Experimentally based structural model of Yih1 provides insight into its function in controlling the key translational regulator Gcn2.

Yeast impact homolog 1 (Yih1), or IMPACT in mammals, is part of a conserved regulatory module controlling the activity of General Control Nonderepressible 2 (Gcn2), a protein kinase that regulates protein synthesis. Yih1/IMPACT is implicated not only in many essential cellular processes, such as neuronal development, immune system regulation and the cell cycle, but also in cancer. Gcn2 must bind to Gcn1 in order to impair the initiation of protein translation. Yih1 hinders this key Gcn1-Gcn2 interaction by binding to Gcn1, thus preventing Gcn2-mediated inhibition of protein synthesis. Here, we solved the structures of the two domains of Saccharomyces cerevisiae Yih1 separately using Nuclear Magnetic Resonance and determined the relative positions of the two domains using a range of biophysical methods. Our findings support a compact structural model of Yih1 in which the residues required for Gcn1 binding are buried in the interface. This model strongly implies that Yih1 undergoes a large conformational rearrangement from a latent closed state to a primed open state to bind Gcn1. Our study provides structural insight into the interactions of Yih1 with partner molecules.

Efficacy of clarithromycin-naproxen-oseltamivir combination therapy versus oseltamivir alone in hospitalized pediatric influenza patients.

PURPOSE: This study aimed to compare the safety and efficacy of clarithromycin-naproxen-oseltamivir combination therapy to that of oseltamivir therapy alone in hospitalized pediatric influenza patients. METHODS: This prospective, single-blind study included children aged 1-18 years hospitalized with influenza, in MacKay Children's Hospital, Taiwan, between December 2017 and December 2019. The primary outcomes were the time to defervescence and decrease of the Pediatric Respiratory Severity Score (PRESS) during hospitalization. The secondary outcomes were serial changes in virus titers, measured using real-time polymerase chain reaction. RESULTS: Fifty-four patients were enrolled (28 in the control group and 26 in the combination group) in total. There were no differences in the patients' baseline characteristics between the groups. The time to defervescence was significantly shorter in the combination group than the oseltamivir group (13.2 h vs. 32.1 h, p = 0.002). The decrease in the virus titer from days 1-3 (log Δ13) was more pronounced in the combination group than the oseltamivir group. (39% vs. 19%, p = 0.001). There were no differences in adverse effects such as vomiting, diarrhea, and abdominal pain during the study or within 30 days after antiviral therapy. CONCLUSION: The clarithromycin-naproxen-oseltamivir combination group experienced a more rapid defervescence and a more rapid decline of influenza virus titer than the group treated with oseltamivir alone. Further consideration should be given to whether the overall benefits of combination therapy in hospitalized pediatric influenza patients outweigh the risks.

Using Deep Learning in Ultrasound Imaging of Bicipital Peritendinous Effusion to Grade Inflammation Severity.

Inflammation of the long head of the biceps tendon is a common cause of shoulder pain. Bicipital peritendinous effusion (BPE) is the most common biceps tendon abnormality and is related to various shoulder injuries. Physicians usually use ultrasound imaging to grade the inflammation severity of the long head of the biceps tendon. However, obtaining a clear and accurate ultrasound image is difficult for inexperienced attending physicians. To reduce physicians' workload and avoid errors, an automated BPE recognition system was developed in this article for classifying inflammation into the following categories-normal and mild, moderate, and severe. An ultrasound image serves as the input in the proposed system; the system determines whether the ultrasound image contains biceps. If the image depicts biceps, then the system predicts BPE severity. In this study, two crucial methods were used for solving problems associated with computer-aided detection. First, the faster regions with convolutional neural network (faster R-CNN) used to extract the region of interest (ROI) area identification to evaluate the influence of dataset scale and spatial image context on performance. Second, various CNN architectures were evaluated and explored. Model performance was analyzed by using various network configurations, parameters, and training sample sizes. The proposed system was used for three-class BPE classification and achieved 75% accuracy. The results obtained for the proposed system were determined to be comparable to those of other related state-of-the-art methods.

Effects of influenza vaccine and sun exposure time against laboratory-confirmed influenza hospitalizations among young children during the 2012-13 to 2015-16 influenza seasons.

