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Background Chronic hepatitis C virus (HCV) infection is associated with increased cardiovascular risks. We aimed to investigate the impact of direct acting antiviral (DAA) on HCV-associated cardiovascular events. Methods In this retrospective cohort study, patients with the diagnosis of chronic HCV were retrieved from multi-institutional electronic medical records, where diagnosis of HCV was based on serum HCV antibody and HCV–RNA test. The patients eligible for analysis were then separated into patients with DAA treatment and patient without DAA treatment. Primary outcomes included acute coronary syndrome, heart failure (HF), venous thromboembolism (VTE), stroke, cardiovascular death, major adverse cardiovascular event (MACE), and all-cause mortality. Outcomes developed during follow-up were compared between DAA treatment and non-DAA treatment groups. Results There were 41 565 patients with chronic HCV infection identified. After exclusion criteria applied, 1984 patients in the DAA treatment group and 413 patients in the non-DAA treatment group were compared for outcomes using inverse probability of treatment weighting. Compared to patients in non-DAA treatment group, patients in DAA treatment group were associated with significantly decreased HF (hazard ratio [HR]: 0.65, 95% confidence interval [CI]: 0.44–0.97, P = 0.035), VTE (HR: 0.19, 95% CI: 0.07–0.49, P = 0.001), MACE (HR: 0.73, 95% CI 0.59–0.92, P = 0.007), and all-cause mortality (HR: 0.50, 95% CI: 0.38–0.67, P Conclusions Chronic HCV patients treated with DAA experienced lower rates of cardiovascular events and all-cause mortality than those without treatment. The reduction of VTE was the most significant impact of DAA treatment among the cardiovascular outcomes.

(1) To investigate the functional and anatomical outcomes of anti-vascular endothelial growth factor (anti-VEGF) treatment in patients with exudative age-related macular degeneration (AMD) with or without obstructive sleep apnea (OSA); (2) In total, 65 patients with AMD with or without OSA who received three consecutive doses of intravitreal anti-VEGF injections were enrolled. The primary outcomes—best-corrected visual acuity (BCVA) and central macular thickness (CMT)—were assessed at 1 and 3 months. Moreover, morphological changes observed through optical coherence tomography were analyzed; (3) In total, 15 of the 65 patients had OSA and were included in the OSA group; the remaining 50 patients were included in the non-OSA (control) group. At 1 and 3 months after treatment, BCVA and CMT had improved but did not differ significantly between the groups. More patients in the OSA group demonstrated subretinal fluid (SRF) resorption at 3 months after treatment than in the non-OSA group (p = 0.009). Changes in other imaging biomarkers, such as intraretinal cysts, retinal pigment epithelium detachment, hyperreflective dots, and ellipsoid zone disruptions, did not differ significantly between the groups; (4) Our results suggest that the BCVA and CMT outcomes 3 months after anti-VEGF treatment are similar between patients with and without OSA. Moreover, patients with OSA may exhibit superior SRF resorption. A large-scale prospective study is mandatory to evaluate the association between SRF resorption and visual outcomes in AMD patients with OSA.

OBJECTIVE Data regarding the prevalence of depression and anxiety among cancer patients, especially before cancer diagnosis, remains scarce. This study investigated the prevalence of these conditions and associated drug use among cancer patients pre- and post-diagnosis. METHODS This population-based cohort study using data from Taiwan's National Health Insurance Research Database recruited patients with a registered cancer diagnosis and matched control between January 1, 2000, and December 31, 2011. We compared the prevalence of anxiety and depressive disorders between cancer patients and non-cancer participants during a 2-year period both pre- and post-diagnosis by Pearson's chi-square test. Psychiatric medication use was also examined for the associated mental condition. RESULTS We examined participants diagnosed with liver (N = 17,154), colorectal (N = 30,391), breast (N = 40,036), gynecological (N = 23,218), and lung (N = 15,671) cancer. Before the cancer diagnosis, the prevalence of depression was higher in non-cancer participants than in gynecological cancer patients (p = 0.018) but anxiety is higher in liver, colorectal, and lung cancer patients when compared to non-cancer participants (p

