactions at the molecular level, this study employed in silico molecular docking involving molecular dynamic simulations of the binding of HCV E2 onto human and rat CD81s. In vitro experiments including surface plasmon resonance measurements and cellular binding assays were applied for simple validations of the in silico results. The in silico studies identified two binding regions on the HCV E2 loop domain, namely E2-site1 and E2-site2, as being crucial for the interactions with CD81s, with the E2-site2 as the determinant factor for human-specific binding. Free energy calculations indicated that the E2/CD81 binding process might follow a two-step model involving (i) the electrostatic interaction-driven initial binding of human-specific E2-site2, followed by (ii) changes in the E2 orientation to facilitate the hydrophobic and van der Waals interaction-driven binding of E2-site1. The sequence of the human-specific, stronger-binding E2-site2 could serve as a candidate template for the future development of HCV-inhibiting peptide drugs. [ABSTRACT FROM AUTHOR]

A recent theory suggests that endocytosis is involved in uptake and intracellular transport of electrotransfected plasmid DNA (pDNA). The goal of the current study was to understand if approaches used previously to improve endocytosis of gene delivery vectors could be applied to enhancing electrotransfection efficiency (eTE). Results from the study showed that photochemically induced endosomal escape, which could increase poly-L-lysine (PLL)-mediated gene delivery, decreased eTE. The decrease could not be blocked by treatment of cells with endonuclease inhibitors (aurintricarboxylic acid and zinc ion) or antioxidants (L-glutamine and ascorbic acid). Chemical treatment of cells with an endosomal trafficking inhibitor that blocks endosome progression, bafilomycin A1, resulted in a significant decrease in eTE. However, treatment of cells with lysosomotropic agents (chloroquine and ammonium chloride) had little effects on eTE. These data suggested that endosomes played important roles in protecting and intracellular trafficking of electrotransfected pDNA. [ABSTRACT FROM AUTHOR]

Background: No population-based irritable bowel syndrome (IBS) incidence data among Taiwanese adults are available. Whether IBS is associated with risk of organic colonic diseases remains unanswered. We investigated 1) the sex- and age-stratified trends in the annual incidence of IBS, and 2) the risk of selected organic diseases in patients with IBS compared with those without IBS among Taiwanese adults during 2003–2013. Methods: Medical claims data for 1 million randomly selected beneficiaries were obtained and analyzed. Patients with IBS were considered eligible for enrollment if they aged between 20 and 100 and had at least two medical encounters with IBS codes within 1 year. To test whether there was a linear secular trend in IBS incidence over time, multivariate Poisson regression with generalized estimating equation model was conducted. The risk of selected organic diseases associated with IBS was examined using multivariate Cox proportional hazard regression. Results: From 2003 to 2013, the incidence of IBS significantly decreased over time [adjusted incidence rate ratio (IRR) = 0.97, p< 0.001]; the incidence of IBS significantly increased with age (adjusted IRR = 1.03, p < 0.001) and was significantly higher in women than in men (adjusted IRR = 1.14, p< 0.001). IBS significantly associated with increased risk of microscopic colitis, inflammatory bowel disease, and colorectal cancer during a 10-year follow-up period. Conclusions: The incidence of IBS increased with age and was slightly higher in women than in men among Taiwanese adults. During 2003–2013, IBS incidence gradually decreased over time. IBS may increase risk of several colonic organic diseases. [ABSTRACT FROM AUTHOR]

Background: Identification of patients at risk of death from cancer surgery should aid in preoperative preparation. The purpose of this study is to assess and adjust the age-adjusted Charlson comorbidity index (ACCI) to identify cancer patients with increased risk of perioperative mortality. Methods: We identified 156,151 patients undergoing surgery for one of the ten common cancers between 2007 and 2011 in the Taiwan National Health Insurance Research Database. Half of the patients were randomly selected, and a multivariate logistic regression analysis was used to develop an adjusted-ACCI score for estimating the risk of 90-day mortality by variables from the original ACCI. The score was validated. The association between the score and perioperative mortality was analyzed. Results: The adjusted-ACCI score yield a better discrimination on mortality after cancer surgery than the original ACCI score, with c-statics of 0.75 versus 0.71. Over 80 years of age, 70–80 years, and renal disease had the strongest impact on mortality, hazard ratios 8.40, 3.63, and 3.09 (P < 0.001), respectively. The overall 90-day mortality rates in the entire cohort varied from 0.9%, 2.9%, 7.0%, and 13.2% in four risk groups stratifying by the adjusted-ACCI score; the adjusted hazard ratio for score 4–7, 8–11, and ≥ 12 was 2.84, 6.07, and 11.17 (P < 0.001), respectively, in 90-day mortality compared to score 0–3. Conclusions: The adjusted-ACCI score helps to identify patients with a higher risk of 90-day mortality after cancer surgery. It might be particularly helpful for preoperative evaluation of patients over 80 years of age. [ABSTRACT FROM AUTHOR]

Objective: The transition from childhood to teenaged years is associated with increased testosterone and a decreased iron status. It is not clear whether higher testosterone levels cause the decreased iron status, and to what extent, obesity-related inflammation influences the iron-testosterone relationship. The aim of the present study was to examine relationships of testosterone, iron status, and anti-/proinflammatory cytokines in relation to nutritional status in boys and young adolescent Taiwanese males. Methods: In total, 137 boys aged 7~13 yr were included. Parameters for obesity, the iron status, testosterone, and inflammatory markers were evaluated. Results: Overweight and obese (ow/obese) boys had higher mean serum testosterone, interleukin (IL)-1β, and nitric oxide (NO) levels compared to their normal-weight counterparts (all p<0.05). Mean serum ferritin was slightly higher in ow/obese boys compared to normal-weight boys, but this did not reach statistical significance. A multiple linear regression showed that serum ferritin (β = -0.7470, p = 0.003) was inversely correlated with testosterone, while serum IL-10 (β = 0.3475, p = 0.009) was positively associated with testosterone after adjusting for covariates. When normal-weight boys were separately assessed from ow/obesity boys, the association between testosterone and serum ferritin became stronger (β = -0.9628, p<0.0001), but the association between testosterone and IL-10 became non-significant (β = 0.1140, p = 0.4065) after adjusting for covariates. In ow/obese boys, only IL-10 was weakly associated with serum testosterone (β = 0.6444, p = 0.051) after adjusting for age. Conclusions: Testosterone and serum ferritin are intrinsically interrelated but this relationship is weaker in ow/obese boys after adjusting for age. [ABSTRACT FROM AUTHOR]

