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A mismatch in footprints of cervical total disc arthroplasty (CTDA) implants occasionally occurred in Asian population and it had been attributed solely to ethnic factor. Yet, cervical degeneration process may play a role. Our purpose was to compare the cervical vertebra morphometric data with and without degeneration. The study included patients with CT scans of cervical spine from our hospital between January, 2019, and September, 2021. The total cervical degenerative index (TCDI) of each patient were collected by adding CDI score for 5 disc-levels. Patients were categorized into normal (TCDI 0-5) and degeneration groups (TCDI 6-60). Various measurements of the C3-C7 vertebral body and endplate were taken. Forty-nine patients in the normal group and 55 in the degeneration group were included. No significant difference was noted in gender, BH, BW, or BMI except age and TCDI (p < .001). During degeneration, disproportional endplate size changes were observed, with an increment ratio of 12-20% in the anteroposterior and 5-17% in the mediolateral plane throughout C3-C7, while vertebral body height remained constant. In conclusion, degeneration process, besides ethnic factor, causes the endplate size and shape mismatch. This information can help spine surgeon choose appropriate implants in CTDA surgery., (© 2024. The Author(s).)

The frequency of percutaneous transluminal angioplasty (PTA) procedures has substantially increased, but its effect on vascular access recreation (VAR) remains inconclusive. We conducted a population-based retrospective analysis of Taiwan hemodialysis (HD) centers from 2004 to 2012. Data was accumulated into center-level characteristics, including patients' demographics, baseline characteristics, PTA procedures, and VAR. Center-level characteristics were summarized annually using appropriate measures. A mixed model assessed the association between PTA frequency and VAR rates, considering within-center correlation and adjusting for potential confounders. A total of 82,005 patients (mean age 62.7 ± 13.9 years, 50.5% male, 48.5% with diabetes mellitus) from 820 HD centers were analyzed. From 2004 to 2012, PTA frequency significantly increased from 1.24 to 3.23 per 1000 HD sessions, while VAR rates did not decline as expected (0.5-0.8 per 1000 HD sessions). Compared with the HD centers of infrequent use of PTA (annual lowest quartile, range 0.39-1.20 per 1000 HD sessions), the ones of frequent use (annual highest quartile, range 2.52-5.10 per 1000 HD sessions) didn't have lower VAR (range 0.54-0.99 vs. 0.50-0.91 per 1000 HD sessions, respectively). After controlling the potential confounders, the HD centers' PTA rates were not significantly associated with lower VAR rates (- 2.6, 95% confidence interval: - 30.3; 25.0, p = 0.85). Frequent use of PTA does not seem to improve VA patency at the center level, with no significant association identified with lower VAR. The indication of PTA in daily practice should be re-evaluated in terms of its efficiency in lowering VAR., (© 2024. The Author(s).)

Identification of an early biomarker and effective testing device to differentiate dry eye disease secondary to autoimmune disease (Sjögren's syndrome dry eye disease) from non-Sjögren's dry eye disease are prerequisites for appropriate treatment. We aimed to demonstrate the capacity of a new photo-detection device to evaluate tear lactoferrin levels as a tool for differentiating systemic conditions associated with dry eye disease. Patients with non-Sjögren's and Sjögren's syndrome dry eye disease (n = 54 and n = 52, respectively) and controls (n = 11) were enrolled. All participants completed the Ocular Surface Disease Index questionnaire. Tear collection was performed with Schirmer test, and tear break-up time was examined using a slit lamp. Tear lactoferrin was evaluated using our newly developed photo-detection device. The average lactoferrin concentration was significantly lower in samples from patients with non-Sjögren's dry eye disease (0.337 ± 0.227 mg/mL, n = 54) and Sjögren's syndrome dry eye disease (0.087 ± 0.010 mg/mL, n = 52) than in control samples (1.272 ± 0.54 mg/mL, n = 11) (p < 0.0001). Further, lactoferrin levels were lower in patients with Sjögren's syndrome dry eye disease than in those with non-Sjögren's dry eye disease (p < 0.001). Our cost-effective, antibody-free, highly sensitive photo-detection device for evaluating tear lactoferrin levels can assist ophthalmologists in differentiating different types of dry eye diseases., (© 2024. The Author(s).)

The European Leukemia Net recommendations provide valuable guidance in treatment decisions of patients with acute myeloid leukemia (AML). However, the genetic complexity and heterogeneity of AML are not fully covered, notwithstanding that gene expression analysis is crucial in the risk stratification of AML. The Stellae-123 score, an AI-based model that captures gene expression patterns, has demonstrated robust survival predictions in AML patients across four western-population cohorts. This study aims to evaluate the applicability of Stellae-123 in a Taiwanese cohort. The Stellae-123 model was applied to 304 de novo AML patients diagnosed and treated at the National Taiwan University Hospital. We find that the pretrained (BeatAML-based) model achieved c-indexes of 0.631 and 0.632 for the prediction of overall survival (OS) and relapse-free survival (RFS), respectively. Model retraining within our cohort further improve the cross-validated c-indexes to 0.667 and 0.667 for OS and RFS prediction, respectively. Multivariable analysis identify both pretrained and retrained models as independent prognostic biomarkers. We further show that incorporating age, Stellae-123, and ELN classification remarkably improves risk stratification, revealing c-indices of 0.73 and 0.728 for OS and RFS, respectively. In summary, the Stellae-123 gene expression signature is a valuable prognostic tool for AML patients and model retraining can improve the accuracy and applicability of the model in different populations., (© 2024. The Author(s).)