This paper proposed a PM 2.5 forecasting model using Long Short-Term Model (LSTM) sequence to sequence combined with the statistical method. Correlation Analysis, XGBoost, and Chemical processed are used as the methods to select the essential features. The air pollution data is extracted from Taiwan Environmental Protection Agency (EPA) for the Taichung City dataset in 2014–2018. The study points out that chemical processed model of particulate matter 10 micrometers or less in diameter (PM10), Sulfur Dioxide (SO2), and Nitrogen Dioxide (NO2) have the highest accuracy or lowest Root Mean Square Error (RMSE) and more short training and testing time among the other models. The chemical processed model of PM10, SO2, and NO2 (model B) has the highest accuracy (lowest RMSE), approximately 1 point lower RMSE values, and the shortest training and testing period among the other models. Furthermore, RMSE calculations based on the stations reveal that training with the entire station dataset has a 3 point higher RMSE value than training with each station dataset.

Purpose Literature suggests that attention deficit hyperactivity disorder (ADHD) is associated with a high risk of unintentional injury. However, few studies have focused on whether risk of burn injury is relatively high among patients with ADHD. The aim of this study was to investigate whether ADHD affects the risk of burn injury. Materials and Methods Individuals aged

BACKGROUND: Pacing-induced cardiomyopathy is an undesired outcome in patients with atrioventricular block (AVB), and our animal model showed lipotoxic cardiomyopathy after pacing.OBJECTIVES: The purpose of this study was to explore the mechanisms and clinical outcomes of statins in AVB patients receiving pacing.METHODS: Rat ventricular cardiomyocytes were treated with atorvastatin, liver X receptor (LXR) agonist, and LXR antagonist during pacing. Pigs were divided into 3 groups: right ventricular pacing, pacing with concomitant atorvastatin treatment, and sham control. Clinically, we enrolled 1717 AVB patients who had received a permanent pacemaker from Chang Gung Memorial Hospital Medical database. The primary outcome (cardiovascular death or heart failure [HF] hospitalization) and individual outcome were compared between statin and nonstatin groups after inverse probability of treatment weighting.RESULTS: Lipid accumulation in rat cardiomyocytes by pacing was significantly reduced by treatment with LXR agonist and atorvastatin, whereas LXR antagonist counteracted the atorvastatin effect on lipid expression. Left ventricular ejection fraction (LVEF) was significantly lower in the AVB pig pacing group compared to the group concomitantly treated with atorvastatin. Moreover, lipid accumulation and fibronectin expression were significantly ameliorated by concomitant treatment with atorvastatin. In the clinical study, the statin group had a significantly lower risk of the primary outcome event (hazard ratio [HR] 0.69; 95% confidence interval [CI] 0.56-0.84), less HF hospitalization (HR 0.45; 95% CI 0.30-0.67), and higher LVEF than the nonstatin group.CONCLUSION: In experimental models, atorvastatin ameliorated lipid accumulation in cardiomyocytes and fibrosis in left ventricular myocardium induced by pacing. Clinically, treatment with statins was associated with less HF hospitalization and cardiovascular death in AVB patients receiving pacemaker therapy.

Rotavirus A (RVA) are a group of diverse viruses causing acute gastroenteritis (AGE) in humans and animals. Zoonotic transmission is an important mechanism for rotavirus evolution and strain diversity in humans, but the extent of pigs as a major reservoir for human infection is not clear.We have surveyed 153 pig farms across Taiwan with a total of 4588 porcine stool samples from three age groups from 2014 to 2017. Nursing piglets (less than one month of age) had higher detection rate for rotavirus than older age groups. Five VP7 (G) genotypes and 5 VP4 (P) genotypes were found in a total of 14 different G/P genotype combinations. In addition, porcine RVA strains had 2 NSP4 (E) genotypes and 3 VP6 (I) genotypes. A P[3]-like genotype was also discovered among strains collected in 2016 and 2017.Most of the genes from Taiwanese porcine strains clustered with each other and the lineages formed by these strains were distinct from the sequences of numerous regional variants or globally circulating porcine strains, suggesting an independent evolutionary history for Taiwanese rotavirus genotypes. The close relationship among porcine RVA strains and some unique porcine-like genotypes detected sporadically among human children in swine farms illustrates that pigs might serve as a reservoir for potential zoonotic transmission and novel genotype evolution in Taiwan's insular environment.