Malignant clonal cells purification can greatly benefit basic and clinical studies in myelodysplastic syndrome (MDS). In this study, we investigated the potential of using type 1 insulin-like growth factor receptor (IGF-IR) as a marker for purification of malignant bone marrow clonal cells from patients with MDS. The average percentage of IGF-IR expression in CD34+ bone marrow cells among 15 normal controls was 4.5%, 70% of which also express the erythroid lineage marker CD235a. This indicates that IGF-IR mainly express in erythropoiesis. The expression of IGF-IR in CD34+ cells of 55 MDS patients was significantly higher than that of cells from the normal controls (54.0 vs. 4.5%). Based on the pattern of IGF-IR expression in MDS patients and normal controls, sorting of IGF-IR-positive and removal of CD235a-positive erythroid lineage cells with combination of FISH detection were performed on MDS samples with chromosomal abnormalities. The percentage of malignant clonal cells significantly increased after sorting. The enrichment effect was more significant in clonal cells with a previous percentage lower than 50%. This enrichment effect was present in samples from patients with +8, 5q-/-5, 20q-/-20 or 7q-/-7 chromosomal abnormalities. These data suggest that IGF-IR can be used as a marker for MDS bone marrow clonal cells and using flow cytometry for positive IGF-IR sorting may effectively purify MDS clonal cells. [ABSTRACT FROM AUTHOR]

Background: Staphylococcus aureus is an important cause of infection, and brings additional concern with methicillin resistance. In addition, nasal methicillin-resistant Staphylococcus aureus (MRSA) colonization rates among health care workers are higher than that for general population. To determine the prevalence rate and risk factors for the colonization of S. aureus, including MRSA, among janitors working in hospitals in northern Taiwan, we conducted this study. Methods: Between June and August, 2014, a total of 186 janitors, 111 working in hospitals and 75 working in non-medical institutions, were recruited. Specimens were obtained from the nares of the subjects for the detection of S. aureus, with a questionnaire completed for each subject. All the S. aureus isolates, including MRSA and methicillin-susceptible S. aureus (MSSA), were further molecularly characterized. Results: The nasal carriage rate of S. aureus was 15.3% for hospital janitors and 13.3% for non-medical janitors. The carriage rate of MRSA was 3.6% for hospital janitors and 1.3% for non-medical janitors. No statistically significant difference was found in the nasal carriage rate of S. aureus (p = 0.707) and MRSA (p = 0.65) between hospital janitors and non-medical janitors. Hospital janitors working in hospital more than 6 years and cleaning microbiologic laboratories were significantly associated with nasal S. aureus colonization. All 5 MRSA isolates carried either staphylococcal cassette chromosome type IV or V and three of them belonged to sequence type (ST) 59, the community clone prevailing in Taiwan. Of the 22 MSSA isolates, six pulsotypes were identified, with one major type for 14 isolates (shared by five STs) and another type for 4 isolates (all belonged to ST 188). Conclusion: Exposure to the hospital environment may not increase the nasal carriage rate of S. aureus, including MRSA, among janitors in hospitals in Taiwan. However, for janitors in the hospital setting, working for more than six years in hospital and cleaning laboratories may be risks factors for carrying S. aureus. [ABSTRACT FROM AUTHOR]

Background & Aims: To evaluate the risk of depressive disorders among patients with Hepatocellular Carcinoma (HCC) using the National Health Insurance Research Database (NHIRD) in Taiwan. Methods: We conducted a retrospective study of a newly diagnosed HCC cohort of 55,973 participants who were selected from the NHIRD. Patients were observed for a maximum of 6 years to determine the rates of newly onset depressive disorders, and Cox regression was used to identify the risk factors associated with depressive disorders in HCC patients. Results: Of the total 55,973 HCC patients, 1,041 patients (1.86%) were diagnosed with depressive disorders during a mean (SD) follow-up period of 1.1 (1.2) years. The Cox multivariate proportional hazards analysis showed that age of 40–59 (HR 1.376, 95% CI 1.049–1.805, p = 0.021), age of 60–79 (HR 1.341, 95% CI 1.025–1.753, p = 0.032), women (HR 1.474 95% CI 1.301–1.669, p < 0.001), metastasis (HR 1.916, 95% CI 1.243–2.953, p = 0.003), and HCV (HR 1.445, 95% CI 1.231–1.697, p < 0.001) were independent risk factors for developing depressive disorders. Conclusions: Our study indicated a subsequent risk of depressive disorders in patients with HCC, and the risk increased for those with female gender, aged 40 to 59, aged 60 to 79, with metastasis, or with HCV. Psychological evaluation and support are two critical issues in these HCC patients with the risk factors. [ABSTRACT FROM AUTHOR]

Background: Breast cancer survivors have an increased risk of bone fracture. But the risk among young patients with adjuvant therapies remains unknown. This population-based study is aimed to assess the incidence and risk of fracture among young (age of 20 to 39 years) breast cancer patients who received adjuvant therapies. Methods: From January 2001 to December 2007, 5,146 newly diagnosed breast cancer patients were enrolled from the National Health Insurance Research Database (NHIRD) in Taiwan. Patients were observed for a maximum of 6 years to determine the incidence of newly onset fracture. Kaplan Meier and Cox regression analyses were used to evaluate the risk of fracture in young breast cancer patients who received adjuvant treatments. Results: Of the total 5,146 young (age of 20 to 39 years) breast cancer patients, the Cox multivariate proportional hazards analysis showed that AIs, radiotherapy, and monoclonal antibodies were significantly associated with a high risk of fracture. Moreover, patients who received AIs for more than 180 days had a high hazard ratio (HR) of 1.77 (95% CI = 0.68–4.57), and patients who received more than four radiotherapy visits had a high HR of 2.54 (95% CI = 1.07–6.06). Under the site-specific analysis, young breast cancer patients who received AIs had the highest risk of hip fracture (HR = 8.520, 95% CI = 1.711–42.432, p < 0.04), whereas patients who received radiotherapy had the highest risk of vertebral fracture (HR = 5.512, 95% CI = 1.847–16.451, p < 0.01). Conclusion: Young breast cancer patients who are receiving AIs, radiotherapy or monoclonal antibody need to be more careful for preventing fracture events. Breast cancer treatment plans are suggested to incorporate fracture prevention interventions. [ABSTRACT FROM AUTHOR]