This longitudinal cohort study investigated the associations of air pollutant exposures, including CO, NO, NO 2 , NO x , O 3 , PM 10 , PM 2.5 , and SO 2 , with long-term kidney function changes in patients with chronic kidney disease (CKD). We enrolled 447 CKD patients who took part in a universal hospital pre-ESRD care program during 2011-2015. The daily average air pollutant exposures and temperature were estimated for each patient, with different levels of air pollutant concentrations defined by 5-knot and restricted cubic spline function. Predicted annual estimated glomerular filtration (eGFR) slope values by one mixed model were considered as the study outcome. The average age of the study population was 77.1 ± 12.6 years, and the median annual eGFR decreased by 2.1 ml/min/1.73 m 2 per year from 30 ml/min/1.73 m 2 at baseline during a mean follow-up time of 3.4 years. The univariable and multivariable analyses revealed no significant linear and non-linear associations between 5-knot air pollutant concentrations and annual eGFR slope. In addition, the visualized spline effect plots show insignificant variation patterns in annual eGFR slope values with increased air pollutant concentrations. These results encourage more extensive studies to clarify the causal relationships and mechanisms of long-term specific air pollutant exposures and longitudinal kidney function change, especially in CKD populations., (© 2023. The Author(s).)

The fasting blood glucose (FBG) values extracted from electronic medical records (EMR) are assumed valid in existing research, which may cause diagnostic bias due to misclassification of fasting status. We proposed a machine learning (ML) algorithm to predict the fasting status of blood samples. This cross-sectional study was conducted using the EMR of a medical center from 2003 to 2018 and a total of 2,196,833 ontological FBGs from the outpatient service were enrolled. The theoretical true fasting status are identified by comparing the values of ontological FBG with average glucose levels derived from concomitant tested HbA1c based on multi-criteria. In addition to multiple logistic regression, we extracted 67 features to predict the fasting status by eXtreme Gradient Boosting (XGBoost). The discrimination and calibration of the prediction models were also assessed. Real-world performance was gauged by the prevalence of ineffective glucose measurement (IGM). Of the 784,340 ontologically labeled fasting samples, 77.1% were considered theoretical FBGs. The median (IQR) glucose and HbA1c level of ontological and theoretical fasting samples in patients without diabetes mellitus (DM) were 94.0 (87.0, 102.0) mg/dL and 5.6 (5.4, 5.9)%, and 92.0 (86.0, 99.0) mg/dL and 5.6 (5.4, 5.9)%, respectively. The XGBoost showed comparable calibration and AUROC of 0.887 than that of 0.868 in multiple logistic regression in the parsimonious approach and identified important predictors of glucose level, home-to-hospital distance, age, and concomitantly serum creatinine and lipid testing. The prevalence of IGM dropped from 27.8% based on ontological FBGs to 0.48% by using algorithm-verified FBGs. The proposed ML algorithm or multiple logistic regression model aids in verification of the fasting status., (© 2022. The Author(s).)

Aspiration due to dysphagia can lead to aspiration, which negatively impacts a patient's overall prognosis. Clinically, videofluoroscopic swallow study (VFSS) is considered the gold-standard instrument to determine physiological impairments of swallowing. According to previously published literature, kinematic analyses of VFSS might provide further information regarding aspiration detection. In this study, 449 files of VFSS studies from 232 patients were divided into three groups: normal, aspiration, and pyriform sinus stasis. Kinematic analyses and between-group comparison were conducted. Significant between-group differences were noted among parameters of anterior hyoid displacement, maximal hyoid displacement, and average velocity of hyoid movement. No significant difference was detected in superior hyoid displacement. Furthermore, receiver-operating characteristic (ROC) analyses of anterior hyoid displacement, velocity of anterior hyoid displacement, and average velocity of maximal hyoid displacement showed acceptable predictability for detecting aspiration. Using 33.0 mm/s as a cutoff value of average velocity of maximal hyoid displacement, the sensitivity of detecting the presence of aspiration was near 90%. The investigators therefore propose that the average velocity of maximal hyoid displacement may serve as a potential screening tool to detect aspiration., (© 2022. The Author(s).)

This study compared changes in plasma complement component 1q (C1q), apelin and adropin concentrations in older obese women after descending (DSW) and ascending stair walking (ASW) training (n = 15/group) performed twice a week for 12 weeks, with gradual increases in exercise time from 5 to 60 min. Fasting blood samples were collected 3 days before the first and 4 days after the last training session. The improvements in the maximal voluntary isometric contraction (MVIC) strength of the knee extensors, functional physical fitness [e.g., 30-s chair stand (CS) performance], resting systolic blood pressure (SBP), insulin sensitivity [e.g., oral glucose tolerance test (OGTT)] and blood lipid profiles [e.g., total cholesterol (TC)] were greater (p < 0.05) in the DSW than ASW group. Plasma C1q decreased (- 51 ± 30%), and apelin (23 ± 15%) and adropin (127 ± 106%) increased (p ≤ .0.05) only after DSW. Significant (p ≤  0.01) partial correlations were found between the pre- to post-DSW changes in C1q, apelin or adropin and changes in outcome measures [e.g., C1q and MVIC (r = - 0.837), apelin and SBP (r = - 0.854), and andropin and OGTT (r = - 0.729)]. These results showed that greater decreases in plasma C1q and greater increases in apelin and adropin concentrations were associated with greater improvements in outcome measures after DSW than after ASW., (© 2021. The Author(s).)