BACKGROUND: Influenza is a major cause of acute respiratory infection burden worldwide, leading to many hospitalizations. An annual influenza vaccine is believed to be the best way to prevent influenza-related illnesses. We focused on the efficacies of other possible preventive measures such as increasing sun exposure time and dietary supplements to prevent these illnesses. METHODS: We conducted a matched-pair case-control study along with the Taiwan Pediatric Infectious Disease Alliance. We included influenza-related hospitalized patients with age ranging from 6 months to 5 years during the 2012-2013, 2013-2014, 2014-2015, and 2015-2016 influenza seasons. The controls were comparable to cases in age, sex, and residential area and had no influenza-related hospitalization records in the same season. We extracted data from vaccination histories and got the patients' guardians to complete questionnaires. Data were analyzed using conditional logistic regression. RESULTS: We enrolled 1514 children (421 influenza-infected cases and 1093 controls) in the study. We found seasonal influenza vaccination to be an independent protective factor against hospitalizations owing to influenza [p < 0.01; odds ratio (OR), 0.427; 95% confidence interval (CI), 0.306-0.594]. Children with mean sun exposure time of >7 h/week had a significantly lower risk of influenza-related hospitalizations than those with the mean sun exposure time of ≤7 h/week (p < 0.05; OR, 0.667; 95% CI, 0.491-0.906). CONCLUSIONS: Seasonal influenza vaccination effectively prevents influenza-related hospitalizations in children aged ≤5 years. Besides, >7 h of sun exposure/week may also be associated with lower risk of influenza-related hospitalizations in children.

From Block Copolymer Nanotubes to Nanospheres: Nonsolvent-Induced Morphology Transformation Using Porous Templates.

Block copolymer nanostructures have attracted great attention because of the wide range of applications such as sensors and drug delivery. The fabrication of block copolymer nanostructures with controlled morphologies and sizes, however, is still challenging. Here, we study the fabrication of nanotubes and nanospheres of polystyrene- block-polybutadiene (PS- b-PBD) using anodic aluminum oxide (AAO) templates. When PS- b-PBD solutions in N-methyl-2-pyrrolidone are introduced into the nanopores of the AAO templates applying the traditional solution wetting method, PS- b-PBD nanotubes can be obtained. When PS- b-PBD solutions in the nanopores are in contact with a nonsolvent, acetic acid, PS- b-PBD nanospheres are formed. Two possible mechanisms are proposed to discuss the formation of the nonsolvent-driven morphology transformation, including the Rayleigh-instability-type transformation mechanism and the nucleation and growth mechanism. The effect of the polymer concentrations on the internal morphologies of the PS- b-PBD nanostructures is discussed; at higher concentrations, PS- b-PBD nanocapsules can also be prepared. Furthermore, core-shell PS- b-PBD/polymethylmethacrylate nanospheres can be fabricated using this strategy with polymer blend solutions. This work not only demonstrates a simple strategy to control the morphologies of block copolymer nanostructures but also deepens the understanding of the interactions between polymer solutions and solvents.

Plane-to-plane analysis of mandibular misalignment in patients with facial asymmetry.

INTRODUCTION: Little is known regarding how the mandible rotates in facial asymmetry. The purpose of this study was to study mandibular misalignment with a new plane-to-plane analysis method in patients with facial asymmetry. METHODS: Optimal symmetry planes (OSPs) were generated by computing the greatest count of paired voxels on opposing sides of the computerized tomography image of the structure. The mandibular OSP was measured against the midfacial OSP for its alignment. The deviation angle formed by the 2 OSPs was broken down into a y-axis component (frontal deviation angle) and a z-axis component (horizontal deviation angle). Fifty-nine patients who sought correction for facial asymmetry were included for study. RESULTS: The new analysis method was feasible. Fifty patients (83%) had significant mandibular misalignment (deviation, ≥4° or 4 mm). The locations of the rotational axes exhibited significant variations that could explain the varied features of the asymmetry. The frontal deviation angle (mean, 3.80° ± 3.89°) was significantly larger than the horizontal deviation angle (mean, 2.77° ± 1.71°). There was no significant correlation between the horizontal deviation angle and the anterior deviation distance or the posterior deviation distance. CONCLUSIONS: Proper mandibular realignment was suggested to be the primary aim in surgical correction of most jawbone asymmetries. Because of the greatly varied rotational axes and the obscure z-axis rotation, realignment could be difficult with the traditional approach. The OSP-based analysis is advocated to guide planning.