Background: Most patients with facial scarring would value even a slight improvement in scar quality. Botulinum toxin A is widely used to alleviate facial dynamic rhytides but is also believed to improve scar quality by reducing wound tension during healing. The main objective was to assess the effect of Botulinum toxin on scars resultant from standardized upper lip wounds. Methods: In this double-blinded, randomized, vehicle-controlled, prospective clinical trial, 60 consecutive consenting adults undergoing cleft lip scar revision (CLSR) surgery between July 2010 and March 2012 were randomized to receive botulinum toxin A (n = 30) or vehicle (normal saline; n = 30) injections into the subjacent orbicularis oris muscle immediately after wound closure. Scars were independently assessed at 6-months follow-up in blinded fashion using: Vancouver Scar Scale (VSS), Visual Analogue Scale (VAS) and photographic plus ultrasound measurements of scar widths. Results: 58 patients completed the trial. All scar assessment modalities revealed statistically significantly better scars in the experimental than the vehicle-control group. Conclusion: Quality of surgical upper lip scars, which are oriented perpendicular to the direction of pull of the underlying orbicularis oris muscle, is significantly improved by its temporary paralysis during wound healing. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Background: Selenium (Se) is an important nutrient that carries out many biological processes including maintaining optimal immune function. Here, inorganic selenite (Se(IV)) was evaluated for its pathogen resistance and potential-associated factors in Caenorhabditis elegans. The immune effects of Se(IV) were investigated by examining the responses of C. elegans to Pseudomonas aerugonisa PA14 strain. Principal Findings: Se(IV)-treated C. elegans showed increased survival under PA14 infection compared with untreated controls. The significant pathogen resistance of Se(IV) on C. elegans might not be attributed to the effects of Se(IV) on PA14 as Se(IV) showed no effect on bacterial quorum-sensing and virulence factors of PA14. This study showed that Se(IV) enhanced the expression of a gene pivotal for the innate immunity in C. elegans. The study found that the pathogen-resistant phenotypes contributed by Se(IV) was absent from the skn-1 mutant worms. Moreover, Se(IV) influenced the subcellular distribution of SKN-1/Nrf in C. elegans upon PA14 infection. Furthermore, Se(IV) increased mRNA levels of SKN-1 target genes (gst-4 and gcs-1). Conclusions: This study found evidence of Se(IV) protecting C. elegans against P. aeruginosa PA14 infection by exerting effects on the innate immunity of C. elegans that is likely mediated via regulation of a SKN-1-dependent signaling pathway. [ABSTRACT FROM AUTHOR]

Background: The influence of different hospital and surgeon volumes on short-term survival after hepatic resection is not clearly clarified. By taking the known prognostic factors into account, the purpose of this study is to assess the combined effects of hospital and surgeon volume on short-term survival after hepatic resection. Methods: 13,159 patients who underwent hepatic resection between 2002 and 2006 were identified in the Taiwan National Health Insurance Research Database. Data were extracted from it and short-term survivals were confirmed through 2006. The Cox proportional hazards model was used to assess the relationship between survival and different hospital, surgeon volume and caseload combinations. Results: High-volume surgeons in high-volume hospitals had the highest short-term survivals, following by high-volume surgeons in low-volume hospitals, low-volume surgeons in high-volume hospitals and low-volume surgeons in low-volume hospitals. Based on Cox proportional hazard models, although high-volume hospitals and surgeons both showed significant lower risks of short-term mortality at hospital and surgeon level analysis, after combining hospital and surgeon volume into account, high-volume surgeons in high-volume hospitals had significantly better outcomes; the hazard ratio of other three caseload combinations ranging from 1.66 to 2.08 (p<0.001) in 3-month mortality, and 1.28 to 1.58 (p<0.01) in 1-year mortality. Conclusions: The combined effects of hospital and surgeon volume influenced the short-term survival after hepatic resection largely. After adjusting for the prognostic factors in the case mix, high-volume surgeons in high-volume hospitals had better short-term survivals. Centralization of hepatic resection to few surgeons and hospitals might improve patients’ prognosis. [ABSTRACT FROM AUTHOR]

Background: The relationship between individual and neighborhood socioeconomic status (SES) and mortality rates in patients with nasopharyngeal carcinoma (NPC) is unknown. This population-based study aimed to examine the association between SES and survival of patients with NPC in Taiwan. Materials and Methods: A population-based follow-up study was conducted of 4691 patients diagnosed with NPC between 2002 and 2006. Each patient was traced to death or for 5 years. Individual SES was defined by enrollee job category. Neighborhood SES was based on household income dichotomized into advantaged and disadvantaged areas. Cox proportional hazards model was used to compare the death-free survival rates between the different SES groups after adjusting for possible confounding factors and risk factors. Results: In NPC patients below the age of 65 years, 5-year overall survival rates were worst for those with low individual SES living in disadvantaged neighborhoods. After adjusting for patient characteristics (age, gender, Charlson Comorbidity Index Score), NPC patients with low individual SES residing in disadvantaged neighborhoods were found to have a 2-fold higher risk of mortality than patients with high individual SES residing in advantaged neighborhoods. We found no significant difference in mortality rates between different SES groups in NPC patients aged 65 and above. Conclusions: Our findings indicate that NPC patients with low individual SES who live in disadvantaged neighborhoods have the higher risk of mortality than their more privileged counterparts. Public health strategies and welfare policies would be well advised to try to offset the inequalities in health care and pay more attention to addressing the needs of this vulnerable group. [ABSTRACT FROM AUTHOR]

Introduction: Increasing evidence has shown that immune surveillance is compromised in a tumor-promoting microenvironment for patients with non-small cell lung cancer (NSCLC), and can be restored by appropriate chemotherapy. Methods: To test this hypothesis, we analyzed microarray gene expression profiles of peripheral blood mononuclear cells from 30 patients with newly-diagnosed advanced stage NSCLC, and 20 age-, sex-, and co-morbidity-matched healthy controls. All the patients received a median of four courses of chemotherapy with cisplatin and gemcitabine for a 28-day cycle as first line treatment. Results: Sixty-nine differentially expressed genes between the patients and controls, and 59 differentially expressed genes before and after chemotherapy were identified. The IL4 pathway was significantly enriched in both tumor progression and chemotherapy signatures. CXCR4 and IL2RG were down-regulated, while DOK2 and S100A15 were up-regulated in the patients, and expressions of all four genes were partially or totally reversed after chemotherapy. Real-time quantitative RT-PCR for the four up-regulated (S100A15, DOK2) and down-regulated (TLR7, TOP1MT) genes in the patients, and the six up-regulated (TLR7, CRISP3, TOP1MT) and down-regulated (S100A15, DOK2, IL2RG) genes after chemotherapy confirmed the validity of the microarray results. Further immunohistochemical analysis of the paraffin-embedded lung cancer tissues identified strong S100A15 nuclear staining not only in stage IV NSCLC as compared to stage IIIB NSCLC (p = 0.005), but also in patients with stable or progressive disease as compared to those with a partial response (p = 0.032). A high percentage of S100A15 nuclear stained cells (HR 1.028, p = 0.01) was the only independent factor associated with three-year overall mortality. Conclusions: Our results suggest a potential role of the IL4 pathway in immune surveillance of advanced stage NSCLC, and immune potentiation of combination chemotherapy. S100A15 may serve as a potential biomarker for tumor staging, and a predictor of poor prognosis in NSCLC. [ABSTRACT FROM AUTHOR]