Near 100% of diffractive efficiency for diffractive optical elements (DOEs) is one of the most required optical performances in broadband imaging applications. Of all flat DOEs, none seems to interest researchers as much as Two-Materials Composed Diffractive Fresnel Lens (TM-DFL) among the most promising flat DOEs. An approach of the near 100% of diffractive efficiency for TM-DFL once developed to determine the design rules mainly takes the advantage of numerical computation by methods of mapping and fitting. Despite a curved line of near 100% of diffractive efficiency can be generated in the Abbe and partial dispersion diagram, it is not able to analytically elaborate the relationship between two optical materials that compose the TM-DFL. Here, we present a theoretical framework, based on the fundaments of Cauchy's equation, Abbe number, partial dispersion, and the diffraction theory of Fresnel lens, for obtaining a general design formalism, so to perform the perfect material matching between two different optical materials for achieving the near 100% of diffractive efficiency for TM-DFL in the broadband imaging applications., (© 2021. The Author(s).)

Triaging and prioritising patients for RT-PCR test had been essential in the management of COVID-19 in resource-scarce countries. In this study, we applied machine learning (ML) to the task of detection of SARS-CoV-2 infection using basic laboratory markers. We performed the statistical analysis and trained an ML model on a retrospective cohort of 5148 patients from 24 hospitals in Hong Kong to classify COVID-19 and other aetiology of pneumonia. We validated the model on three temporal validation sets from different waves of infection in Hong Kong. For predicting SARS-CoV-2 infection, the ML model achieved high AUCs and specificity but low sensitivity in all three validation sets (AUC: 89.9-95.8%; Sensitivity: 55.5-77.8%; Specificity: 91.5-98.3%). When used in adjunction with radiologist interpretations of chest radiographs, the sensitivity was over 90% while keeping moderate specificity. Our study showed that machine learning model based on readily available laboratory markers could achieve high accuracy in predicting SARS-CoV-2 infection., (© 2021. The Author(s).)

The factors associated with the timely creation of distal vascular access for hemodialysis initiation are unclear. We aimed to explore the association between the slope of estimated glomerular filtration rate (eGFR) and the successful usage of vascular access upon hemodialysis initiation. This single center retrospective cohort study enrolled chronic kidney disease patients who undertook a multidisciplinary care program from 2003 to 2016. Using eGFR slope as predictor, we evaluated the vascular access created timely upon hemodialysis initiation. Among the 987 patients, vascular access was created at a median eGFR of 5.8 min/ml/1.73 m 2 , with a median duration of 3.1 months before hemodialysis. The proportions of vascular access created timely, created not timely (vascular access immature), and not created were 68.5%, 8.8%, and 22.7%, respectively. There was a significant negative association of eGFR upon vascular access creation with eGFR slope (r = - 0.182, P < 0.001). The fastest eGFR slope patients (the first quartile or < - 10 min/ml/1.73 m 2 /year) had the lowest percentage of vascular access created timely. In the multivariable logistic regression analysis, only higher eGFR upon vascular access creation (P = 0.001) and eGFR slope (P = 0.009) were significantly associated with vascular access created timely. The adjusted odds ratios of each quartile of eGFR slopes for vascular access created timely were 0.46 (95% confidence interval 0.27-0.86), 1.30 (0.62, 2.72), 1.00 (reference), and 0.95 (0.48-1.87), respectively. eGFR slope is associated with the timely creation of vascular access for the initiation of hemodialysis in a reverse-J-shaped pattern and may help determine the time of vascular access creation.

The spreading of viral hepatitis among injecting drug users (IDU) is an emerging public health concern. This study explored the prevalence and the risks of hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus (HDV) among IDU-dominant prisoners in Taiwan. HBV surface antigen (HBsAg), antibodies to HCV (anti-HCV) and HDV (anti-HDV), viral load and HCV genotypes were measured in 1137(67.0%) of 1697 prisoners. 89.2% of participants were IDUs and none had HIV infection. The prevalence of HBsAg, anti-HCV, dual HBsAg/anti-HCV, HBsAg/anti-HDV, and triple HBsAg/anti-HCV/anti-HDV was 13.6%, 34.8%, 4.9%, 3.4%, and 2.8%, respectively. HBV viremia rate was significantly lower in HBV/HCV-coinfected than HBV mono-infected subjects (66.1% versus 89.9%, adjusted odds ratio/95% confidence intervals [aOR/CI] = 0.27/0.10-0.73). 47.5% anti-HCV-seropositive subjects (n = 396) were non-viremic, including 23.2% subjects were antivirals-induced. The predominant HCV genotypes were genotype 6(40.9%), 1a(24.0%) and 3(11.1%). HBsAg seropositivity was negatively correlated with HCV viremia among the treatment naïve HCV subjects (44.7% versus 72.4%, aOR/CI = 0.27/0.13-0.58). Anti-HCV seropositivity significantly increased the risk of anti-HDV-seropositivity among HBsAg carriers (57.1% versus 7.1%, aOR/CI = 15.73/6.04-40.96). In conclusion, IUDs remain as reservoirs for multiple hepatitis viruses infection among HIV-uninfected prisoners in Taiwan. HCV infection increased the risk of HDV infection but suppressed HBV replication in HBsAg carriers. An effective strategy is mandatory to control the epidemic in this high-risk group.

Low transferrin saturation (TSAT), calculated by serum iron divided by total iron-binding capacity (TIBC), indicates iron deficiency. Because malnutrition and inflammation are associated with low TIBC in chronic kidney disease (CKD), TSAT might not reflect iron status or risk for anemia. We examined whether low serum iron was a risk factor for anemia in CKD patients with normal TSAT. Thus we compare the risk for anemia in 2500 CKD stage 1-4 patients divided by TSAT (cutoff: 20%) and serum iron (cutoff: 70 μg/dL in men, 60 μg/dL in women). Our results confirmed low TIBC (< 200 μg/dL) was associated with hypoalbuminemia and high C-reactive protein. In fully-adjusted logistic regression, both "normal TSAT low iron" and "low TSAT low iron" groups were associated with baseline anemia (hemoglobin < 11 g/dL) (odds ratios (OR) 1.56; 95% confidence interval (CI) 1.13-2.16 and OR 2.36; 95% CI 1.76-3.18, respectively) compared with the reference group (normal TSAT normal iron). Sensitivity tests with different cutoffs for TSAT and iron also showed similar results. In patients without anemia, both groups were associated with anemia after 1 year (OR 1.69; 95% CI 1.00-2.83 and OR 1.94; 95% CI 1.11-3.40, respectively). In conclusion, CKD stage 1-4 patients with normal TSAT but low serum iron are still at risk for anemia.

Little is known about the association between deep vein thrombosis (DVT) and arterial complications in patients with type 2 diabetes (T2DM). The aim of this retrospective cohort study was to assess the influence of prior DVT on major adverse limb events (MALEs) and major adverse cardiovascular events (MACEs) in T2DM. A total of 1,628,675 patients with T2DM with or without a history of DVT from 2001 to 2013 were identified in the National Health Insurance Research Database of Taiwan. Before matching, the patients in the DVT group (n = 2020) were older than the control group (66.3 vs. 58.3 years). Patients in the DVT group were more likely to be female than the control group (54.3% vs. 47.5%). Before matching, the DVT group had higher prevalence of most comorbidities, more prescription of antiplatelet, antihypertensive agents and insulins, but less prescription of metformin and sulfonylurea. During a mean follow-up of 5.2 years (standard deviation: 3.9 years), the matched DVT group (n = 2017) have a significantly increased risk of MALE (8.4% vs. 5.2%; subdistribution hazard ratio [SHR] 1.60, 95% CI 1.34-1.90), foot ulcer (5.2% vs. 2.6%, SHR 1.96, 95% CI 1.57-2.45), gangrene (3.4% vs. 2.3%, SHR 1.44, 95% CI 1.10-1.90) and amputation (2.5% vs. 1.7%; SHR 1.42, 95% CI 1.03-1.95) than the 10,085 matched controls without DVT. They also tended to have a greater risk of all-cause mortality (38.1% vs. 33.1%; hazard ratio [HR] 1.18, 95% CI 1.09-1.27) and systemic thromboembolism (4.2% vs. 2.6%; SHR 1.56, 95% CI 1.22-1.99), respectively. We showed the presence of DVT may be associated with an increased risk of MALEs, major amputation, and thromboembolism, contributing to a higher mortality rate in T2DM.

This animal study aimed to elucidate the relationship of low-dose, narrow-band UVB at 308 nm with vitamin D synthesis. C57BL/6 female mice, at 3 weeks-of-age, were randomly divided into the following six groups (n = 6 at each time point of vitamin D measurement), which were: (1) normal diet without UVB irradiation; (2) VDd diet without UVB irradiation; and (3)-(6) VDd diet with 308 nm-UVB irradiation of 12.5, 25, 50, and 100 μω/cm 2 , respectively. All of the groups needing UVB irradiation received an exposure of 10 min per day, five days per week, and a duration of 3-5 weeks. The mice recovering from severe VDd (plasma total 25-hydroxyvitamin D level increasing from approximately 3 to over 30 ng/mL) only occurred in groups with a UVB irradiation dosage of either 50 or 100 μω/cm 2 . The optimal, estimated dosage for mice to recover from severe VDd was 355 mJ/cm 2 within 3 weeks. Low-dose, narrow-band UVB irradiation at 308 nm is effective in improving VDd in mice. The results obtained, in addition to the especially small side effects of the above UVB irradiation formula, could be further translated to treating VDd-related disorders.

Ultrasound (US) neuromodulation, especially sonogenetics, has been demonstrated with potential applications in noninvasive and targeted treatment of various neurological disorders. Despite the growing interest, the mechanism for US neuromodulation remains elusive, and the optimal condition for eliciting a neural response with minimal adverse effect has not been identified. Here, we investigate the Piezo1 activation and intracellular calcium response elicited by acoustical streaming induced shear stress under various US exposure conditions. We find that Piezo1 activation and resultant intracellular calcium response depend critically on shear stress amplitude and pulse length of the stimulation. Under the same insonification acoustic energy, we further identify an optical pulse length that leads to maximum cell deformation, Piezo1 activation, and calcium response with minimal injury, confirmed by numerical modeling of Piezo1 channel gating dynamics. Our results provide insight into the mechanism of ultrasonic activation of Piezo1 and highlight the importance of optimizing US exposure conditions in sonogenetics applications.

Dyslipidemia is common in patients with chronic kidney disease (CKD), however the relationship between dyslipidemia and mortality in patients with moderate to severe CKD remains controversial. Non-high-density lipoprotein (HDL) cholesterol has been reported to be a more accurate predictor of clinical outcomes than conventional lipid measurements. Hence, the aim of this study was to investigate associations between non-HDL cholesterol and the risk of overall and cardiovascular mortality in patients with CKD stage 3-5. We enrolled 429 pre-dialysis patients with stage 3 to 5 CKD from May 2006 to January 2010. The patients were divided into four groups according to quartiles of non-HDL cholesterol. The patients were followed until death or until January 2020. During a median 11.6 years of follow-up, there were 78 (18.2%) deaths overall and 32 (7.5%) cardiovascular deaths. In adjusted models, the patients in quartile 1 (hazard ratio [HR] 3.368; 95% confidence interval [CI] 1.388-8.176; p = 0.007), quartile 3 (HR 3.666; 95% CI 1.486-9.044; p = 0.005), and quartile 4 (HR 2.868; 95% CI 1.136-7.240; p = 0.026) of non-HDL cholesterol had a higher risk of overall mortality (vs. quartile 2). In addition, the patients in quartile 1 (HR 19.503; 95% CI 2.185-174.0925 p = 0.008), quartile 3 (HR 28.702; 95% CI 2.990-275.559; p = 0.004), and quartile 4 (HR 11.136; 95% CI 1.126-110.108; p = 0.039) had a higher risk of cardiovascular mortality (vs. quartile 2). Our study showed a U-shaped relationship between non-HDL cholesterol and the risk of overall and cardiovascular mortality in patients with CKD stage 3-5. Assessing non-HDL cholesterol may help to identify subjects at high-risk of adverse outcomes.

Methamphetamine is a prevalent recreational drug among men who have sex with men (MSM) living with HIV and could cause the cognitive impairment and memory loss. However, studies on the association between methamphetamine use and adherence to antiretroviral treatment (ART) are limited and had inconsistent findings. This study aimed to determine the impact of methamphetamine use on adherence to ART among MSM living with HIV. From December 2018 to October 2019, MSM living with HIV were recruited (N = 351) and non-adherence to ART was defined as a Medication Adherence Report Scale score of <23. Overall, 16.0% of the participants reported methamphetamine use in the prior three months and 13.4% of the participants had non-adherence to ART. The proportion of non-adherence to ART among HIV-positive MSM were 28.6% and 10.5% with and without methamphetamine use, respectively. After controlling for demographics, illicit drug use, and co-morbidities, methamphetamine use during the prior three months was associated with a higher risk of non-adherence to ART (adjusted odds ratio = 3.08; 95% confidence intervals: 1.24-7.69). Compared with HIV-positive MSM with non-adherence to ART, HIV-positive MSM with good adherence to ART had a higher CD4 counts and were more likely to achieve an undetectable viral load. Since poor adherence to ART is associated with an increased HIV viral load and the risk of HIV transmission to others, our study suggests that it is imperative to screen HIV-positive patients for methamphetamine use and to provide effective therapy to reduce methamphetamine use and the associated non-adherence to ART.

Cancer cell migration plays a crucial role during the metastatic process. Reversible tyrosine phosphorylation by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) have been implicated in the regulation of cancer cell migration and invasion. However, the underlying mechanisms have not been fully elucidated. Here, we show that depletion of the FERM and PDZ domain-containing protein tyrosine phosphatase PTPN3 enhances lung cancer cell migration/invasion and metastasis by promoting actin filament assembly and focal adhesion dynamics. We further identified Src and DAAM1 (dishevelled associated activator of morphogenesis 1) as interactors of PTPN3. DAAM1 is a formin-like protein involved in the regulation of actin cytoskeletal remodeling. PTPN3 inhibits Src activity and Src-mediated phosphorylation of Tyr652 on DAAM1. The tyrosine phosphorylation of DAAM1 is essential for DAAM1 homodimer formation and actin polymerization. Ectopic expression of a DAAM1 phosphodeficient mutant inhibited F-actin assembly and suppressed lung cancer cell migration and invasion. Our findings reveal a novel mechanism by which reversible tyrosine phosphorylation of DAAM1 by Src and PTPN3 regulates actin dynamics and lung cancer invasiveness.

Resulting from accumulative microtrauma, impaired healing and oxidative stress, tendinopathy is a debilitating and relentlessly deteriorating disease that greatly affects daily function and quality of life. Current therapy usually provides symptomatic relief only. Sufferers undergo repetitive and protracted treatment courses that rarely alter the disease process. We aim to develop a sustained-release regimen with an intrinsic therapeutic effect in tendinopathy treatment, using oxidised hyaluronic acid/adipic acid dihydrazide hydrogel (HA hydrogel) as both the drug carrier and a mitigating agent of symptoms. We show that HA hydrogel can mitigate tendinopathy changes both in vitro (mechanically induced tendinopathy model) and in vivo (collagenase-induced tendinopathy model). A potent anti-oxidative (pigallocatechin gallate) incorporated into HA hydrogel conferred an additional protective effect in both models. The results indicate that when administered early, combined medications targeting different pathogenesis pathways can resolve tendinopathy. Although facilitating the healing process and mitigating oxidative stress are promising therapeutic strategies, the most effective regimen for tendinopathy treatment has to be determined yet. The established experimental model and drug carrier system provide a platform for exploring new therapeutics against this debilitating disease.

Rapid and accurate identification of pathogen is a major quarantine strategy for outbreak prevention. We used capillary electrophoresis-random amplified polymorphic DNA (CE-RAPD) to generate highly discriminatory pathogen profiles, reduced batch effects between profiles by novel normalization procedure and pattern of technical repeats, followed by target similarity evaluation using target identification score (TIS). A full target signature contains several patterns. TIS system was optimized by training set isolates that included three species, and validated using two hundred clinical Klebsiella pneumoniae isolates. Hierarchical clustering analysis showed CE-RAPD profiles arrange clusters according to the species or the source. Moreover, samples with similar profile may display similar antibiotic susceptibility. By using a signature of four patterns, the TIS system could accurately identify target among different isolates. The variation between isolates may be caused by small change in genome. TIS system provides a standardized tool for building of outbreak firewall and facilitate data exchange.

Esophageal squamous neoplasm presents a spectrum of different diatheses. A precise assessment for individualized treatment depends on the accuracy of the initial diagnosis. Detection relies on comprehensive and accurate white-light, iodine staining, and narrow-band imaging endoscopy. These methods have limitations in addition to its invasive nature and the potential risks related to the method. These limitations include difficulties in precise tumor delineation to enable complete resection, inflammation and malignancy differentiation, and stage determination. The resolution of these problems depends on the surgeon's ability and experience with available technology for visualization and resection. We proposed a method for identifying early esophageal cancerous lesion by endoscopy and hyperspectral endoscopic imaging. Experimental result shows the characteristic spectrum of a normal esophagus, precancerous lesion, canceration, and intraepithelial papillary capillary loop can be identified through principal component score chart. The narrow-band imaging (NBI) image shows remarkable spectral characteristic distribution, and the sensitivity and specificity of the proposed method are higher than those of other methods by ~0.8 and ~0.88, respectively. The proposed method enables the accurate visualization of target organs, it may be useful to capsule endoscope and telemedicine, which requires highly precise images for diagnosis.

The regular arrangements of β-strands around a central axis in β-barrels and of α-helices in coiled coils contrast with the irregular tertiary structures of most globular proteins, and have fascinated structural biologists since they were first discovered. Simple parametric models have been used to design a wide range of α-helical coiled-coil structures, but to date there has been no success with β-barrels. Here we show that accurate de novo design of β-barrels requires considerable symmetry-breaking to achieve continuous hydrogen-bond connectivity and eliminate backbone strain. We then build ensembles of β-barrel backbone models with cavity shapes that match the fluorogenic compound DFHBI, and use a hierarchical grid-based search method to simultaneously optimize the rigid-body placement of DFHBI in these cavities and the identities of the surrounding amino acids to achieve high shape and chemical complementarity. The designs have high structural accuracy and bind and fluorescently activate DFHBI in vitro and in Escherichia coli, yeast and mammalian cells. This de novo design of small-molecule binding activity, using backbones custom-built to bind the ligand, should enable the design of increasingly sophisticated ligand-binding proteins, sensors and catalysts that are not limited by the backbone geometries available in known protein structures.

We have investigated the use of fluorescent molecular rotors as probes for detection of p53 binding to DNA. These are a class of fluorophores that undergo twisted intramolecular charge transfer (TICT). They are non-fluorescent in a freely rotating conformation and experience a fluorescence increase when restricted in the planar conformation. We hypothesized that intercalation of a molecular rotor between DNA base pairs would result in a fluorescence turn-on signal. Upon displacement by a DNA binding protein, measurable loss of signal would facilitate use of the molecular rotor in the fluorescent intercalator displacement (FID) assay. A panel of probes was interrogated using the well-established p53 model system across various DNA response elements. A novel, readily synthesizable molecular rotor incorporating an acridine orange DNA intercalating group (AO-R) outperformed other conventional dyes in the FID assay. It enabled relative measurement of p53 sequence-specific DNA interactions and study of the dominant-negative effects of cancer-associated p53 mutants. In a further application, AO-R also proved useful for staining apoptotic cells in live zebrafish embryos.

Despite extensive efforts in recent years, the blood-brain barrier (BBB) remains a significant obstacle for drug delivery. This study proposes using a clinical extracorporeal shockwave instrument to open the BBB, combined with a laser assisted bi-axial locating platform to achieve non-invasive, controllable-focus and reversible BBB opening in the brains of rats. Under shockwave treatment with an intensity level of 5 (P - 9.79 MPa, energy flux density (EFD) 0.21 mJ/mm 2 ) and a pulse repetition frequency of 5 Hz, the BBB could be opened after 50 shocks without the use of an ultrasound contrast agent. With the proposed method, the BBB opening can be precisely controlled in terms of depth, size and location. Moreover, a shockwave based gene transfection was demonstrated using a luciferase gene.

Here, we discuss the development of a paper-based diagnostic device that is inexpensive, portable, easy-to-use, robust, and capable of running simultaneous tests to monitor a relevant inflammatory protein for clinical diagnoses i.e. C-reactive protein (CRP). In this study, we first attempted to make a paper-based diagnostic device via the wax printing method, a process that was used in previous studies. This device has two distinct advantages: 1) reduced manufacturing and assay costs and operation duration via using wax printing method to define hydrophobic boundaries (for fluidic devices or general POC devices); and, 2) the hydrophilicity of filter paper, which is used to purify and chromatographically correct interference caused by whole blood components with a tiny amount of blood sample (only 5 μL). Diagnosis was based on serum stain length retained inside the paper channels of our device. This is a balanced function between surface tension and chromatographic force following immune reactions (CRP assays) with a paper-embedded biomarker.

Chronic kidney disease (CKD) is frequently complicated with hyponatremia, probably because of fluid overload or diuretic usage. Hyponatremia in CKD population is associated with increased mortality, but the effect on renal outcome was unknown. We investigated whether hyponatremia is associated with fluid status and is a prognostic indicator for adverse outcomes in a CKD cohort of 4,766 patients with 1,009 diuretic users. We found that diuretic users had worse clinical outcomes compared with diuretic non-users. Hyponatremia (serum sodium <135 mEq/L) was associated with excessive volume and volume depletion, measured as total body water by bioimpedance analysis, in diuretic users, but not in diuretic non-users. Furthermore, in Cox survival analysis, hyponatremia was associated with an increased risk for renal replacement therapy (hazard ratio, 1.45; 95% CI, 1.13-1.85, P < 0.05) in diuretic users, but not in diuretic non-users (P for interaction <0.05); restricted cubic spline model also showed a similar result. Hyponatremia was not associated with all-cause mortality or cardiovascular event whereas hypernatremia (serum sodium >141 mEq/L) was associated with an increased risk for all-cause mortality. Thus, hyponatremia is an indicator of fluid imbalance and also a prognostic factor for renal replacement therapy in CKD patients treated with diuretics.

Intraocular vascular endothelial growth factor (VEGF) levels play an important role in the pathogenesis of blindness-related diseases, such as age-related macular degeneration (AMD). Here, we aimed to develop a paper-based enzyme-linked immunosorbent assay (P-ELISA) to analyze the suppression of aqueous VEGF concentrations following intravitreal injection (IVI) of anti-VEGF antibody (bevacizumab or ranibizumab). A total of 25 eyes with wet AMD, one with myopic neovascularization, and one with polypoidal choroidal vasculopathy were enrolled in this study. The limit of detection using P-ELISA was 0.03 pg/mL. Forty-six consecutive samples of aqueous humor were acquired. From all samples, 66.67% (10/15) achieved complete VEGF suppression (below the detection limit) within 5 weeks of receiving IVI of anti-VEGF antibody. Only 13.33% of samples (2/15) achieved complete VEGF suppression 5 weeks after receiving treatment. In some patients, elevated VEGF was still detected 5 weeks after receipt of anti-VEGF antibody, and all samples (10/10) were found to have elevated VEGF levels 49 days after treatment. Thus, we suggest that monthly IVI of anti-VEGF antibody may be required to ensure durable VEGF inhibition. Ultrasensitive P-ELISA can detect elevated VEGF at an earlier time point and may facilitate decision-making regarding appropriate treatment strategies., Competing Interests: M.-Y.H., K.H.L., and C.M.C. are inventors of a patent (patent no.: TW 201428105) owned by National Tsing Hua University based on the work reported in this paper. M.-Y.H. and C.M.C. have a patent pending in the USA based on the work reported in this paper (patent no:US20140315224 A1). Y.-C.H., D.-K.H., S.-C.L., K.-H.L., C.-Y.W., Y.-P.W. and H.-Y.C. have no potential conflicts of interest to declare.

Chronic hepatitis C virus (HCV) infection had been associated with cytokine imbalance. Cytokine dynamics in response to peginterferon/ribavirin therapy have an impact on the treatment efficacy for HCV patients. Ninety-two treatment-naive chronic hepatitis C patients were treated with 24 or 48 weeks of peginterferon/ribavirin therapy according to their viral genotypes. Sustained virologic response (SVR) is defined as undetectable HCV RNA throughout a 24-week post-treatment follow-up period. Dynamic serum levels of the following cytokines: (1) Th1-mediated cytokines: IFN-γ, interleukin-2, and TNF-alpha; (2)Th2-mediated cytokines: interleukin-4, interleukin-5, interleukin-6, and interleukin-10 and (3)immuno-modulatory cytokines: interleukin-1β, interleukin-8, and interleukin-12 were determined by Fluorescent Bead immunoassay. Serial dynamic cytokine expression demonstrated that not only elevated IFN-γ concentrations at specific time points but also the total IFN-γ amount was strongly linked to non-response in peginterferon/ribavirin therapy. IFN-γ levels could serve as an independent predictor for SVR analyzed by multivariate logistic regression test. The accuracy of discriminating responders from non-responders was acceptable when IFN-γ cut-off levels were set at 180, 120, and 40 pg/ml at the 4th week, 12th week, and end-of-treatment of therapy, respectively. Elevated on-treatment IFN-γ concentration was significantly associated with treatment failure among interleukin-28B rs8099917TT carriers and those patients failed to achieve rapid virologic response.

This retrospective cohort study investigated the progression risk of sequential complication in Asian type 2 diabetes (T2D) patients using the Taiwan Pay-for-Performance Diabetes Registry and claim data from November 2003 to February 2009. 226,310 adult T2D patients without complication were followed from diagnosis to complications, including myocardial infarction (MI), other ischemic heart disease (IHD), congestive heart failure (CHF), stroke, chronic kidney disease (CKD), retinopathy, amputation, death or to the end of study. Cumulative incidences (CIs) of first and second complications were analyzed in 30 and 4 years using the cumulative incidence competing risk method. IHD (29.8%), CKD (24.5%) and stroke (16.0%) are the most common first complications. The further development of T2D complications depends on a patient's existing complication profiles. Patients who initially developed cardiovascular complications had a higher risk (9.2% to 24.4%) of developing IHD or CKD, respectively. All-cause mortality was the most likely consequence for patients with a prior MI (12.0%), so as stroke in patients with a prior MI (10.8%) or IHD (8.9%). Patients with CKD had higher risk of developing IHD (16.3%), stroke (8.9%) and all-cause mortality (8.7%) than end-stage renal disease (4.0%). Following an amputation, patients had a considerable risk of all-cause mortality (42.1%).

In this study we measured the degrees to which the Schottky barrier heights (SBHs) are lowered in ZnO nanowire (NW) devices under illumination with UV light. We measured the I-V characteristics of ZnO nanowire devices to confirm that ZnO is an n-type semiconductor and that the on/off ratio is approximately 10(4). From temperature-dependent I-V measurements we obtained a SBH of 0.661 eV for a ZnO NW Schottky device in the dark. The photosensitivity of Schottky devices under UV illumination at a power density of 3 μW/cm(2) was 9186%. Variations in the SBH account for the superior characteristics of n-type Schottky devices under illumination with UV light. The SBH variations were due to the coupled mechanism of adsorption and desorption of O2 and the increase in the carrier density. Furthermore, through temperature-dependent I-V measurements, we determined the SBHs in the dark and under illumination with UV light at power densities of 0.5, 1, 2, and 3 μW/cm(2) to be 0.661, 0.216, 0.178, 0.125, and 0.068 eV, respectively. These findings should be applicable in the design of highly sensitive nanoscale optoelectronic devices.

The influence of patatin-like phospholipase domain-containing 3 (PNPLA3) genetic variants in the development of liver steatosis in Asian chronic hepatitis C patients remains elusive. A total of 1018 biopsy-proven chronic hepatitis C patients were enrolled for evaluation. The proportions of PNPLA3 rs738409 GG genotype carriage were 7.8% (44/563), 15.8% (58/367) and 19.3% (17/88) in patients with no (liver fat content < 5%), mild (5-33%) and moderate/severe (> 66%) hepatic steatosis, respectively (trend P < 0.001). Stepwise logistic regression analysis revealed that the strongest factor independently associated with steatosis was the carriage of the PNPLA3 rs738409 GG genotype (odds ratio [OR]/95% confidence intervals [CI]:2.34/1.557-3.515, P < 0.001). Among the patients with BMI < 24 kg/m(2), carriage of the rs738409 GG genotype was the only factor associated with hepatic steatosis (OR/CI:3.44/1.824-6.500, P < 0.001). PNPLA3 genetic variants had minimal effects on hepatic steatosis among overweight or obese patients. Compared to patients with BMI < 24 kg/m(2)/non-GG genotype, those with BMI >24 kg/m(2)/GG genotype were more likely to have hepatic steatosis (OR/CI:3.87/2.292-6.524, P < 0.001). In conclusions, both PNPLA3 genetic variants and BMI played important roles in hepatic steatosis among Asian chronic hepatitis C patients. However, the genetic effect was mainly restricted to non-obese patients.

A higher risk of dementia was reported in patients undergoing maintenance hemodialysis (HD) compared to those undergoing peritoneal dialysis (PD). Selection bias and competing risk of death were not considered in previous studies. The aim of this study was to investigate dementia risk in patients undergoing HD and PD by using the Taiwan Longitudinal Health Insurance Database. We enrolled 52,332 incident HD patients and 3292 incident PD patients who were older than 40 years between January 1, 1998 and December 31, 2007. During the study period, 3775 patients were diagnosed with dementia in the HD group (177.5 per 10,000 person-years incidence rate) and 181 patients in the PD group (145.9 per 10,000 person-years incidence rate). The results revealed that the higher hazard ratio of HD compared with PD for dementia disappeared after controlling for demographic characteristics, propensity score, and competing death risk (subdistribution hazard ratio was 1.086; 95% confidence interval, 0.940-1.255). In conclusion, HD did not increase the risk of dementia in dialysis-dependent patients compared to PD.

A good diagnostic procedure avoids wasting medical resources, is easy to use, resists contamination, and provides accurate information quickly to allow for rapid follow-up therapies. We developed a novel diagnostic procedure using a "cotton-based diagnostic device" capable of real-time detection, i.e., in vitro diagnostics (IVD), which avoids reagent contamination problems common to existing biomedical devices and achieves the abovementioned goals of economy, efficiency, ease of use, and speed. Our research reinforces the advantages of an easy-to-use, highly accurate diagnostic device created from an inexpensive and readily available U.S. FDA-approved material (i.e., cotton as flow channel and chromatography paper as reaction zone) that adopts a standard calibration curve method in a buffer system (i.e., nitrite, BSA, urobilinogen and uric acid assays) to accurately obtain semi-quantitative information and limit the cross-contamination common to multiple-use tools. Our system, which specifically targets urinalysis diagnostics and employs a multiple biomarker approach, requires no electricity, no professional training, and is exceptionally portable for use in remote or home settings. This could be particularly useful in less industrialized areas.