Background Studies have reported an association between allergy and panic disorder. However, few studies have explored the relationship between allergic rhinitis and panic disorder. Previous studies were limited by cross-sectional study designs, self-reported symptoms, absence of matched controls, and lack of consideration of the influence of steroid and comorbidities. This study aimed to explore the longitudinal association between allergic rhinitis and panic disorder in a large population-based cohort of young people. Methods In this study, 79,917 new cases of allergic rhinitis between 1998 and 2012 in individuals younger than 20 years were identified from Taiwan's National Health Insurance Research Database. One control (nonallergic rhinitis) per case (allergic rhinitis) was randomly selected from the remaining sample, matching for age, sex, residence, and insurance premium. Both groups were followed until the end of 2013 for incidence of panic disorder. Cox regression analysis was performed, adjusting for sex, age, residence, insurance premium, systemic steroids, asthma, atopic dermatitis, allergic conjunctivitis, attention deficit hyperactivity disorder, depression, and Charlson index. Results Allergic rhinitis was associated with a 2-fold increase in risk for panic disorder after adjustment for other variables. Additional independent risk factor of panic disorders were female sex, older age group, and depression. Limitations Lifestyle, substance use, smoking by the patient or family members, and psychosocial stressors were not evaluated. Conclusions Allergic rhinitis was associated with increased risk of panic disorder. Assessment and intervention of allergy rhinitis among young people with panic disorder are critical.

Background: Obesity has been regarded as a risk factor for epiblepharon. This study aims to investigate the age- and sex-specific relationship between epiblepharon and obesity in children.Methods: A retrospective case-control study was conducted using Chang Gung Research Database. Children ≤ 18 years of age with epiblepharon were identified from 1 January 2009 to 31 December 2019. Children were classified into four groups: underweight, normal, overweight and obese groups.Results: A total of 513 patients and 1026 controls (57.7% of males) aged 1 to 18 matched by sex and age were included in the analysis. The median body mass index (BMI) of children with epiblepharon was significantly higher than that of children without epiblepharon (p < 0.001). In the subgroup analysis, among boys aged 4 to 9 years, the BMI in boys with epiblepharon was significantly higher than that in boys without epiblepharon (p < 0.05) and the risk of epiblepahron in overweight and obese boys was significantly higher than in non-overweight boys (OR = 1.74, 95% CI = 1.07-2.82; OR = 3.06, 95% CI = 1.56-6.03). On the other hand, among girls aged 13 to 18 years, the BMI in adolescent girls with epiblepharon was significantly higher than that in the control group (p < 0.05) and overweight and obese girls had statistically higher risk of persistent epiblepharon than non-overweight girls (OR =3.70, 95% CI = 1.38-9.97).Conclusions: The association between obesity and epiblepharon varies in strength according to age in a sex-specific manner.

Failure to recognize a carotid-cavernous fistula (CCF) promptly may lead to worse prognosis due to a setback in providing proper treatment. To promote early diagnosis of non-traumatic CCF, we report a case with classic clinical symptoms and signs that was diagnosed and followed up with carotid Doppler sonography (CDS) and transcranial color-coded duplex (TCD).A 45-year-old woman developed an intermittent headache, pulsatile tinnitus, and double vision sequentially within ten days. Progressive left retro-orbital pain, continuous ringing in the left ear, sensory impairment of trigeminal nerve and abducens nerve palsy were also noted on examination. Despite insignificant findings on computed tomography (CT) of the brain, TCD revealed an aberrant flow pattern with high velocity and low resistance at the left carotid siphon. Digital subtraction angiography (DSA) later confirmed a left direct type CCF by illustrating a quick opacification of left cavernous sinus via the internal carotid artery.In addition to invasive DSA, non-invasive CDS and TCD may serve as useful apparatus during the initial evaluation and subsequent follow-ups. The positive sonographic clues, including abnormal turbulent and hemodynamic parameters, are quite exhibitive in the existence of CCFs.

Background: The aim of this study was to compare the risk of developing sudden sensorineural hearing loss (SSHL) in patients with hypopharyngeal cancer with that in patients with nasopharyngeal carcinoma (NPC). Methods: A population-based, retrospective cohort study was performed using the Taiwan National Health Research Database databank. Patients selected for this study were diagnosed with hypopharyngeal cancer or NPC and treated with radiotherapy in the period from 2001 to 2004. Routine follow-up was conducted for 8 years (2004–2012), and the incidence of SSHL was calculated at the final follow-up. Results: There was no significant difference in the risk of developing SSHL between the hypopharyngeal cancer group and its control group (p = 1.000). In hypopharyngeal cancer and NPC groups, the rates of SSHL were 0.12% and 1.00%, respectively (p < 0.001). The cumulative hazard of SSHL during the follow-up period was significantly higher in the NPC group than in the control group (p < 0.001). Conclusion: Radiotherapy in patients with hypopharyngeal cancer did not increase the risk of developing SSHL, but postirradiation NPC was significantly associated with an increased incidence of SSHL.