Background: Studies have confirmed that osteoporosis has been considered as one of the complications of diabetes, and the health hazards to patients are more obvious. This study is mainly based on the Taiwan National Health Insurance Database (TNHID). Through the analysis of TNHID, it is shown that the combined treatment of traditional Chinese medicine (TCM) medicine in patients of diabetes with osteoporosis (T2DOP) with lower related risks. Methods: According to the study design, 3131 patients selected from TNHID who received TCM treatment were matched by 1-fold propensity score according to gender, age, and inclusion date as the control group. Cox proportional hazards analyzes were performed to compare fracture surgery, hospitalization, and all-cause mortality during a mean follow-up from 2000 to 2015. Results: A total of 1055/1469/715 subjects (16.85%/23.46%/11.42%) had fracture surgery/inpatient/all-cause mortality of which 433/624/318 (13.83%/19.93%/10.16%) were in the TCM group) and 622/845/397 (19.87%/26.99%/12.68%) in the control group. Cox proportional hazards regression analysis showed that subjects in the TCM group had lower rates of fracture surgery, inpatient and all-cause mortality (adjusted HR = 0.467; 95% CI = 0.225–0.680, P<0.001; adjusted HR = 0.556; 95% CI = 0.330–0.751, P<0.001; adjusted HR = 0.704; 95% CI = 0.476–0.923, P = 0.012). Kaplan-Meier analysis showed that the cumulative risk of fracture surgery, inpatient and all-cause mortality was significantly different between the case and control groups (all log-rank p<0.001). Conclusion: This study provides longitudinal evidence through a cohort study of the value of integrated TCM for T2DOP. More research is needed to fully understand the clinical significance of these results. [ABSTRACT FROM AUTHOR]

People experience a healthy energy gained from the environment and an inner feeling, called the Qi experience. The flow experience has been a popular topic in Western studies, especially within the fields of psychology and health, and in all kinds of activities. Our current study used quantitative and qualitative methods to analyze the relationship between the Qi experience and the flow experience. After collecting data using open-ended questions, we integrated and connected the Qi experience into five orientations: (1) the feeling of Qi; (2) the mind; (3) Qi and consciousness; (4) physical, mental, and spiritual benefits; and (5) the feeling of Tao. The results revealed a high level of consistency between the flow experience and the Qi experience (r = 0.90, p<0.00, which supports the conclusion that the concept of the flow experience in Qigong activity seems to be the same as that in East Asian disciplines, called the Qi experience. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine whether functional walking performance measured with Timed Up-and-Go (TUG) and center of pressure (CoP) progression pattern is different across adolescents with various curve severity of idiopathic scoliosis (IS). The CoP coordinates during a stance phase for self-paced level walking between adolescent with three different severities of IS (mild IS, moderate IS, and severe IS) and age-matched normal subjects were measured with foot pressure measurement. The average data of three trials were compared among groups with repeated measure analysis of variance. Results showed that the TUG was different between normal and AIS subjects, indicating use of TUG as a marker of functional walking performance in AIS is plausible but studies with larger sample size is needed before using TUG to identify AIS with different scoliosis severity. The results also showed that the CoP displacement, velocity and acceleration during a stance phase was different across groups, and with the most prominent deviations found in the moderate IS group. The medial-lateral shifting of the CoP trajectory at mid-foot regions in all IS groups deviated the most. A tendency of asymmetry in CoP progression pattern between feet in IS groups was also found. The deviation of the spine alignment in frontal plane could change the CoP progression patterns during level walking, suggesting the risk of the locomotors subjecting to abnormal loading during daily walking. Education and conservative interventions might be needed for preservation of medical outcome and prevention of back pain and/or musculoskeletal consequences later in the lives of AIS with and without surgical correction. [ABSTRACT FROM AUTHOR]

Two amyloid-β peptides (Aβ40 and Aβ42) feature prominently in the extracellular brain deposits associated with Alzheimer’s disease. While Aβ40 is the prevalent form in the cerebrospinal fluid, the fraction of Aβ42 increases in the amyloid deposits over the course of disease development. The low in vivo concentration (pM-nM) and metastable nature of Aβ oligomers have made identification of their size, composition, cellular binding sites and mechanism of action challenging and elusive. Furthermore, recent studies have suggested that synergistic effects between Aβ40 and Aβ42 alter both the formation and stability of various peptide oligomers as well as their cytotoxicity. These studies often utilized Aβ oligomers that were prepared in solution and at μM peptide concentrations. The current work was performed using physiological Aβ concentrations and single-molecule microscopy to follow peptide binding and association on primary cultured neurons. When the cells were exposed to a 1:1 mixture of nM Aβ40:Aβ42, significantly larger membrane-bound oligomers developed compared to those formed from either peptide alone. Fluorescence resonance energy transfer experiments at the single molecule level reveal that these larger oligomers contained both Aβ40 and Aβ42, but that the growth of these oligomers was predominantly by addition of Aβ42. Both pure peptides form very few oligomers larger than dimers, but either membrane bound Aβ40/42 complex, or Aβ40, bind Aβ42 to form increasingly larger oligomers. These findings may explain how Aβ42-dominant oligomers, suspected of being more cytotoxic, develop on the neuronal membrane under physiological conditions. [ABSTRACT FROM AUTHOR]

Background:No large-scale study has explored the combined effect of patients’ individual and neighborhood socioeconomic status (SES) on their access to a low-volume provider for breast cancer surgery. The purpose of this study was to explore under a nationwide universal health insurance system whether breast cancer patients from a lower individual and neighborhood SES are disproportionately receiving breast cancer surgery from low-volume providers. Methods:5,750 patients who underwent breast cancer surgery in 2006 were identified from the Taiwan National Health Insurance Research Database. The Cox proportional hazards model was used to compare the access to a low-volume provider between the different individual and neighborhood SES groups after adjusting for possible confounding and risk factors. Hosmer-Lemeshow goodness-of-fit statistic was used to determine how well the model fit the data. Results:Univariate analysis data shows that patients in disadvantaged neighborhood were more likely to receive breast cancer surgery at low-volume hospitals; and lower-SES patients were more likely to receive surgery from low-volume surgeons. In multivariate analysis, after adjusting for patient characteristics, the odds ratios of moderate- and low-SES patients in disadvantaged neighborhood receiving surgery at low-volume hospitals was 1.47 (95% confidence interval=1.19-1.81) and 1.31 (95% confidence interval=1.05-1.64) respectively compared with high-SES patients in advantaged neighborhood. Moderate- and low-SES patients from either advantaged or disadvantaged neighborhood had an odds ratios ranging from 1.51 to 1.80 (p<0.001) to receiving surgery from low-volume surgeons. In Hosmer-Lemeshow goodness-of-fit test, p>0.05 that shows the model has a good fit. Conclusions:In this population-based cross-sectional study, even under a nationwide universal health insurance system, disparities in access to healthcare existed. Breast cancer patients from a lower individual and neighborhood SES are more likely to receive breast cancer surgery from low-volume providers. The authorities and public health policies should keep focusing on these vulnerable groups. [ABSTRACT FROM AUTHOR]

