Establishing Non-Inferiority of a New Treatment in a Three-Arm Trial: Apply a Step-Down Hierarchical Model in a Papulopustular Acne Study and an Oral Prophylactic Antibiotics Study

Clinical trials comparing a test treatment with an active control therapy have become very popular in drug and medical device development in the last decade. An active controlled trial without a placebo, however, exhibits some major challenges in design, analysis, and interpretation, such as the determination of the non-inferiority margin or the assumption of constancy condition. When there are no ethical concerns, the comparison of a test drug with placebo usually provides the most convincing proof of the efficacy of a new treatment. Therefore, it may be advisable to conduct a three-arm trial — including placebo, active control, and the new treatment - if it is ethically justifiable such as a papulopustular acne study and an oral prophylactic antibiotics study. In this paper, we propose a statistical methodology for a three-arm non-inferiority trial with binary outcomes. We adapt the step-down hierarchical hypotheses and give a three-step testing procedure which is more realistic in conducting a clinical trial. We derived an optimal sample size allocation rule in an ethical and reliable manner to minimize the total sample size and hence to shorten the duration of the trials. Real examples from a papulopustular acne study and an oral prophylactic antibiotics study are used to demonstrate our methodology

Neural Network with Local Converging Input (NNLCI) for Supersonic Flow Problems with Unstructured Grids

In recent years, surrogate models based on deep neural networks (DNN) have been widely used to solve partial differential equations, which were traditionally handled by means of numerical simulations. This kind of surrogate models, however, focuses on global interpolation of the training dataset, and thus requires a large network structure. The process is both time consuming and computationally costly, thereby restricting their use for high-fidelity prediction of complex physical problems. In the present study, we develop a neural network with local converging input (NNLCI) for high-fidelity prediction using unstructured data. The framework utilizes the local domain of dependence with converging coarse solutions as input, which greatly reduces computational resource and training time. As a validation case, the NNLCI method is applied to study inviscid supersonic flows in channels with bumps. Different bump geometries and locations are considered to benchmark the effectiveness and versability of the proposed approach. Detailed flow structures, including shock-wave interactions, are examined systematically.Comment: 23 pages, 21 figure

Massive Ca-induced Membrane Fusion and Phospholipid Changes Triggered by Reverse Na/Ca Exchange in BHK Fibroblasts

Baby hamster kidney (BHK) fibroblasts increase their cell capacitance by 25–100% within 5 s upon activating maximal Ca influx via constitutively expressed cardiac Na/Ca exchangers (NCX1). Free Ca, measured with fluo-5N, transiently exceeds 0.2 mM with total Ca influx amounting to ∼5 mmol/liter cell volume. Capacitance responses are half-maximal when NCX1 promotes a free cytoplasmic Ca of 0.12 mM (Hill coefficient ≈ 2). Capacitance can return to baseline in 1–3 min, and responses can be repeated several times. The membrane tracer, FM 4-64, is taken up during recovery and can be released at a subsequent Ca influx episode. Given recent interest in signaling lipids in membrane fusion, we used green fluorescent protein (GFP) fusions with phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and diacylglycerol (DAG) binding domains to analyze phospholipid changes in relation to these responses. PI(4,5)P2 is rapidly cleaved upon activating Ca influx and recovers within 2 min. However, PI(4,5)P2 depletion by activation of overexpressed hM1 muscarinic receptors causes only little membrane fusion, and subsequent fusion in response to Ca influx remains massive. Two results suggest that DAG may be generated from sources other than PI(4,5)P in these protocols. First, acylglycerols are generated in response to elevated Ca, even when PI(4,5)P2 is metabolically depleted. Second, DAG-binding C1A-GFP domains, which are brought to the cell surface by exogenous ligands, translocate rapidly back to the cytoplasm in response to Ca influx. Nevertheless, inhibitors of PLCs and cPLA2, PI(4,5)P2-binding peptides, and PLD modification by butanol do not block membrane fusion. The cationic agents, FM 4-64 and heptalysine, bind profusely to the extracellular cell surface during membrane fusion. While this binding might reflect phosphatidylserine (PS) “scrambling” between monolayers, it is unaffected by a PS-binding protein, lactadherin, and by polylysine from the cytoplasmic side. Furthermore, the PS indicator, annexin-V, binds only slowly after fusion. Therefore, we suggest that the luminal surfaces of membrane vesicles that fuse to the plasmalemma may be rather anionic. In summary, our results provide no support for any regulatory or modulatory role of phospholipids in Ca-induced membrane fusion in fibroblasts

Effects of Moderate Exercise on Relieving Mental Load of Elementary School Teachers