Objective To investigate the safety of adenoidectomy and risk factors of re-adenoidectomy, and intend to provide evidence-based information to clinicians for further consideration. Methods and materials This study was based on data obtained from Taiwan’s National Health Insurance Research Database from the period 2002–2011. We utilized that data from the hospitalization group and collected information regarding those individuals who accepted adenoidectomy with or without tonsillectomy and post-adenoidectomy bleeding. Thereafter, we performed univariate and multi-variate analysis to explore the possible risk factors of re-adenoidectomy. Results A total of 5435 individuals who accepted a first adenoidectomy with or without tonsillectomy were collected. After further tracing treatment of these individuals, 107 (1.97%) accepted the revision adenoidectomy until 2011. Post-op bleeding was approximately 0.28%. The revision rate associated with patient age showed the following: 0–4 years (0.61%), 4–12 years (2.06%) and 12–18 years (2.56%). The revision rate associated with surgeon age showed: 28–41 years (1.42%), 41–50 years (2.96%), 50–65 years (2.74%); the surgeons’ surgery volume showed low (4.34%), medium (0.71%), and higher (1.02%). There are 4 diseases (otitis media with effusion, sinusitis, chronic pharyngitis, and sleep disorder) that showed a significant relationship with the revision rate when subject to univariate and multivariate analysis. The revision rate incorporating hospital locations, volumes and levels revealed no significant difference with each other. Conclusions Adenoidectomy is a generally safe surgical procedure, with low complication and low revision rate. Our study indicated that the revision rate of adenoidectomy might be lower when performed by young visiting staff with medium to higher surgical volume in the medium to higher volume hospital. If patients had diseases such as otitis media with effusion, sinusitis, chronic pharyngitis, and sleep disorder, they would be subject to higher rate of re-adenoidectomy. Surgeons should be aware and sufficiently explain this information to the parents before surgery.

We report the first nationwide population-based cohort study using Taiwan's National Health Insurance Research Database on the association between enterovirus (EV) infection and the incidence of sleep disorders in a pediatric population.Two matched groups of children under 18 years of age were included in the analyses for nonapneic sleep disorder and obstructive sleep apnea (OSA). Among them, 316 subjects were diagnosed with OSA during the surveillance period, including 182 in the EV infection group and 134 in the non-EV infection group.Hospitalization because of EV infection was associated with OSA after adjusting for age, sex, urbanization atopic disease and perinatal complications (adjusted hazard ratio: 1.62, 95% confidence interval: 1.18-2.21; P = 0.003). An additional factor significantly associated with sleep apnea was allergic rhinitis (hazard ratio: 4.82, 95% confidence interval: 3.45-6.72).Children with severe EV infection (ie, requiring hospitalization) carry a significantly higher risk of developing OSA, particularly in those with allergic rhinitis. As pediatric obstructive sleep apnea is a treatable sleep disorder, we emphasize regular follow-up and early detection in children with EV infection.

Background Synthesis of a variety of biological circuits for specific functional purposes has made a tremendous progress in recent years. The ultimate goal of combining molecular biology and engineering is to realize a functional biocomputer. To address this challenge, all previous efforts work toward building up the bio-computer as the ultimate goal. To this aim, there should be a key module, named control unit (CU), to direct a serious of logic or arithmetic operations within the processor. Methods This research task develops a bio-CU to work with a bio-ALU, which is realized from the combination of previously developed genetic logic gates to fulfill the kernel function of CPU as those done in the silicon computer. Results A possible framework of the bio-CPU has demonstrated how to connect a bio-CU with a bio-ALU to conduct a fetch-decode-execute cycle of a macro instruction. It presents not only capability of 4-bit full adder but coordination of related modules in biocomputer. Conclusions We have demonstrated computer simulation for applications of the genetic circuits in biocomputer construction. It’s expected to inspire follow-up study to synthesize potential configurations of the future biocomputer.

Summary: The Muscleblind-like protein family (MBNL) plays an important role in regulating the transition between differentiation and pluripotency and in the pathogenesis of myotonic dystrophy type 1 (DM1), a CTG expansion disorder. How different MBNL isoforms contribute to the differentiation and are affected in DM1 has not been investigated. Here, we show that the MBNL1 cytoplasmic, but not nuclear, isoform promotes neurite morphogenesis and reverses the morphological defects caused by expanded CUG RNA. Cytoplasmic MBNL1 is polyubiquitinated by lysine 63 (K63). Reduced cytoplasmic MBNL1 in the DM1 mouse brain is consistent with the reduced extent of K63 ubiquitination. Expanded CUG RNA induced the deubiqutination of cytoplasmic MBNL1, which resulted in nuclear translocation and morphological impairment that could be ameliorated by inhibiting K63-linked polyubiquitin chain degradation. Our results suggest that K63-linked ubiquitination of MBNL1 is required for its cytoplasmic localization and that deubiquitination of cytoplasmic MBNL1 is pathogenic in the DM1 brain. : Wang et al. find that MBNL1 ubiquitination is required for cytoplasmic localization and promotion of neurite outgrowth. In myotonic dystrophy, expanded CUG repeat RNA leads to MBNL1 deubiquitination, resulting in nuclear-translocation-associated morphological defects that can be rescued by preventing degradation of lysine 63-linked polyubiquitin chains or enhancing MBNL1 ubiquitination. Keywords: MBNL1, polyubiquitination, myotonic dystrophy, nucleocytoplasmic localization, neurite outgrowth

Preventive effect of stimulants on the risk of brain injuries had been reported. The aim of this study is to determine the extent to which methylphenidate (MPH) prescription moderates the risk of traumatic brain injuries (TBI) in individuals with attention-deficit/hyperactivity disorder (ADHD). Individuals with a recent diagnosis of ADHD between January 1997 and December 2013 (n = 163,618) were identified from Taiwan's National Health Insurance Research Database. A total of 124,438 adolescents and children with ADHD and without prior TBI diagnoses were included and evaluated for subsequent TBI. Methylphenidate prescription duration was subgrouped by the annual average cumulative defined daily dose (DDD): 0, >0 to ≤28, > 28 to ≤84, and >84. We identified 11,463 diagnoses of TBI among 124,438 adolescents and children with ADHD. A Cox regression model was used to investigate whether MPH prescription influenced the risk for TBI after adjusting for sex, age, level of urbanization, seizure, autism and sedative-anxiolytics use. A reduced TBI incidence was observed with MPH prescription DDDs > 84. The protective effect of MPH against TBI persisted after adjusting for confounding factors [hazard ratio (HR) = 0.49; 95% confidence interval (CI): 0.47-0.51]. There was also statistically significant difference in risk for TBI in subjects receiving > 0 to ≤28 or >28 to ≤84 DDDs of MPH treatment (HR = 0.88, 95% CI = 0.83-0.92; HR = 0.76, 95% CI = 0.72-0.80, respectively) when compared with subjects not receiving treatment with MPH. Treatment with MPH for greater than 84 DDDs reduced the risk for TBI among children with ADHD.

In Taiwan, acute gastroenteritis outbreaks caused by a new norovirus genotype GII.2 increased sharply toward the end of 2016. Unlike previous outbreaks, which often involved restaurants, GII.2 outbreaks mainly occurred in schools. Phylogenetic analysis indicates that these noroviruses are recombinant GII.P16-GII.2 strains.

Aims Attention-deficit/hyperactivity disorder (ADHD) is associated with a higher risk of burn injury than in the normal population. Nevertheless, the influence of methylphenidate (MPH) on the risk of burn injury remains unclear. This retrospective cohort study analysed the effect of MPH on the risk of burn injury in children with ADHD. Method Data were from Taiwan's National Health Insurance Research Database (NHIRD). The sample comprised individuals younger than 18 years with a diagnosis of ADHD (n = 90 634) in Taiwan's NHIRD between January 1996 and December 2013. We examined the cumulative effect of MPH on burn injury risk using Cox proportional hazards models. We conducted a sensitivity analysis for immortal time bias using a time-dependent Cox model and within-patient comparisons using the self-controlled case series model. Results Children with ADHD taking MPH had a reduced risk of burn injury, with a cumulative duration of treatment dose-related effect, compared with those not taking MPH. Compared with children with ADHD not taking MPH, the adjusted hazard ratio for burn injury was 0.70 in children taking MPH for Conclusion This study showed that MPH treatment was associated with a lower risk of burn injury in a cumulative duration of treatment dose-related effect manner.