Background:Oral cancer leads to a considerable use of health care resources. Wide resection of the tumor and reconstruction with a pedicle flap/ free flap is widely used. This study was conducted to investigate if young age at the time of diagnosis of oral cancer requiring this treatment confers a worse prognosis. Methods:A total of 2339 patients who underwent resections for oral cancer from 2004 to 2005 were identified from The Taiwan National Health Insurance Research Database. Survival analysis, Cox proportional regression model, propensity scores, and sensitivity test were used to evaluate the association between 5-year survival rates and age. Results:In the Cox proportional regression model, the older age group (>65 years) had the worst survival rate (hazard ratio [HR], 1.80; 95% confidence interval [CI], 1.45-2.22; P<0.001). When analyzed using the propensity scores, the adjusted 5-year survival rates were also poorer for oral cancer patients with older age (>65 years), compared to those with younger age (<45 years) (P<0.001). In sensitivity test, the adjusted hazard ratio remained no statistically elevated in the younger age group (<45 years). Conclusions:For those oral cancer patients who underwent wide excision and reconstruction, young age did not confer a worse prognosis using a Cox proportional regression model, propensity scores or sensitivity test. Young oral cancer patients may be treated using general guidelines and do not require more aggressive treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This retrospective study was designed to investigate the correlation between a novel immunosubtyping method for hepatocellular carcinoma (HCC) and biological behavior of tumor cells. A series of 346 patients, who received hepatectomy at two surgical centers from January 2007 to October 2010, were enrolled in this study. The expressions of cytokeratin 19 (CK19), glypican 3 (GPC3), and CD34 were detected by immunohistochemical staining. The clinical stage was assessed using the sixth edition tumor–node–metastasis (TNM) system (UICC/AJCC, 2010).Vascular invasion comprised both microscopic and macroscopic invasion. The tumor size, lymph node involvement, and metastasis were determined by pathological as well as imaging studies. Recurrence was defined as the appearance of new lesions with radiological features typical of HCC, seen by at least two imaging methods. Survival curves for the patients were plotted using the Kaplan–Meier method, and differences between the curves were assessed using the log-rank test. Significant differences in morphology, histological grading, and TNM staging were observed between groups. Based on the immunohistochemical staining, the enrolled cases were divided into CK19+/GPC3+, CK19−/GPC3+ and CK19−/GPC3− three subtypes. CK19+/GPC3+ HCC has the highest risk of multifocality, microvascular invasion, regional lymph node involvement, and distant metastasis, followed by CK19−/GPC3+ HCC, then CK19−/GPC3−HCC. CK19+/GPC3+ HCC has the shortest recurrence time compared to other immunophenotype HCCs. CK19 and GPC3 expression profiling is an independent prognostic indicator in patients with HCC, and a larger sample size is needed to further investigate the effect of this immunosubtyping model in stratifying the outcome of HCC patients. [ABSTRACT FROM AUTHOR]

Background: Human infections with avian influenza viruses (AIVs) have frequently raised global concerns of emerging, interspecies-transmissible viruses with pandemic potential. Waterfowl, the predominant reservoir of influenza viruses in nature, harbor precursors of different genetic lineages that have contributed to novel pandemic influenza viruses in the past. Methods: Two duck influenza H5N2 viruses, DV518 and DV413, isolated through virological surveillance at a live-poultry market in Taiwan, showed phylogenetic relatedness but exhibited different replication capabilities in mammalian Madin-Darby Canine Kidney (MDCK) cells. This study characterizes the replication properties of the two duck H5N2 viruses and the determinants involved. Results: The DV518 virus replicated more efficiently than DV413 in both MDCK and chicken DF1 cells. Interestingly, the infection of MDCK cells by DV518 formed heterogeneous plaques with great differences in size [large (L) and small (S)], and the two viral strains (p518-L and p518-S) obtained from plaque purification exhibited distinguishable replication kinetics in MDCK cells. Nonetheless, both plaque-purified DV518 strains still maintained their growth advantages over the plaque-purified p413 strain. Moreover, three amino acid substitutions in PA (P224S), PB2 (E72D), and M1 (A128T) were identified in intra-duck variations (p518-L vs p518-S), whereas other changes in HA (N170D), NA (I56T), and NP (Y289H) were present in inter-duck variations (DV518 vs DV413). Both p518-L and p518-S strains had the N170D substitution in HA, which might be related to their greater binding to MDCK cells. Additionally, polymerase activity assays on 293T cells demonstrated the role of vRNP in modulating the replication capability of the duck p518-L viruses in mammalian cells. Conclusion: These results demonstrate that intra-host phenotypic variation occurs even within an individual duck. In view of recent human infections by low pathogenic AIVs, this study suggests possible determinants involved in the stepwise selection of virus variants from the duck influenza virus population which may facilitate inter-species transmission. [ABSTRACT FROM AUTHOR]

Objective: In addition to IgA, the deposition of complement (C)3 in dermal vessels is commonly found in Henoch-Schönlein purpura (HSP). The aim of this study is to elucidate the role of circulating complement proteins in the pathogenesis of childhood HSP. Methods: Plasma levels of C3a, C4a, C5a, and Bb in 30 HSP patients and 30 healthy controls were detected by enzyme-linked immunosorbent assay (ELISA). The expression of C3a receptor (C3aR), C5a receptor (CD88), E-selectin, intercellular adhesion molecule 1 (ICAM-1), C3, C5, interleukin (IL)-8, monocyte chemotactic protein (MCP)-1, and RANTES by human dermal microvascular endothelial cells (HMVEC-d) was evaluated either by flow cytometry or by ELISA. Results: At the acute stage, HSP patients had higher plasma levels of C3a (359.5 ± 115.3 vs. 183.3 ± 94.1 ng/ml, p < 0.0001), C5a (181.4 ± 86.1 vs. 33.7 ± 26.3 ng/ml, p < 0.0001), and Bb (3.7 ± 2.6 vs. 1.0 ± 0.6 μg/ml, p < 0.0001), but not C4a than healthy controls. Although HSP patient-derived acute phase plasma did not alter the presentation of C3aR and CD88 on HMVEC-d, it enhanced the production of endothelial C3 and C5. Moreover, C5a was shown in vitro to up-regulate the expression of IL-8, MCP-1, E-selectin, and ICAM-1 by HMVEC-d with a dose-dependent manner. Conclusion: In HSP, the activation of the complement system in part through the alternative pathway may have resulted in increased plasma levels of C3a and C5a, which, especially C5a, may play a role in the disease pathogenesis by activating endothelium of cutaneous small vessels. [ABSTRACT FROM AUTHOR]