Microwave-annealing-induced nanowetting of block copolymers in cylindrical nanopores.

Block copolymers have attracted great attention because of their abilities to self-assemble into well-ordered microphase-separated structures. To generate nanopatterns of block copolymers with long-range ordering and low-defect densities in shorter time scales, microwave annealing has recently been applied. Microwave annealing, however, has so far only been used for block copolymer bulks and thin films. In this work, we discover that microwave annealing can be successfully applied to three-dimensional block copolymer nanostructures by studying the infiltration and microphase separation of block copolymers in cylindrical nanopores upon microwave irradiation. Cylinder-forming and lamella-forming poly(styrene-block-dimethylsiloxane) (PS-b-PDMS) are introduced into the nanopores of anodic aluminum oxide (AAO) templates. In addition, AAO templates with different pore sizes are used to study the effect of the commensurabilities between the pore diameters and the repeating periods of the block copolymers on the morphologies of the block copolymer nanostructures.

Effect of Continuity of Care on Quality of Life in Older Adults With Chronic Diseases: A Meta-Analysis.

As the population ages, continuity of care (CoC) has increasingly become a particular important issue. Articles published from 1994 to 2014 were identified from electronic databases. Studies with randomized controlled design and elderly adults with chronic illness were included if Short Form-36 (SF-36) was used as an outcome indicator to evaluate the effect of CoC. Seven studies were included for analysis with the sum of 1,394 participants. The results showed that CoC intervention can significantly improve physical function, physical role function, general health, social function, and vitality of QoL for elderly people with chronic disease.

Use of the matching optimal symmetry plane method in planning surgical correction of facial asymmetry--a preliminary report of 20 patients.

PURPOSE: A voxel-based median plane (optimal symmetry plane [OSP]) was developed to assess facial bone asymmetry. The purpose of the present study was to introduce a new method of planning surgical correction of facial asymmetry using the OSPs as guides and test its effectiveness. PATIENTS AND METHODS: A retrospective study was conducted of 20 facial asymmetry patients with a mandibular deviation of 4 mm or greater or 4° or more that required surgical correction. In the test group (n = 8), the plans for asymmetry correction were formulated using the matching OSP method, in which the OSPs of the facial bones are tracked and matched during the model surgery setup. In the control group (n = 12), traditional planning was conducted. The traditional plans were cross-checked for symmetry through tracking and revised as needed. The symmetry results of the plans were compared between the 2 groups and within the control group. The outcome measures were the deviation distances between the OSPs of the midface and mandible at the anterior or posterior mandible, the occlusal plane cant, and the angle formed by the 2 OSPs. Surgery was performed in accordance with the final plans, and the results were assessed for symmetry. RESULTS: The traditional plans left a major mandibular deviation in 5 of the 12 control subjects compared with none in the test group. The test group did significantly better than the control group. The revised plans were significantly better than the initial plans. Postoperatively, significant improvements in symmetry were observed. CONCLUSION: The new method resulted in surgical plans that brought about significantly less postoperative mandibular deviation while maintaining a reasonable occlusion.

Testing for efficacy in adaptive clinical trials with enrichment.

Adaptive design of clinical trials has attracted considerable interest because of its potential of reducing costs and saving time in the clinical development process. In this paper, we consider the problem of assessing the effectiveness of a test treatment over a control by a two-arm randomized clinical trial in a potentially heterogenous patient population. In particular, we study enrichment designs that use accumulating data from a clinical trial to adaptively determine patient subpopulation in which the treatment effect is eventually assessed. A hypothesis testing procedure and a lower confidence limit are presented for the treatment effect in the selected patient subgroups. The performances of the new methods are compared with existing approaches through a simulation study.

A note on confidence bounds after fixed-sequence multiple tests.

We are concerned with the problem of estimating the treatment effects at the effective doses in a dose-finding study. Under monotone dose-response, the effective doses can be identified through the estimation of the minimum effective dose, for which there is an extensive set of statistical tools. In particular, when a fixed-sequence multiple testing procedure is used to estimate the minimum effective dose, Hsu and Berger (1999) show that the confidence lower bounds for the treatment effects can be constructed without the need to adjust for multiplicity. Their method, called the dose-response method, is simple to use, but does not account for the magnitude of the observed treatment effects. As a result, the dose-response method will estimate the treatment effects at effective doses with confidence bounds invariably identical to the hypothesized value. In this paper, we propose an error-splitting method as a variant of the dose-response method to construct confidence bounds at the identified effective doses after a fixed-sequence multiple testing procedure. Our proposed method has the virtue of simplicity as in the dose-response method, preserves the nominal coverage probability, and provides sharper bounds than the dose-response method in most cases.

Multiple comparisons of drug efficacy between subgroups defined by genetic polymorphisms.

In contrast to using genome-wide association studies to discover associations between genes or single-nucleotide polymorphisms in the genome with disease status or outcome, some recent pharmacogenomic studies have focused on whether polymorphisms in genes involved in metabolizing drugs significantly impact their efficacy. Whether a drug starts as an active compound and gets metabolized and eliminated from the body or starts as an inactive compound and gets metabolized to an active form, patients in subgroups separated by polymorphism of a gene needed to metabolize the drug might derive differential benefit from that drug. With the use of the Clopidogrel in Unstable Angina to Prevent Recurrent Events trial for Plavix as an example, this article proposes Multiple Comparisons with Control (Subgroup) and Multiple Comparisons with the Best (Subgroup) as methods to infer whether some subgroups of patients derive more or less benefit than wild-type patients and which subgroup or subgroups of patients derive maximum benefit or practically maximum benefit from the drug.

Acute effects of plyometric jumping and intermittent running on serum bone markers in young males.

The purpose of this study was to investigate whether different modes of single-bout exercise would cause different responses in short-term bone metabolism. 24 untrained male college students (19.1 ± 0.1 years old) were recruited and randomly assigned to three groups: (1) a single-bout plyometric exercise group (the PL group, n = 8), (2) a 200-meter × 10 intermittent running group (the IR group, n = 8) and (3) a sedentary control group, which followed the same time schedule of experimentation without performing any exercise (the CON group, n = 8). Serial blood samples were collected before (baseline) and 5 min, 15 min, 1 h, 3 h, 6 h, 24 h, 48 h, and 72 h after exercise trials. Within 15 min of exercise, the PL and IR groups showed significantly higher serum phosphorus than did the control group (P < 0.05). Osteocalcin levels were significantly higher in the PL group at 5 min and 1 h after exercise (P < 0.05), while serum tartrate-resistant acid phosphatase (TRAP) showed no differences among groups. Exercises with different mechanical impact levels responded differently in serum bone formation markers as shown by osteocalcin. Because the increase in osteocalcin in the PL group was revealed shortly after the exercise bout, the changes might due to an exercise-induced mechanical impact rather than bone cellular activities.

On Two-stage Seamless Adaptive Design in Clinical Trials.

In recent years, the use of adaptive design methods in clinical research and development based on accrued data has become very popular because of its efficiency and flexibility in modifying trial and/or statistical procedures of ongoing clinical trials. One of the most commonly considered adaptive designs is probably a two-stage seamless adaptive trial design that combines two separate studies into one single study. In many cases, study endpoints considered in a two-stage seamless adaptive design may be similar but different (e.g. a biomarker versus a regular clinical endpoint or the same study endpoint with different treatment durations). In this case, it is important to determine how the data collected from both stages should be combined for the final analysis. It is also of interest to know how the sample size calculation/allocation should be done for achieving the study objectives originally set for the two stages (separate studies). In this article, formulas for sample size calculation/allocation are derived for cases in which the study endpoints are continuous, discrete (e.g. binary responses), and contain time-to-event data assuming that there is a well-established relationship between the study endpoints at different stages, and that the study objectives at different stages are the same. In cases in which the study objectives at different stages are different (e.g. dose finding at the first stage and efficacy confirmation at the second stage) and when there is a shift in patient population caused by protocol amendments, the derived test statistics and formulas for sample size calculation and allocation are necessarily modified for controlling the overall type I error at the prespecified level.