Hsuan Lee,1,* Vincent Chin-Hung Chen,2,3,* Yao-Hsu Yang,4– 6 Ting-Yu Kuo,4 Tzu-Chin Lin,7,8 Shu-I Wu,9,10 Kai-Liang Kao,11,12 Jun-Cheng Weng,3,13 Brent Allan Kelsen,14,15 Sophie Hsin-Yi Liang2,16 1Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; 2Department of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Department of Psychiatry, Chang Gung Memorial Hospital at Chiayi,Chiayi,Taiwan; 4Health Information and Epidemiology Laboratory of Chang Gung Memorial Hospital, Chiayi Branch, Chiayi,Taiwan; 5Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital,Taiwan; 6School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 7Bethel Psychiatric Clinic, Taipei, Taiwan; 8Institute of Science, Technology and Society, National Yang-Ming University Taipei, Taiwan; 9Mackay Memorial Hospital, Section of Psychiatry, Taipei, Taiwan; 10Department of Medicine, Mackay Medical College, Taipei, Taiwan; 11Department of Pediatrics, Far Eastern Memorial Hospital, Taipei, Taiwan; 12Department of Industrial Management, Oriental Institute of Technology, Taipei, Taiwan; 13Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan; 14Language Center, National Taipei University, New Taipei City, Taiwan; 15Department of Psychology, Auckland University of Technology, Auckland, New Zealand; 16Department of Child Psychiatry, Chang Gung Memorial Hospital at Taoyuan, Taoyuan, Taiwan*These authors contributed equally to this workCorrespondence: Sophie Hsin-Yi LiangDepartment of Child Psychiatry, Chang Gung Memorial Hospital at Taoyuan, No. 123, Dinghu Road, Guishan Township, Taoyuan 333, TaiwanEmail sophie.lhy@gmail.comBackground: Young individuals with attention-deficit hyperactivity disorder (ADHD) may have an elevated risk of influenza because of the difficulty in complying with the behavioral procedures that help protect against influenza. Moreover, the effects of sufficient methylphenidate treatment on influenza have received little attention.Objective: This study evaluated the association between ADHD medication usage and influenza and assessed the effect of duration of ADHD treatment on the risk of influenza using a nationwide population-based database.Methods: This study investigated methylphenidate usage and the risk of influenza among children and adolescents with ADHD. We identified 5259 young individuals aged less than 18 years who were diagnosed as having ADHD between 1996 and 2013 from the National Health Insurance Research Database of Taiwan, and we tested whether methylphenidate use affects influenza risk using Cox proportional hazard models.Results: After controlling for confounding factors, the results indicated that influenza risk significantly reduced in the group of ADHD patients who were prescribed methylphenidate for 90 days and more (hazard ratio [HR]: 0.62, 95% confidence interval [CI]: 0.52– 0.75, p< 0.001), demonstrating a 38% reduction in the risk of influenza in this group. However, this was not observed in the group of ADHD patients who used methylphenidate for 1– 90 days (HR: 0.69, 95% CI: 0.89– 1.05, p=0.12).Conclusion: The lower incidence of influenza observed in the group prescribed with methylphenidate for a longer period highlights the importance of compliance to medication and psychoeducation with regard to ADHD management.Keywords: ADHD, influenza, methylphenidate

Anxiety and depression are common emotional problems in children and adolescents. This study used a long-term tracking large database to investigate whether the proportion of children who were diagnosed with speech and language impairments were later diagnosed with anxiety or depression were significantly greater than that of matched group of the same age and gender without speech and language impairments. More than 4300 eligible children with speech and language impairments and matched controls were identified and assessed for anxiety and depression. The risk of anxiety and depressive disorders in children with speech and language impairments were examined with Cox regression analyses and adjusting for covariables (gender, age, and comorbidities). The results showed that speech and language impairments were positively associated with anxiety disorders (adjusted hazard ratio [AHR] 2.87, 95% confidence interval [CI] 2.20–3.76) and depressive disorders (AHR 2.51, 95% CI 1.52–4.13). The number of boys with speech and language impairments was more than twofold that of girls, but boys did not different from girls in the risk of anxiety disorders (AHR 0.95, 95% CI 0.75–1.20) and depressive disorders (AHR 0.72, 95% CI 0.47–1.11). Infantile autism and intellectual disabilities were positively associated with anxiety (AHR 1.54, 95% CI 1.07–2.21; AHR 1.47, 95% CI 1.09–1.98), and the latter was positively associated with depression (AHR 1.83, 95% CI 1.06–3.17). In addition to speech and language impairments interventions, our findings supported the necessity of identification and interventions in anxiety and depressive disorders among children with speech and language impairments from elementary school until youth.

In this paper, we consider a joint design of the user clustering and content caching in the cache-enabled heterogenous network (HetNet) in which users in the network have distinct content preferences. The joint clustering and caching in the HetNet relies on multitude of factors, such as channel gains in all links, which may not be fully known in practice. Besides, clustering and caching may exhibit a fundamental tradeoff between the content hit probability and the spectral efficiency. We are therefore motivated to tackle this challenging problem by the deep reinforcement learning (DRL). In particular, the deep deterministic policy gradient (DDPG) algorithm is employed to manage the dynamics of clustering and caching in the HetNet with a sizable action space. Simulation results are presented to demonstrate the effectiveness of the proposed algorithm.

To ensure a physicochemically desired sequence motif to adapt a specific type of secondary structures, we compile an α-helix database allowing complicate search patterns to facilitate a data-driven design of therapeutic peptides. Nearly 1.7 million helical peptides in >130 thousand proteins are extracted along with their interacting partners from the protein data bank (PDB). The sequences of the peptides are indexed with patterns and gaps and deposited in our Therapeutic Peptide Design dataBase (TP-DB). We here demonstrate its utility in three medicinal design cases. By our pattern-based search engine but not PHI-BLAST, we can identify a pathogenic protein, Helicobacter pylori neutrophil-activating protein (HP-NAP), a virulence factor of H. pylori, which contains a motif DYKYLE that belongs to the affinity determinant motif DYKXX[DE] of the FLAG-tag and can be recognized by the anti-FLAG M2 antibody. By doing so, the known purification-tag-specific antibody is repurposed into a diagnostic kit for H. pylori. Also by leveraging TP-DB, we discovered a stretch of helical peptide matching the potent membrane-insertion pattern WXXWXXW, elucidated by MD simulations. The newly synthesized peptide has a better minimal inhibitory concentration (MIC) and much lower cytotoxicity against Candida albicans (fungus) than that of previously characterized homologous antimicrobial peptides. In a similar vein, taking the discontinued anchoring residues in the helix-helix interaction interface as the search pattern, TP-DB returns several helical peptides as potential tumor suppressors of hepatocellular carcinoma (HCC) whose helicity and binding affinity were examined by MD simulations. Taken together, we believe that TP-DB and its pattern-based search engine provide a new opportunity for a (secondary-)structure-based design of peptide drugs and diagnostic kits for pathogens without inferring evolutionary homology between sequences sharing the same pattern. TP-DB is made available at http://dyn.life.nthu.edu.tw/design/.

// Erh-Hsuan Lin 1, 2, 3, 4 , Yu-Rung Kao 1 , Chih-An Lin 5 , Ting-Yu Kuo 4 , Sheng-Ping Yang 2 , Chiung-Fang Hsu 1 , Teh-Ying Chou 3, 6 , Chao-Chi Ho 7 , Cheng-Wen Wu 1, 2, 3, 4 1 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 2 Institute of Microbiology and Immunology, National Yang Ming University, Taipei, Taiwan 3 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan 4 Institute of Biochemistry and Molecular Biology, National Yang Ming University, Taipei, Taiwan 5 Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Medical College, Taipei, Taiwan 6 Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 7 Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University Medical College, Taipei, Taiwan Correspondence to: Cheng-Wen Wu, e-mail: cwwu@ym.edu.tw Keywords: lung adenocarcinoma, Hedgehog pathway, HHIP, drug resistance, HGF/MET Received: July 30, 2015 Accepted: March 02, 2016 Published: March 22, 2016 ABSTRACT Hedgehog (HH) pathway plays an important role in embryonic development, but is largely inactive in adult except for tissue repair. Aberrant activation of HH pathway has been found in a variety of cancer types. In non-small cell lung cancer, however, the role and importance of HH pathway remain controversial. In the current study, we found that HH pathway was maintained in low activity in lung adenocarcinoma (LAC) cells under normal culture condition, but was highly induced in response to stress conditions. Activation of HH pathway promoted cell survival, growth, and invasion partially through HGF and MET signaling. Hedgehog-Interacting Protein (HHIP), a cell-surface negative regulator of HH pathway, was epigenetically silenced in LAC. Overexpression of HHIP blocked the activation of HH and HGF/MET pathways, and made cells significantly more susceptible to stress conditions. In LAC cells with acquired resistance to Epidermal Growth Factor Receptor Tyrosin Kinase Inhibitor (EGFR-TKI), we found that a part of tumor cells were much more sensitive to HH or HGF/MET inhibitors, suggesting an oncogenic addiction shift from EGFR to HH and HGF/MET pathways. In conclusion, this study showed that HH pathway is a survival signaling that drives LAC cell growth under stress conditions, and HHIP is a key regulator to block the induction of HH pathway. Targeting the HH pathway through inhibitors or HHIP thus holds promise to address EGFR-TKI resistance in LAC in clinic.

This study theoretically investigates plasmon-mediated optical binding forces, which are exerted on metal homo or heterodimers, induced by the normal illumination of a linearly polarized plane wave or Gaussian beam. Using the multiple multipole method, we analyzed the optical force in terms of Maxwell׳s stress tensor for various interparticle distance at some specific wavelengths. Numerical results show that for a given wavelength there are several stable equilibrium distances between two nanoparticles (NPs) of a homodimer, which are slightly shorter than some integer multiples of the wavelength in medium, such that metal dimer acts as bonded together. At these specific interparticle distances, the optical force between dimer is null and serves a restoring force, which is repulsive and attractive, respectively, as the two NPs are moving closer to and away from each other. The spring constant of the restoring force at the first stable equilibrium is always the largest, indicating that the first stable equilibrium distance is the most stable one. Moreover, the central line (orientation) of a dimer tends to be perpendicular to the polarization of light. For the cases of heterodimers, the phenomenon of stable equilibrium interparticle distance still exists, except there is an extra net photophoretic force drifting the heterodimer as one. Moreover, gradient force provided by a Gaussian beam may reduce the stability of these equilibriums, so larger NPs are preferred to stabilize a dimer under illumination of Gaussian beam. The finding may pave the way for using optical manipulation on the gold or silver colloidal self-assembly.

Magnetic resonance imaging (MRI) has been one of the most frequently-used diagnostic tools with high dimensional precision and positioning accuracy in clinical practices. To achieve contrast enhancement, utilization of high-efficient MR imaging contrast agents becomes a prime consideration and is indispensably reinforced the diagnosis precision, especially for the emerging precision medicine. Gadolinium (Gd)-based complexes has been widely used in current clinical MRI operations, however, numerous side effects were reported and highlighted in clinic. Those drawbacks render specific unmet needs to be clinically and technically improved with a new version of Gd-based compound. Here we report a newly-synthesized amphiphilic Gadodiamide-conjugated-carboxymethyl-hexanoyl chitosan (termed as CHC-Gd) hybrid. The gadodiamide was selected is due to it's smallest molecular size among other Gd-based complexes reported in literature, which assumed to give least influence on the resulting physicochemical properties such as colloidal stability, nanostructural evolution, and cytocompability, particularly self-assembly capability, of the resulting hybrid upon practical uses. Experimental outcomes showed a successful synthesis of the CHC-Gd hybrid using a one-pot synthesis protocol, where the gadodiamide complexes were covalently attached to the carboxyl groups along the CHC backbone. Self-assembly behavior can be observed to form a sphere-like nanoparticle of 100–200 nm in size as of amphiphilic native CHC macromolecule. Experimental outcomes indicated a largely improved cytocompatibility of the hybrid, compared with free Gd, suggesting the Gd⁺³ ions were well stabilized in the CHC nanostructure. Excellent contrastability in-vitro and in particular in vivo were measured, where for in-vivo test, a 10-40-folded reduction in dosage, compared with clinical Gd dose, was used and demonstrated a comparative-to-better imaging resolution and brightness. Therefore, from this preliminary investigation, a potential translation to clinical practice through the use of newly-synthesized amphiphilic CHC-Gd hybrid appears to be relatively promising. Refereed/Peer-reviewed