Long-term endurance exercise could increase activity of parasympathetic nervous and decrease activity of sympathetic nervous at rest. However, previous studies all focused on the effect of endurance training on heart rate variability (HRV) for athletes or sedentary subjects. In Taiwan, elementary school teachers teaching and processing the children’s and administrative problems always stand and walk. They will sit down only when they review and correct the students’ home work. Thus, the goal of this study was to elucidate the beneficial effect of moderate intensity exercise on relieving mental load of elementary school teachers. There were 20 participants in the exercise group and another 20 participants in the nonexercise group. The exercising teachers performed 12 weeks of moderate intensity exercise training for an average of 30 minutes per day, 3 times per week. HRV was measured before and after the 4th, 6th, and 12th weeks. The time and frequency domain parameters of HRV all had significant increases between the beginning and after 12 weeks of training. However, the time and frequency domain parameters of HRV in the nonexercise group had significant decreases between the beginning and after 12 weeks of training. The long-term moderate exercises can relieve mental load of elementary school teachers. Moreover, age was the considerable factor affecting HRV in this study

Long-term results of intensity-modulated radiotherapy concomitant with chemotherapy for hypopharyngeal carcinoma aimed at laryngeal preservation

<p>Abstract</p> <p>Background</p> <p>The objective of this retrospective study is to investigate laryngeal preservation and long-term treatment results in hypopharyngeal carcinoma treated with intensity-modulated radiotherapy (IMRT) combined with chemotherapy.</p> <p>Methods</p> <p>Twenty-seven patients with hypopharyngeal carcinoma (stage II-IV) were enrolled and underwent concurrent chemoradiotherapy. The chemotherapy regimens were monthly cisplatin and 5-fluorouracil for six patients and weekly cisplatin for 19 patients. All patients were treated with IMRT with simultaneous integrated boost technique. Acute and late toxicities were recorded based on CTCAE 3.0 (Common Terminology Criteria for Adverse Events).</p> <p>Results</p> <p>The median follow-up time for survivors was 53.0 months (range 36-82 months). The initial complete response rate was 85.2%, with a laryngeal preservation rate of 63.0%. The 5-year functional laryngeal, local-regional control, disease-free and overall survival rates were 59.7%, 63.3%, 51.0% and 34.8%, respectively. The most common greater than or equal to grade 3 acute and late effects were dysphagia (63.0%, 17 of 27 patients) and laryngeal stricture (18.5%, 5 of 27 patients), respectively. Patients belonging to the high risk group showed significantly higher risk of tracheostomy compared to the low risk group (p = 0.014).</p> <p>Conclusions</p> <p>After long-term follow-up, our results confirmed that patients with hypopharyngeal carcinoma treated with IMRT concurrent with platinum-based chemotherapy attain high functional laryngeal and local-regional control survival rates. However, the late effect of laryngeal stricture remains a problem, particularly for high risk group patients.</p

Statistical identification of gene association by CID in application of constructing ER regulatory network

<p>Abstract</p> <p>Background</p> <p>A variety of high-throughput techniques are now available for constructing comprehensive gene regulatory networks in systems biology. In this study, we report a new statistical approach for facilitating <it>in silico </it>inference of regulatory network structure. The new measure of association, coefficient of intrinsic dependence (CID), is model-free and can be applied to both continuous and categorical distributions. When given two variables X and Y, CID answers whether Y is dependent on X by examining the conditional distribution of Y given X. In this paper, we apply CID to analyze the regulatory relationships between transcription factors (TFs) (X) and their downstream genes (Y) based on clinical data. More specifically, we use estrogen receptor α (ERα) as the variable X, and the analyses are based on 48 clinical breast cancer gene expression arrays (48A).</p> <p>Results</p> <p>The analytical utility of CID was evaluated in comparison with four commonly used statistical methods, Galton-Pearson's correlation coefficient (GPCC), Student's <it>t</it>-test (STT), coefficient of determination (CoD), and mutual information (MI). When being compared to GPCC, CoD, and MI, CID reveals its preferential ability to discover the regulatory association where distribution of the mRNA expression levels on X and Y does not fit linear models. On the other hand, when CID is used to measure the association of a continuous variable (Y) against a discrete variable (X), it shows similar performance as compared to STT, and appears to outperform CoD and MI. In addition, this study established a two-layer transcriptional regulatory network to exemplify the usage of CID, in combination with GPCC, in deciphering gene networks based on gene expression profiles from patient arrays.</p> <p>Conclusion</p> <p>CID is shown to provide useful information for identifying associations between genes and transcription factors of interest in patient arrays. When coupled with the relationships detected by GPCC, the association predicted by CID are applicable to the construction of transcriptional regulatory networks. This study shows how information from different data sources and learning algorithms can be integrated to investigate whether relevant regulatory mechanisms identified in cell models can also be partially re-identified in clinical samples of breast cancers.</p> <p>Availability</p> <p>the implementation of CID in R codes can be freely downloaded from <url>http://homepage.ntu.edu.tw/~lyliu/BC/</url>.</p