Objectives: To examine the association of individual income and end of life (EOL) care in older cancer decedents in Taiwan. Design: Retrospective cohort study. Setting: National Health Insurance Research Database (NHIRD) in Taiwan. Participants: 28,978 decedents >65 years were diagnosed with cancer and died during 2009-2011 in Taiwan. Of these decedents, 10941, 16535, and 1502 were categorized by individual income as having low, moderate, and high SES, respectively. Main outcome measures: Indicators of aggressiveness of EOL care: chemotherapy use before EOL, more than one emergency department (ER) visit, more than one hospital admission, hospital length of stay >14 days, intensive care unit (ICU) admission, and dying in a hospital. Results: Low individual income was associated with more aggressive EOL treatment (estimate -0.30 for moderate income, -0.27 for high income, both p<0.01). The major source of aggressiveness was the tendency for older decedents with low income to die in the acute care hospital. The indicators had an increasing trend from 2009 to 2011, except for hospital stay >14 days. Conclusions: Low individual income is associated with more aggressive EOL treatment in older cancer decedents. Public health providers should make available appropriate education and hospice resources to these decedents and their families, to reduce the amount of aggressive terminal care such decedents receive. [ABSTRACT FROM AUTHOR]

Purpose: Gastric cancer is a leading cause of death, particularly in the developing world. The literature reports individual socioeconomic status (SES) or neighborhood SES as related to survival, but the effect of both has not been studied. This study investigated the effect of individual and neighborhood SES simultaneously on mortality in gastric cancer patients in Taiwan. Materials and Methods: A study was conducted of 3,396 patients diagnosed with gastric cancer between 2002 and 2006. Each patient was followed for five years or until death. Individual SES was defined by income-related insurance premium (low, moderate, and high). Neighborhood SES was based on household income dichotomized into advantaged and disadvantaged areas. Multilevel logistic regression model was used to compare survival rates by SES group after adjusting for possible confounding factors. Results: In patients younger than 65 years, 5-year overall survival rates were lowest for those with low individual SES. After adjusting for patient characteristics (age, gender, Charlson Comorbidity Index Score), gastric cancer patients with high individual SES had 68% risk reduction of mortality (adjusted odds ratio [OR] of mortality, 0.32; 95% confidence interval [CI], 0.17–0.61). Patients aged 65 and above had no statistically significant difference in mortality rates by individual SES group. Different neighborhood SES did not statistically differ in the survival rates. Conclusion: Gastric cancer patients aged less than 65 years old with low individual SES have higher risk of mortality, even under an universal healthcare system. Public health strategies, education and welfare policies should seek to correct the inequality in gastric cancer survival, especially in those with lower individual SES. [ABSTRACT FROM AUTHOR]

Abnormal immunophenotypes of hematopoietic cells can be detected by flow cytometry (FCM) to assist the diagnosis of myelodysplastic syndromes (MDS). We previously established a FCM scoring system for the diagnosis of low-grade MDS. In this study, additional valuable antigens were involved in an updated FCM scoring system (u-FCMSS) for all MDS subtypes. The u-FCMSS showed better sensitivity and specificity (89.4% and 96.5%) in distinguishing MDS from non-clonal cytopenia diseases. Validation analysis of u-FCMSS exhibited comparable sensitivity and specificity (86.7% and 93.3%) and high agreement rate (88.9%) of FCM diagnosis with morphological diagnosis at optimal cut-off (score 3). The distribution of FCM scores in different disease stages was also analyzed. The results suggested that early scoring from abnormal expression of mature myeloid/lymphoid antigens and advanced scoring from abnormal expression of stem/progenitor antigens expression constituted the majority of FCM scores of low-grade and high-grade MDS, respectively. High early scoring was generally accompanied by low IPSS-R score and superior survival, whereas high advanced scoring was accompanied by high IPSS-R score and inferior survival. In addition, the low-risk MDS patients with high early scoring and low advanced scoring were revealed as candidates for immunosuppressive therapy, whereas those with high advanced scoring and low early scoring may be more suitable for decitabine treatment. In conclusion, the u-FCMSS is a useful tool for diagnosis, prognosis and treatment selection in MDS. Differences in classes of antigens expressed and in distribution of FCM scores may reflect distinctive stage characteristics of MDS during disease progression. [ABSTRACT FROM AUTHOR]

COVID-19 displays diverse disease severities and symptoms including acute systemic inflammation and hypercytokinemia, with subsequent dysregulation of immune cells. Bacterial superinfections in COVID-19 can further complicate the disease course and are associated with increased mortality. However, there is limited understanding of how SARS-CoV-2 pathogenesis and hypercytokinemia impede the innate immune function against bacterial superinfections. We assessed the influence of COVID-19 plasma hypercytokinemia on the functional responses of myeloid immune cells upon bacterial challenges from acute-phase COVID-19 patients and their corresponding recovery (rec)-phase. We show that a severe hypercytokinemia status in COVID-19 patients correlates with the development of bacterial superinfections. Neutrophils and monocytes derived from COVID-19 patients in their acute-phase showed an impaired intracellular microbicidal capacity upon bacterial challenges. The impaired microbicidal capacity was reflected by abrogated MPO and reduced NETs production in neutrophils along with reduced ROS production in both neutrophils and monocytes. Moreover, we observed a distinct pattern of cell surface receptor expression on both neutrophils and monocytes, in line with suppressed autocrine and paracrine cytokine signaling. This phenotype was characterized by a high expression of CD66b, CXCR4 and low expression of CXCR1, CXCR2 and CD15 in neutrophils and low expression of HLA-DR, CD86 and high expression of CD163 and CD11b in monocytes. Furthermore, the impaired antibacterial effector function was mediated by synergistic effect of the cytokines TNF-α, IFN-γ and IL-4. COVID-19 patients receiving dexamethasone showed a significant reduction of overall inflammatory markers in the plasma as well as exhibited an enhanced immune response towards bacterial challenge ex vivo. Finally, broad anti-inflammatory treatment was associated with a reduction in CRP, IL-6 levels as well as length of ICU and hospital stay in critically ill COVID-19 patients. Our data provides insights into the transient functional dysregulation of myeloid immune cells against subsequent bacterial infections in COVID-19 patients and describe a beneficial role for the use of dexamethasone in these patients. Author summary: COVID-19 caused by SARS-CoV-2 induces immune-paralysis characterized by misdirected host responses and altered levels of inflammatory mediators. Additionally, bacterial superinfections can further exacerbate the disease. Here, we report an in-depth functional characterization of the effector response and phenotypic properties of neutrophils and monocytes derived from critically ill COVID-19 patients towards bacterial superinfection. We show that elevated levels of specific cytokine clusters, positively correlate with the development of bacterial superinfections in these patients. Neutrophils and monocytes of critically ill COVID-19 patients showed impaired bactericidal capacity, which was mediated by elevated inflammatory mediators in the plasma. The observed impaired bactericidal capacity in critically ill COVID-19 patients was due to reduced classical effector functions of neutrophils and monocytes. Interestingly, lower levels of overall inflammatory mediators as well as reduction in length of ICU and hospital stay in critically ill COVID-19 patients treated with dexamethasone was observed. These data suggest that the exhaustion and paralysis of the cellular innate immunity against bacterial challenge in critically ill COVID-19 patients is driven by a misdirected host-response, characterized by a hyperinflammatory environment including dysregulated cytokine levels. These results further emphasize the utility and importance of dampening these inflammatory mediators via broad anti-inflammatory therapy in COVID-19 patients, which improves the antibacterial effector functions of neutrophils and monocytes. [ABSTRACT FROM AUTHOR]

Graphic design thinking is a key skill for landscape architects, but little is known about the links between the design process and brain activity. Based on Goel's frontal lobe lateralization hypothesis (FLLH), we used functional magnetic resonance imaging (fMRI) to scan the brain activity of 24 designers engaging in four design processes—viewing, copy drawing, preliminary ideas, and refinement—during graphic design thinking. The captured scans produced evidence of dramatic differences between brain activity when copying an existing graphic and when engaging in graphic design thinking. The results confirm that designs involving more graphic design thinking exhibit significantly more activity in the left prefrontal cortex. These findings illuminate the design process and suggest the possibility of developing specific activities or exercises to promote graphic design thinking in landscape architecture. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) mainly occur in elderly individuals in Western countries. However, MDS is commonly found in young individuals (<60 years) in Asia. The reason for the high incidence in younger individuals is still unclear, and the differences in disease features between young and elderly patients with MDS have been not well recognized. To explore these issues, in this study, we analyzed the clinical and experimental characteristics of MDS in the patients younger and older than 60 years old and characterized the potential age-associated differences. The results showed that over half of the patients with MDS (61.9%) were younger than 60 years old upon the first diagnosis. The younger patients were more likely to be female, who have lower risk and less advanced MDS. The occurrence of trisomy 8 and bone marrow failure were more frequent in the younger patients than the older ones. The marrow CD34+ cells in the younger patients showed lower proliferation and higher apoptosis in comparison with that in the older ones. Obvious amplification of T cells and low CFU formation could be found in the younger patients. CFU formation was significantly increased in the younger patients after the removal of activated T cells. In addition, the younger patients had a lower frequency of p15INK4B methylation, longer survival expectancy and less AML transformation. In summary, the younger patients with MDS in China may show more benign disease features than the older ones. Enhanced immunological response may be involved in the pathogenesis of MDS in the patients younger than 60 years. [ABSTRACT FROM AUTHOR]

Infection with influenza virus is a major public health problem, causing serious illness and death each year. Emergence of drug-resistant influenza virus strains limits the effectiveness of drug treatment. Importantly, a dual H275Y/I223R mutation detected in the pandemic influenza A 2009 virus strain results in multidrug resistance to current neuraminidase (NA) drugs. Therefore, discovery of new agents for treating multiple drug-resistant (MDR) influenza virus infections is important. Here, we propose a parallel screening strategy that simultaneously screens wild-type (WT) and MDR NAs, and identifies inhibitors matching the subsite characteristics of both NA-binding sites. These may maintain their potency when drug-resistant mutations arise. Initially, we analyzed the subsite of the dual H275Y/I223R NA mutant. Analysis of the site-moiety maps of NA protein structures show that the mutant subsite has a relatively small volume and is highly polar compared with the WT subsite. Moreover, the mutant subsite has a high preference for forming hydrogen-bonding interactions with polar moieties. These changes may drive multidrug resistance. Using this strategy, we identified a new inhibitor, Remazol Brilliant Blue R (RB19, an anthraquinone dye), which inhibited WT NA and MDR NA with IC50 values of 3.4 and 4.5 µM, respectively. RB19 comprises a rigid core scaffold and a flexible chain with a large polar moiety. The former interacts with highly conserved residues, decreasing the probability of resistance. The latter forms van der Waals contacts with the WT subsite and yields hydrogen bonds with the mutant subsite by switching the orientation of its flexible side chain. Both scaffolds of RB19 are good starting points for lead optimization. The results reveal a parallel screening strategy for identifying resistance mechanisms and discovering anti-resistance neuraminidase inhibitors. We believe that this strategy may be applied to other diseases with high mutation rates, such as cancer and human immunodeficiency virus type 1. [ABSTRACT FROM AUTHOR]

Objective: To assess the healthcare utilization, economic burden, and long-term neurological complications and mortality of an adult population with Japanese encephalitis (JE). Methods: This study utilized two nationwide datasets in Taiwan: the Notifiable Disease Dataset of confirmed cases from the Centers for Disease Control to identify JE patients, and the National Health Insurance Research Database to obtain patients' healthcare utilization. Survival analyses were performed to identify prognostic factors associated with the all-cause mortality of patients. Results: This study included 352 adult cases with JE (aged≥20 years). The mean age of JE patients was 45 years. Stroke (event rate: 3.49/100 person-years) was the most common neurological complication, followed by epilepsy/convulsions (3.13/100 person-years), encephalopathy/delirium (2.20/100 person-years), and parkinsonism (1.97/100 person-years). Among the 336 hospitalized patients at JE diagnosis, 58.33% required intensive care. Among 79 patients who died following JE diagnosis, 48.84% of death events occurred within the year of diagnosis. The medical costs increased considerably at JE diagnosis and subsequent-year costs remained significantly higher than the costs before diagnosis (p<0.05). Having a four-dose JE vaccination (i.e., born after 1976) versus no JE vaccination history (i.e., born before 1963) was significantly associated with lower all-cause mortality (hazard ratio: 0.221 [95% confidence interval: 0.067, 0.725]). Comorbid diabetes and incident epilepsy/convulsion events significantly increased the mortality risk by 2.47- and 1.85-fold, respectively (p<0.05). Conclusion: A considerable medical burden associated with JE was observed in affected adults, even in the years following JE diagnosis. Vaccination should be considered to prevent this sporadic, but lethal, viral infection. Author summary: The epidemiology of adulthood Japanese encephalitis (JE) remains limited, and data on the economic burden associated with JE is lacking. This study is the first to comprehensively examine the healthcare burden (i.e., healthcare utilization and costs, neurological complications, all-cause mortality) of an adult population with JE, utilizing a nationwide cohort of JE-infected adults with up to 16 years of follow-up. In the first 6 months following JE diagnosis, a higher rate of neurological disorders was found, compared to the years after the diagnosis, with stroke being the most common neurological complication, followed by epilepsy/convulsions. The healthcare utilization of JE patients was higher in the first 6 months after the diagnosis compared to the years following the diagnosis. Medical costs increased considerably at JE diagnosis and subsequent-year costs after diagnosis remained higher than the cost before diagnosis. Having comorbid diabetes or incident epilepsy/convulsion events was a significant risk factor for mortality of adults with JE. Being born after 1976 in Taiwan, and thus likely receiving a four-dose schedule of vaccination, was associated with reduced mortality. Therefore, special attention is required for JE patients with comorbid diabetes or incident epilepsy/convulsion events, and JE vaccination should be considered to prevent this sporadic but lethal viral infection. [ABSTRACT FROM AUTHOR]

Public health administrators do not have effective models to predict excess influenza-associated mortality and monitor viral changes associated with it. This study evaluated the effect of matching/mismatching vaccine strains, type/subtype pattern changes in Taiwan's influenza viruses, and the impact of post-SARS (severe acute respiratory syndrome) public health efforts on excess influenza-associated mortalities among the elderly. A negative binomial model was developed to estimate Taiwan's monthly influenza-associated mortality among the elderly. We calculated three winter and annual excess influenzaassociated mortalities [pneumonia and influenza (P&I), respiratory and circulatory, and all-cause] from the 1999-2000 through the 2006-2007 influenza seasons. Obtaining influenza virus sequences from the months/years in which death from P&I was excessive, we investigated molecular variation in vaccine-mismatched influenza viruses by comparing hemagglutinin 1 (HA1) of the circulating and vaccine strains. We found that the higher the isolation rate of A (H3N2) and vaccine-mismatched influenza viruses, the greater the monthly P&I mortality. However, this significant positive association became negative for higher matching of A (H3N2) and public health efforts with post-SARS effect. Mean excess P&I mortality for winters was significantly higher before 2003 than after that year [mean ± S.D.: 1.44±1.35 vs. 0.35±1.13, p = 0.04]. Further analysis revealed that vaccine-matched circulating influenza A viruses were significantly associated with lower excess P&I mortality during post-SARS winters (i.e., 2005-2007) than during pre-SARS winters [0.0360.06 vs. 1.57±1.27, p = 0.01]. Stratification of these vaccine-matching and post-SARS effect showed substantial trends toward lower elderly excess P&I mortalities in winters with either mismatching vaccines during the post-SARS period or matching vaccines during the pre-SARS period. Importantly, all three excess mortalities were at their highest in May, 2003, when inter-hospital nosocomial infections were peaking. Furthermore, vaccine-mismatched H3N2 viruses circulating in the years with high excess P&I mortality exhibited both a lower amino acid identity percentage of HA1 between vaccine and circulating strains and a higher numbers of variations at epitope B. Our model can help future decision makers to estimate excess P&I mortality effectively, select and test virus strains for antigenic variation, and evaluate public health strategy effectiveness. [ABSTRACT FROM AUTHOR]

Epitopes that are conserved among SARS-like coronaviruses are attractive targets for design of cross-reactive vaccines and therapeutics. CR3022 is a SARS-CoV neutralizing antibody to a highly conserved epitope on the receptor binding domain (RBD) on the spike protein that is able to cross-react with SARS-CoV-2, but with lower affinity. Using x-ray crystallography, mutagenesis, and binding experiments, we illustrate that of four amino acid differences in the CR3022 epitope between SARS-CoV-2 and SARS-CoV, a single mutation P384A fully determines the affinity difference. CR3022 does not neutralize SARS-CoV-2, but the increased affinity to SARS-CoV-2 P384A mutant now enables neutralization with a similar potency to SARS-CoV. We further investigated CR3022 interaction with the SARS-CoV spike protein by negative-stain EM and cryo-EM. Three CR3022 Fabs bind per trimer with the RBD observed in different up-conformations due to considerable flexibility of the RBD. In one of these conformations, quaternary interactions are made by CR3022 to the N-terminal domain (NTD) of an adjacent subunit. Overall, this study provides insights into antigenic variation and potential cross-neutralizing epitopes on SARS-like viruses. Author summary: The ongoing COVID-19 pandemic is caused by SARS-CoV-2. Due to the genetic similarity of SARS-CoV-2 and SARS-CoV, which caused an epidemic in 2003, a few of the SARS-CoV antibodies have now been found to also cross-react with SARS-CoV-2. One such antibody is CR3022, which was isolated from a convalescent SARS patient 14 years ago. However, the 100-fold lower binding to SARS-CoV-2 does not enable neutralization of SARS-CoV-2 compared to SARS-CoV. This study shows that one (P384A) of the four mutational differences in the CR3022 epitope between SARS-CoV and SARS-COV-2 fully accounts for the differences in CR3022 binding affinity and neutralization. These findings advance our understanding of antibody cross-reactivity among SARS-like CoVs with implications for vaccine and therapeutic design. [ABSTRACT FROM AUTHOR]

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

Aspartate transaminase-platelet ratio index (APRI) and fibrosis 4 (FIB-4) are two non-invasive indexes to predict liver fibrosis in liver disease. This study was to use APRI and FIB-4 to detect chronic virus hepatitis in community screenings. From 2004 to 2013, a series of community-based health screenings for residents aged 40 and older were held in Tainan city. APRI and FIB-4 of each participant were calculated and their association further analyzed with hepatitis status. We enrolled 180359 participants including 18726 (10.4%) hepatitis B virus (HBV), 13428 (7.4%) hepatitis C virus (HCV), 1337 (0.7%) HBV plus HCV and 146868 (81.5%) Non-HBV Non-HCV. The prevalence of chronic HCV increased with the elevation of APRI cut-offs or FIB-4 cut-offs (13.9%, 28.1%, 38.8%, 45.2%, to 49.9% in APRI≥0.3, 0.5, 0.7, 0.9,1.1, p<0.001 for the linear trend; or 15.8%, 26.4%, 34.4% to 39.7% in FIB-4≥1.75, 2.75, 3.5, 4.25, p<0.001). At the township level, APRI≥ 0.7 and FIB-4≥ 3.5 were highly correlated with HCV infection (r = 0.95, p<0.001 in APRI and r = 0.809, p<0.001 in FIB-4) and hepatocellular carcinoma (HCC) development (r = 0.894, p<0.001 in APRI and r = 0.804, p<0.001 in FIB-4), but not correlated with HBV infection. Community screenings derived APRI or FIB-4 can identify patient subsets with increased of underlying HCV infection and risk of incident HCC. [ABSTRACT FROM AUTHOR]