Relationship between polycyclic aromatic hydrocarbon-DNA adducts, environmental tobacco smoke, and child development in the World Trade Center cohort.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs), including benzo[a]pyrene (BaP), are air pollutants released by the World Trade Center (WTC) fires and urban combustion sources. BaP-DNA adducts provide a measure of PAH-specific genetic damage, which has been associated with increased risk of adverse birth outcomes and cancer. We previously reported that levels of BaP-DNA adducts in maternal and umbilical cord blood obtained at delivery were elevated among subjects who had resided within 1 mile of the WTC site during the month after 9/11; and that elevated blood adducts in combination with in utero exposure to environmental tobacco smoke (ETS) were significantly associated with decreased fetal growth. OBJECTIVE: Our aim was to assess possible effects of prenatal exposure to WTC pollutants on child development. METHODS: After 11 September 2001, we enrolled a cohort of nonsmoking pregnant women who delivered at three lower Manhattan hospitals. We have followed a subset of children through their third birthdays and measured cognitive and motor development using the Bayley-II Scales of Child Development (BSID-II). RESULTS: In multivariate analyses, we found a significant interaction between cord blood adducts and in utero exposure to ETS on mental development index score at 3 years of age (p = 0.02, n = 98) whereas neither adducts nor ETS alone was a significant predictor of (BSID-II) cognitive development. CONCLUSION: Although limited by small numbers, these results suggest that exposure to elevated levels of PAHs in conjunction with prenatal ETS exposure may have contributed to a modest reduction in cognitive development among cohort children.

Relation between prenatal lipid-soluble micronutrient status, environmental pollutant exposure, and birth outcomes.

BACKGROUND: Adverse postnatal health effects have been associated with compromised fetal growth, which makes it essential to understand its determinants. Significant effects of environmental pollutants on birth outcomes have been observed in our study population, and nutritional status may be an additional factor influencing fetal development and effects of environmental toxins. OBJECTIVE: The objective of the study was to examine the relations between birth outcomes and lipid-soluble plasma micronutrient concentrations and to explore interactions between micronutrients and environmental pollutant exposure in newborns in Krakow, Poland. DESIGN: In this prospective cohort study, retinol, alpha-tocopherol, and carotenoids were measured in maternal and cord blood samples obtained at delivery (251 maternal-newborn pairs), and birth weight, birth length, head circumference (HC), and gestational age were evaluated. Linear regression analysis was used to estimate the effects of micronutrients while covariates were controlled for. Interaction terms assessed whether the effects of polycyclic aromatic hydrocarbons (PAHs), common environmental pollutants, varied by nutrient status. RESULTS: Infants whose mothers had low plasma alpha-tocopherol concentrations (below the median) weighed 92.9 g less and had 0.41-cm smaller HCs than did infants whose mothers had high alpha-tocopherol concentrations. Infants with low plasma retinol (below the median) weighed 125.9 g less and had 0.31-cm smaller HCs. There was no evidence of an interaction between PAHs and micronutrients, although power was limited. CONCLUSION: Maternal alpha-tocopherol and cord retinol concentrations were significantly and positively associated with BW and HC. These micronutrients may have direct effects or may be markers for other underlying determinants of these pregnancy outcomes.

Effect of prenatal exposure to airborne polycyclic aromatic hydrocarbons on neurodevelopment in the first 3 years of life among inner-city children.

Our prospective cohort study of nonsmoking African-American and Dominican mothers and children in New York City is evaluating the role of prenatal exposure to urban pollutants, including polycyclic aromatic hydrocarbons (PAHs) , environmental tobacco smoke (ETS) , and pesticides, in the pathogenesis of neurobehavioral disorders. We used the Bayley Scales of Infant Development to evaluate the effects on child mental and psychomotor development of prenatal exposure to airborne PAHs monitored during pregnancy by personal air sampling. Behavioral development was assessed by the Child Behavior Checklist. We adjusted for potential confounders including sociodemographic factors and prenatal exposure to ETS and chlorpyrifos. Prenatal exposure to PAHs was not associated with psychomotor development index or behavioral problems. However, high prenatal exposure to PAHs (upper quartile) was associated with lower mental development index at age 3 [beta=-5.69; 95% confidence interval (CI), -9.05 to -2.33; p<0.01]. The odds of cognitive developmental delay were also significantly greater for children with high prenatal exposure (odds ratio=2.89; 95% CI, 1.33 to 6.25; p=0.01). General estimated equation analysis showed a significant age times PAH effect on mental development (p=0.01), confirming the age-specific regression findings. Further adjustment for lead did not alter the relationships. There were no differences in effect sizes by ethnicity. The results require confirmation but suggest that environmental PAHs at levels recently encountered in New York City air may adversely affect children's cognitive development at 3 years of age, with implications for school performance.

Relationships among polycyclic aromatic hydrocarbon-DNA adducts, proximity to the World Trade Center, and effects on fetal growth.

Polycyclic aromatic hydrocarbons (PAHs) are toxic pollutants released by the World Trade Center (WTC) fires and various urban combustion sources. Benzo[a]pyrene (BaP) is a representative member of the class of PAHs. PAH-DNA adducts, or BaP-DNA adducts as their proxy, provide a measure of chemical-specific genetic damage that has been associated with increased risk of adverse birth outcomes and cancer. To learn whether PAHs from the WTC disaster increased levels of genetic damage in pregnant women and their newborns, we analyzed BaP-DNA adducts in maternal (n = 170) and umbilical cord blood (n = 203) obtained at delivery from nonsmoking women who were pregnant on 11 September 2001 and were enrolled at delivery at three downtown Manhattan hospitals. The mean adduct levels in cord and maternal blood were highest among newborns and mothers who resided within 1 mi of the WTC site during the month after 11 September, intermediate among those who worked but did not live within this area, and lowest in those who neither worked nor lived within 1 mi (reference group). Among newborns of mothers living within 1 mi of the WTC site during this period, levels of cord blood adducts were inversely correlated with linear distance from the WTC site (p = 0.02). To learn whether PAHs from the WTC disaster may have affected birth outcomes, we analyzed the relationship between these outcomes and DNA adducts in umbilical cord blood, excluding preterm births to reduce variability. There were no independent fetal growth effects of either PAH-DNA adducts or environmental tobacco smoke (ETS), but adducts in combination with in utero exposure to ETS were associated with decreased fetal growth. Specifically, a doubling of adducts among ETS-exposed subjects corresponded to an estimated average 276-g (8%) reduction in birth weight (p = 0.03) and a 1.3-cm (3%) reduction in head circumference (p = 0.04). The findings suggest that exposure to elevated levels of PAHs, indicated by PAH-DNA adducts in cord blood, may have contributed to reduced fetal growth in women exposed to the WTC event.

Biomarkers in maternal and newborn blood indicate heightened fetal susceptibility to procarcinogenic DNA damage.

Polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (BaP) are widespread air contaminants released by transportation vehicles, power generation, and other combustion sources. Experimental evidence indicates that the developing fetus is more susceptible than the adult to carcinogenic effects of PAHs, although laboratory studies in rodents suggest that the dose to fetal tissues is an order of magnitude lower than that to maternal tissues. To assess fetal versus adult susceptibility to PAHs and environmental tobacco smoke (ETS), we compared carcinogen-DNA adducts (a biomarker associated with increased cancer risk) and cotinine (a biomarker of tobacco smoke exposure) in paired blood samples collected from mothers and newborns in New York City. We enrolled 265 nonsmoker African-American and Latina mother-newborn pairs in New York City between 1997 and 2001 (estimated average ambient air BaP concentrations < 0.5 ng/m3). Despite the estimated 10-fold lower fetal dose, mean levels of BaP-DNA adducts as determined by high-performance liquid chromatography-fluorescence were comparable in paired New York City newborn and maternal samples (0.24 adducts per 10(8) nucleotides, 45% of newborns with detectable adducts vs. 0.22 per 10(8) nucleotides, 41% of mothers with detectable adducts). However, by the Wilcoxon signed-rank test, the levels in newborns were higher (p = 0.02). Mean cotinine was higher in newborns than in mothers (1.7 ng/mL, 47% detectable vs. 1.28 ng/mL, 44% detectable). Consistent with our prior study in a Caucasian Polish population, these results indicate increased susceptibility of the fetus to DNA damage and reduced ability to clear ETS constituents. The findings have implications for risk assessment, given the need to protect children as a sensitive subset of the population.