Effect of music interventions on anxiety during labor: a systematic review and meta-analysis of randomized controlled trials

Background Anxiety is commonly experienced during the delivery process and has shown to have adverse effects on maternal and infant health outcomes. Music interventions tend to reduce the effects of anxiety in diverse populations, are low cost, are easily accessible, and have high acceptability. The aim of this review and meta-analysis was to assess the effectiveness of music interventions in reducing anxiety levels among women during labor. Methods Seven databases from inception to the end of December, 2018, without any language or time restriction including Embase, PubMed, the Cochrane Library, the Cumulative Index to Nursing and Allied Health, PsycINFO, Airiti Library, and PerioPath: Index to Taiwan Periodical Literature were searched using key terms related to pregnancy, anxiety, and music. Randomized controlled trials that assessed the effect of music during labor and measured anxiety levels as an outcome were included. Meta-analyses were conducted to assess anxiety reduction following a music intervention compared to that after placebo treatment. Results A total of 14 studies that investigated a total of 1,310 participants were included in this review. The meta-analyses indicated that those in the intervention group had a significant decrease in anxiety scores (standardized mean difference = −2.40, 95% confidence interval (CI) [−3.29 to −1.52], p < 0.001; I2 = 97.66%), heart rate (HR) (difference in means = −3.04 beats/min, 95% CI [−4.79 to −1.29] beats/min, p = 0.001; I2 = 0.00%), systolic blood pressure (SBP) (difference in means = −3.71 mmHg, 95% CI [−7.07 to −0.35] mmHg, p = 0.031; I2 = 58.47%), and diastolic blood pressure (DBP) (difference in means = −3.54 mmHg, 95% CI [−5.27 to −1.81] mmHg, p < 0.001; I2 = 0.00%) as compared to the women in the control group. Conclusions Music interventions may decrease anxiety scores and physiological indexes related to anxiety (HR, SBP, and DBP). Music interventions may be a good non-pharmacological approach for decreasing anxiety levels during labor

Preseismic anomalies in soil-gas radon associated with 2016 M 6.6 Meinong earthquake, Southern Taiwan

Taiwan is tectonically situated in a terrain resulting from the oblique collision between the Philippine Sea plate and the continental margin of the Asiatic plate, with a continuous stress causing the density of strong-moderate earthquakes and regional active faults. The continuous time series of soil radon for earthquake studies have been recorded and some significant variations associated with strong earthquakes have been observed. Earthquake prediction is not still operative but these correlations should be added to the literature about seismo-geochemical transients associated to strong earthquakes. Rain-pore pressure related variations, crustal weakness at the studied faults system is consistent with the simultaneous radon anomalies observed. During the observations, a significant increase of soil radon concentrations was observed at Chunglun-T1 (CL-T1), Hsinhua (HH), Pingtung (PT), and Chihshan (CS) stations approximately two weeks before the Meinong earthquake (ML = 6.6, 6 February 2016) in Southern Taiwan. The precursory changes in a multi-stations array may reflect the preparation stage of a large earthquake. Precursory signals are observed simultaneously and it can apply certain algorithms the approximate location and magnitude of the impending earthquake

Structures of Helicobacter pylori Shikimate Kinase Reveal a Selective Inhibitor-Induced-Fit Mechanism

Shikimate kinase (SK), which catalyzes the specific phosphorylation of the 3-hydroxyl group of shikimic acid in the presence of ATP, is the enzyme in the fifth step of the shikimate pathway for biosynthesis of aromatic amino acids. This pathway is present in bacteria, fungi, and plants but absent in mammals and therefore represents an attractive target pathway for the development of new antimicrobial agents, herbicides, and antiparasitic agents. Here we investigated the detailed structure–activity relationship of SK from Helicobacter pylori (HpSK). Site-directed mutagenesis and isothermal titration calorimetry studies revealed critical conserved residues (D33, F48, R57, R116, and R132) that interact with shikimate and are therefore involved in catalysis. Crystal structures of HpSK·SO4, R57A, and HpSK•shikimate-3-phosphate•ADP show a characteristic three-layer architecture and a conformationally elastic region consisting of F48, R57, R116, and R132, occupied by shikimate. The structure of the inhibitor complex, E114A•162535, was also determined, which revealed a dramatic shift in the elastic LID region and resulted in conformational locking into a distinctive form. These results reveal considerable insight into the active-site chemistry of SKs and a selective inhibitor-induced-fit mechanism

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe