Coseismic seafloor deformation in the trench region during the Mw8.8 Maule megathrust earthquake.
The Mw 8.8 megathrust earthquake that occurred on 27 February 2010 offshore the Maule region of central Chile triggered a destructive tsunami. Whether the earthquake rupture extended to the shallow part of the plate boundary near the trench remains controversial. The up-dip limit of rupture during large subduction zone earthquakes has important implications for tsunami generation and for the rheological behavior of the sedimentary prism in accretionary margins. However, in general, the slip models derived from tsunami wave modeling and seismological data are poorly constrained by direct seafloor geodetic observations. We difference swath bathymetric data acquired across the trench in 2008, 2011 and 2012 and find ~3-5 m of uplift of the seafloor landward of the deformation front, at the eastern edge of the trench. Modeling suggests this is compatible with slip extending seaward, at least, to within ~6 km of the deformation front. After the Mw 9.0 Tohoku-oki earthquake, this result for the Maule earthquake represents only the second time that repeated bathymetric data has been used to detect the deformation following megathrust earthquakes, providing methodological guidelines for this relatively inexpensive way of obtaining seafloor geodetic data across subduction zone.


Escherichia coli methionine aminopeptidase: implications of crystallographic analyses of the native, mutant, and inhibited enzymes for the mechanism of catalysis.
By improving the expression and purification of Escherichia coli methionine aminopeptidase (eMetAP) and using slightly different crystallization conditions, the resolution of the parent structure was extended from 2.4 to 1.9 A resolution. This has permitted visualization of the coordination geometry and solvent structure of the active-site dinuclear metal center. One solvent molecule (likely a mu-hydroxide) bridges the trigonal bipyramidal (Co1) and octahedral (Co2) cobalt ions. A second solvent (possibly a hydroxide ion) is bound terminally to Co2. A monovalent cation binding site was also identified about 13 A away from the metal center at an interface between the two subdomains of the protein. The first structure of a substrate-like inhibitor, (3R)-amino-(2S)-hydroxyheptanoyl-L-Ala-L-Leu-L-Val-L-Phe-OMe, bound to a methionine aminopeptidase, has also been determined. This inhibitor coordinates the metal center through four interactions as follows: (i) ligation of the N-terminal (3R)-nitrogen to Co2, (ii, iii) bridging coordination of the (2S)-hydroxyl group, and (iv) terminal ligation to Co1 by the keto oxygen of the pseudo-peptide linkage. Inhibitor binding occurs with the displacement of two solvent ligands and the expansion of the coordination sphere of Co1. In addition to the tetradentate, bis-chelate metal coordination, the substrate analogue forms hydrogen bonds with His79 and His178, two conserved residues within the active site of all MetAPs. To evaluate their importance in catalysis His79 and His178 were replaced with alanine. Both substitutions, but especially that of His79, reduce activity. The structure of the His79Ala apoenzyme and the comparison of its electronic absorption spectra with other variants suggest that the loss in activity is not due to a conformational change or a defective metal center. Two different reaction mechanisms are proposed and are compared to those of related enzymes. These results also suggest that inhibitors analogous to that reported here may be useful in preventing angiogenesis in cancer and in the treatment of microbial and fungal infections.


A phase I/II study of bortezomib in combination with paclitaxel, carboplatin, and concurrent thoracic radiation therapy for non-small-cell lung cancer: North Central Cancer Treatment Group (NCCTG)-N0321.
Despite the advances in radiation techniques and chemotherapy, survival with current platinum-based chemotherapy and concomitant thoracic radiation remains dismal. Bortezomib, a proteasome inhibitor, modulates apoptosis and cell cycle through disruption of protein degradation. The combination of bortezomib and carboplatin/paclitaxel and concurrent radiation in unresectable stage III non-small-cell lung cancer was evaluated in this phase I/II study. Patients with histologic or cytologic confirmed stage III nonmetastatic non-small-cell lung cancer who were candidates for radiation therapy were eligible. In the phase I portion, patients received escalating doses of bortezomib, paclitaxel, and carboplatin concomitantly with thoracic radiation (60 Gy/30 daily fractions) using a modified 3 + 3 design. The primary endpoint for the phase II portion was the 12-month survival rate (12MS). A one-stage design with an interim analysis yielded 81% power to detect a true 12MS of 75%, with a 0.09 level of significance if the true 12MS was 60% using a sample size of 60 patients. Secondary endpoints consisted of adverse events (AEs), overall survival, progression-free survival, and the confirmed response rate. Thirty-one patients enrolled during the phase I portion of the trial, of which four cancelled before receiving treatment, leaving 27 evaluable patients. Of these 27 patients, two dose-limiting toxicities were observed, one (grade 3 pneumonitis) at dose level 1 (bortezomib at 0.5 mg/m, paclitaxel at 150 mg/m, and carboplatin at area under the curve of 5) and one (grade 4 neutropenia lasting ≥8 days) at dose level 6 (bortezomib 1.2 mg/m, paclitaxel 175 mg/m, and carboplatin at area under the curve of 6). During the phase I portion, the most common grade 3 of 4 AEs were leukopenia (44%), neutropenia (37%), dyspnea (22%), and dysphagia (11%). Dose level 6 was declared to be the recommended phase II dose (RP2D) and the phase II portion of the study opened. After the first 26 evaluable patients were enrolled to the RP2D, a per protocol interim analysis occurred. Of these 26 patients, 23 (88%) survived at least 6 months (95% confidence interval [CI], 70-98%), which was enough to continue to full accrual per study design. However, due to slow accrual, the study was stopped after 27 evaluable patients were enrolled (6-phase I RP2D; 21-phase II). Of these 27 patients, the 12MS was 73% (95% CI, 58-92%), the median overall survival was 25.0 months (95% CI, 15.6-35.8), and the median progression-free survival was 8.4 months (95% CI, 4.1-10.5). The confirmed response rate was 26% (seven of 27; 95% CI, 11-46%), consisting of four partial responses and three complete responses. Grade 3+ and grade 4+ AEs occurred in 82% and 56% of patients, respectively. One patient experienced grade 5 pneumonitis that was possibly related to the treatment. Grade 3 and 4 hematological toxicities were observed in 82% and 56% patients, respectively. The addition of bortezomib to concurrent carboplatin/paclitaxel and radiation seemed to be feasible, although associated with increased hematological toxicities. A favorable median overall survival of 25 months suggests a potential benefit for this regimen.


The stress hormone corticosterone in a marine top predator reflects short-term changes in food availability.
In many seabird studies, single annual proxies of prey abundance have been used to explain variability in breeding performance, but much more important is probably the timing of prey availability relative to the breeding season when energy demand is at a maximum. Until now, intraseasonal variation in prey availability has been difficult to quantify in seabirds. Using a state-of-the-art ocean drift model of larval cod Gadus morhua, an important constituent of the diet of common guillemots Uria aalge in the southwestern Barents Sea, we were able to show clear, short-term correlations between food availability and measurements of the stress hormone corticosterone (CORT) in parental guillemots over a 3-year period (2009-2011). The model allowed the extraction of abundance and size of cod larvae with very high spatial (4 km) and temporal resolutions (1 day) and showed that cod larvae from adjacent northern spawning grounds in Norway were always available near the guillemot breeding colony while those from more distant southerly spawning grounds were less frequent, but larger. The latter arrived in waves whose magnitude and timing, and thus overlap with the guillemot breeding season, varied between years. CORT levels in adult guillemots were lower in birds caught after a week with high frequencies of southern cod larvae. This pattern was restricted to the two years (2009 and 2010) in which southern larvae arrived before the end of the guillemot breeding season. Any such pattern was masked in 2011 by already exceptionally high numbers of cod larvae in the region throughout chick-rearing period. The findings suggest that CORT levels in breeding birds increase when the arrival of southern sizable larvae does not match the period of peak energy requirements during breeding.


In vitro cytotoxicity of four calcium silicate-based endodontic cements on human monocytes, a colorimetric MTT assay.
This study was performed to evaluate the cytotoxicity of four calcium silicate-based endodontic cements at different storage times after mixing. Capillary tubes were filled with Biodentine (Septodont), Calcium Enriched Mixture (CEM cement, BioniqueDent), Tech Biosealer Endo (Tech Biosealer) and ProRoot MTA (Dentsply Tulsa Dental). Empty tubes and tubes containing Dycal were used as negative and positive control groups respectively. Filled capillary tubes were kept in 0.2 mL microtubes and incubated at 37℃. Each material was divided into 3 groups for testing at intervals of 24 hr, 7 day and 28 day after mixing. Human monocytes were isolated from peripheral blood mononuclear cells and cocultered with 24 hr, 7 day and 28 day samples of different materials for 24 and 48 hr. Cell viability was evaluated using an MTT assay. In all groups, the viability of monocytes significantly improved with increasing storage time regardless of the incubation time (p < 0.001). After 24 hr of incubation, there was no significant difference between the materials regarding monocyte viability. However, at 48 hr of incubation, ProRoot MTA and Biodentine were less cytotoxic than CEM cement and Biosealer (p < 0.01). Biodentine and ProRoot MTA had similar biocompatibility. Mixing ProRoot MTA with PBS in place of distilled water had no effect on its biocompatibility. Biosealer and CEM cement after 48 hr of incubation were significantly more cytotoxic to on monocyte cells compared to ProRoot MTA and Biodentine.


Feature-based attention is independent of object appearance.
How attention interacts with low-level visual representations to give rise to perception remains a central yet controversial question in neuroscience. While several previous studies suggest that the units of attentional selection are individual objects, other evidence points instead toward lower-level features, such as an attended color or direction of motion. We used both human fMRI and psychophysics to investigate the relationship between object-based and feature-based attention. Specifically, we focused on whether feature-based attention is modulated by object appearance, comparing three conditions: (a) features appearing as one object; (b) features appearing as two separate but identical objects; (c) features appearing as two different objects. Stimuli were two random-dot fields presented bilaterally to central fixation, and object appearance was induced by the presence of one or two boxes around the fields. In the fMRI experiment, participants performed a luminance discrimination task on one side, and ignored the other side, where we probed for enhanced activity when either it was perceived as belonging to a same object, or shared features with the task side. In the psychophysical experiments, participants performed luminance discrimination on both sides with overlapping red and green dots, now attending to either the same features (red/red or green/green) or different features (red/green or green/red) on both sides. Results show that feature-based attentional enhancement exists in all three conditions, i.e., regardless whether features appear as one object, two identical objects, or two different objects. Our findings indicate that feature-based attention differs from object-based attention in that it is not dependent upon object appearance. Thus feature-based attention may be mediated by earlier cortical processes independent of perceiving visual features into well-formed objects.


BRCA1 c.68_69delAG (exon2), c.181T>G (exon5), c.798_799delTT and 943ins10 (exon11) mutations in Burkina Faso.
The worldwide variation of BRCA mutations is well known. The c.68_69delAG, c.181T>G, c.798_799delTT mutations in BRCA1 were observed in Moroccan, Algerian and Tunisian Breast Cancer families and were described founder mutation in Northern Africa. The 943ins10 is also recognized a founder mutation in West Africa. To our knowledge no study has been published on BRCA1/2 germline mutations and hereditary breast cancer (HBC) in population of Burkina Faso. The aim of the present study (first in Burkina Faso) was to screen for these four mutations in 15 unrelated patients with HBC. Mutation analysis was performed by Sanger sequencing of coding exon2, Exon5 and exon11A sequences of the BRCA1 gene. Blood specimens of 15 patients from Burkina Faso, with HBC were collected at the University Hospital Yalgado OUEDRAOGO (CHU-YO) of Ouagadougou in Burkina Faso. c.68_69delAG (exon2), c.181T>G (exon5), c.798_799delTT and 943ins10 (exon11) mutations were not detected in any of the 15 women diagnosed with family breast cancer history. Genetic analysis in this study, we show that targeting relevant exons in BRCA1 genes did not allow detection of mutations in the population of Burkina Faso. Therefore, such an approach may be of interest to perfom a complete sequencing of BRCA1 and BRCA2 genes in families at a high risk of developing breast cancer in Burkina Faso.


Results of Treatment with Modern Fractionated Radiotherapy, Contemporary Stereotactic Radiosurgery, and Transsphenoidal Surgery in Nonfunctioning Pituitary Macroadenoma.
To compare the effects of contemporary stereotactic radiosurgery (SRS), modern fractionated radiotherapy (FRT), and transsphenoidal surgery on nonfunctioning pituitary macroadenoma. We enrolled patients with nonfunctioning pituitary macroadenoma. To compare treatment outcomes, the patients were categorized into three groups according to the treatment modality: group 1, patients receiving modern FRT; group 2, patients receiving contemporary SRS; and group 3, patients receiving transsphenoidal surgery. In total, 548 patients with nonfunctioning pituitary macroadenoma were selected for our study. Univariate and multivariate Cox regression analysis results indicated that the treatment modalities were significant independent prognostic factors. In multivariable Cox proportional hazard regression analysis, the adjusted hazard ratios (aHR; 95% confidence interval (CI)) of local recurrence were 0.27 (0.10-0.91) and 1.95 (1.25-2.37) for the SRS and transsphenoidal surgery cohorts, respectively, in comparison with the FRT cohort. The aHR (95% CI) of all-cause mortality was 1.03 (0.68-1.56) for the transsphenoidal surgery cohort in comparison with the FRT cohort, without statistical significance. However, the aHR (95% CI) of all-cause mortality was 0.36 (0.15-0.85) for the SRS cohort in comparison with the FRT cohort. Contemporary SRS has optimal effects on local recurrence and survival compared with modern FRT and transsphenoidal surgery. Modern FRT is associated with more favorable local control and equal survival compared with transsphenoidal surgery.


Analysis of the effect of 5-hydroxykynurenamine,, a serotonin metabolite, on isolated cerebral arteries, aortas and atria.
In helically cut strips of dog and human cerebral arteries, the addition of 5-hydroxykynurenamine (5-HK) caused dose-related contractions, and this contractile response was attenuated by methysergide and lysergic acid diethylamide (LSD). Treatment of the strips with 5-HK in concentrations higher than 2 X 10- minus 6 M shifted the dose-response curve of serotonin to the right and downward. The inhibitory effect of 5-HK was reversed only partially by repeated washings, whereas the inhibition caused by methysergide and LSD was completely reversed. The contractile response to K-+ (30 mM) was reduced only slightly even at the highest concentration of 5-HK used (5 X 10-minus 5 M). In strips of rabbit aortas, the contractile effect of serotonin was markedly attenuated by 5-HK, whereas that of norepinephrine was reduced only slightly. In isolated rabbit right atria, 5-HK produced a transient increase in the rate as did serotonin, 5-HK being approximately 1/20 as potent as serotonin. The positive effect was not influenced by methysergide but was markedly attenuated or abolished by 10-minus 6 M propranolol and 3 X 10-minus 6 M cocaine. Treatment with 5-HK (5 X 10-minus 5 M) did not modify the chronotropic response to isoproterenol. It appears that 5-HK produces vascular contractions via serotonergic receptors, inhibits specifically the contractile response of arteries and aortas to serotonin and causes a tachycardia in rabbit atria by liberating catecholamines from adrenergic nerves.


The matrix polysaccharide (1;3,1;4)-β-D-glucan is involved in silicon-dependent strengthening of rice cell wall.
Poales [represented by rice (Oryza sativa L.)] in angiosperms and Equisetum (horsetails) in Pteridophytes are two major groups of heavy silicon (Si) accumulators. In rice, Si is polymerized preferentially in the epidermal cell wall, forming Si-cuticle double layers and Si-cellulose double layers beneath the cuticle. This Si layer is thought to exert various beneficial effects on the growth and development of land plants. Although the recent discovery of the influx and efflux transporters of silicic acid has shed some light on the molecular mechanisms of Si uptake and transport in rice, the mechanism underlying the final incorporation of polymerized Si into the cell wall remains elusive. Despite their phylogenetic distance, the cell walls of the two Si accumulators, Poales and Equisetum, share another common component, i.e. (1;3,1;4)-β-D-glucan, also known as mixed-linkage glucan (MLG), a matrix polysaccharide not found in other plants. Based on this coincidence, a possible correlation between the functions of Si and MLG in the cell wall has been suggested, but no experimental evidence has been obtained in support of this functional correlation. Here, we present an analysis of the correlative action of Si and MLG on the mechanical properties of leaf blades using a transgenic rice line in which the MLG level was reduced by overexpressing EGL1, which encodes (1;3,1;4)-β-D-glucanase. The reduction in MLG did not affect total Si accumulation, but it significantly altered the Si distribution profile and reduced the Si-dependent mechanical properties of the leaf blades, strongly suggesting a functional correlation between Si and MLG.


Maternal obesity and the risk for orofacial clefts in the offspring.
To estimate whether obese women have an increased risk of orofacial clefts in their offspring, compared with average-weight women. The study was based on information on maternal body mass index (BMI) collected in early pregnancy and on the existence of orofacial clefts in the offspring, ascertained from multiple sources. The study included 1686 women who had infants with an orofacial cleft and as controls all delivered women (n = 988,171) during the study period, 1992 through 2001. Infants with chromosome anomalies were excluded. The women were divided into underweight (BMI <19.8), average weight (reference group, BMI 19.8 to 26), overweight (BMI 26.1 to 29), and obese (BMI >29). Adjustments were made for year of birth, maternal age, parity, and maternal smoking. Obese (BMI >29) mothers had an overall increased risk for having an infant with orofacial clefts: odds ratio 1.30 (95% confidence interval 1.11 to 1.53). This increased risk was higher when the cleft was associated with other major malformations than when it was isolated. There was no statistically significant difference between the risk estimates for cleft lip and cleft palate. In this large sample, a positive association appears between maternal obesity in early pregnancy and orofacial clefts in the offspring. The explanation for this association is not known, but a relationship with undetected type 2 diabetes is one possibility.


99mTc-MDP as an imaging tool to evaluate the in vivo biodistribution of solid lipid nanoparticles.
The aim of this study was to establish the in vivo uptake and tissue distribution of 99mTc-MDP-encapsulated Solid Lipid Nanoparticles (SLNs) post administration. Radioactive 99mTc-MDP encapsulated into SLNs was administered to rats to trace their biodistribution through imaging and ex vivo studies. As expected IV injected 99mTc-MDP exhibited predominant visual bone uptake and a high localisation of particles in the kidneys (3.87%ID/g) followed by bone (2.66%ID/g). IV administered 99mTc-MDP encapsulated by SLN showed similar uptake than 99mTc-MDP. Orally administrated 99mTc-MDP showed no uptake in any organs except the GI-tract while orally administered 99mTc-MDP-SLN showed distinct transfer of 99mTc-MDP from the GI tract with measurable levels in the kidneys and bone.


Myo-inositol(1,4,5)trisphosphorothioate binds to specific [3H]inositol(1,4,5)trisphosphate sites in rat cerebellum and is resistant to 5-phosphatase.
D-Myo-inositol(1,4,5)trisphosphorothioate, a synthetic analogue of inositol(1,4,5)trisphosphate was shown to bind with a relatively high affinity to specific sites on rat cerebellar membranes labelled with [3H]inositol(1,4,5)trisphosphate. Use of this binding assay has also established that unlike the trisphosphate, the trisphosphorothioate is completely resistant to a specific 5-phosphatase prepared from human erythrocytes. The ability of this novel analogue to release intracellular Ca2+ has already been reported and it offers considerable potential in the investigation of phosphoinositide-linked receptors.


GRADE Guidelines: 29. Rating the certainty in time-to-event outcomes-Study limitations due to censoring of participants with missing data in intervention studies.
To provide Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) guidance for the consideration of study limitations (risk of bias) due to missing participant outcome data for time-to-event outcomes in intervention studies. We developed this guidance through an iterative process that included membership consultation, feedback, presentation, and iterative discussion at meetings of the GRADE working group. The GRADE working group has published guidance on how to account for missing participant outcome data in binary and continuous outcomes. When analyzing time-to-event outcomes (e.g., overall survival and time-to-treatment failure) data of participants for whom the outcome of interest (e.g., death and relapse) has not been observed are dealt with through censoring. To do so, standard methods require that censored individuals are representative for those remaining in the study. Two types of censoring can be distinguished, end of study censoring and censoring because of missing data, commonly named loss to follow-up censoring. However, both types are not distinguishable with the usual information on censoring available to review authors. Dealing with individuals for whom data are missing during follow-up in the same way as individuals for whom full follow-up is available at the end of the study increases the risk of bias. Considerable differences in the treatment arms in the distribution of censoring over time (early versus late censoring), the overall degree of missing follow-up data, and the reasons why individuals were lost to follow-up may reduce the certainty in the study results. With often only very limited data available, review and guideline authors are required to make transparent and well-considered judgments when judging risk of bias of individual studies and then come to an overall grading decision for the entire body of evidence. Concern for risk of bias resulting from censoring of participants for whom follow-up data are missing in the underlying studies of a body of evidence can be expressed in the study limitations (risk of bias) domain of the GRADE approach.


Polymorphism of the TRAP gene of Plasmodium falciparum.
Natural sequence variation of the thrombospondin related anonymous protein (TRAP) gene of Plasmodium falciparum has been investigated by DNA analysis following the polymerase chain reaction amplification, and this shows the gene to be highly polymorphic. The region containing the sequence motif Trp-Ser-Pro-Cys-Ser-Val-Thr-Cys-Gly (WSPCSVTCG), common to TRAP, the circumsporozoite protein, properdin, and thrombospondin, was invariant. Elsewhere in the molecule, over 50 amino acid substitutions are described including the insertion of an in-frame, small-variable tandemly repeating motif between amino acid residues 352 and 353. Only one silent mutation was observed. Most nucleotide changes that occur in the first two codon positions result in conservative amino acid changes. Restriction fragment length polymorphism (RFLP) analysis was used to examine inheritance of TRAP in a cross between the HB3 and 3D7 clones of P. falciparum. Out of nine progeny examined, four possessed the HB3 gene and five the 3D7 gene. The TRAP gene hybridized to chromosome 13. Previous work has shown that a subtelomeric region of chromosome 13 from the 3D7 parent (marked by the HRP-III gene) was favoured strongly in this cross. The TRAP gene, however, is over 1 Mb away from this subtelomeric region and exhibits no such linkage because of chromosome crossovers. Five geographically separate isolates shared the same TRAP sequence as well as the same variant of the Th2R/Th3R region from the circumsporozoite protein. The correlation between independent markers in these isolates suggests that they have a common provenance.


Extranodal natural killer/T cell lymphoma: we should and we can do more.
Extranodal natural killer/T cell lymphoma, nasal type (ENKL) is a rare disease, which is much more prevalent in Asia. With the advent of L-asparaginase-based regimen, the outcome of ENKL was improved obviously. Sequential chemotherapy and radiotherapy is the standard treatment for early-stage ENKL. However, the outcome of advanced-stage diseases is not satisfactory. Therefore, risk-stratification is needed for ENKL. The prognostic factors include IPI, KIPI, plasma EBV-DNA, and interim-PET/CT. However, these parameters are not validated in the era of L-asparaginase. The role of high-dose chemotherapy and heamatopoietic stem cell transplantation require further investigation.


IDDM in rats induced by thymectomy and irradiation.
A diabetic syndrome closely resembling human IDDM has been induced in rats of specific pathogen-free origin by a combination of thymectomy and irradiation, with an overall incidence (10 wk postirradiation) in female rats of 34% for acute disease and 47% for islet lesions. Males were slightly more susceptible than females. Clinical features of the syndrome included hyperglycemia, insulinopenia, ketosis, and lipidemia, and corresponding islet pathology ranged from diffuse atrophy to focal atrophy and insulitis. Onset was usually acute, and the disease fatal unless early insulin therapy was initiated. Lymphocytic thyroiditis also was observed in a proportion of thymectomized and irradiated rats (49% in females) over the same period but with no apparent correlation to the occurrence of diabetes. A significant decrease in the incidence of disease was found in thymectomized and irradiated rats of conventional origin when compared with genetically identical specific pathogen-free rats, implicating a role for environmental factors in disease susceptibility. Diabetes inducement also was found to be strain related but not RT1u dependent. Both clinical signs and islet lesions were inhibited by early reconstitution of thymectomized and irradiated animals with syngeneic lymphoid cells from normal donors. Islet lesions and glucose intolerance could be transferred to syngeneic recipients by concanavalin A-activated lymphoid cells from acute diabetic donors. The close similarities between this experimental syndrome induced by immunological manipulation and the clinical condition in humans provide further evidence for an immune-mediated pathogenesis for IDDM.


High frequency of horizontal gene transfer in the oceans.
Oceanic bacteria perform many environmental functions, including biogeochemical cycling of many elements, metabolizing of greenhouse gases, functioning in oceanic food webs (microbial loop), and producing valuable natural products and viruses. We demonstrate that the widespread capability of marine bacteria to participate in horizontal gene transfer (HGT) in coastal and oceanic environments may be the result of gene transfer agents (GTAs), viral-like particles produced by α-Proteobacteria. We documented GTA-mediated gene transfer frequencies a thousand to a hundred million times higher than prior estimates of HGT in the oceans, with as high as 47% of the culturable natural microbial community confirmed as gene recipients. These findings suggest a plausible mechanism by which marine bacteria acquire novel traits, thus ensuring resilience in the face of environmental change.


A nano-positioning system for macromolecular structural analysis.
Very often, the positions of flexible domains within macromolecules as well as within macromolecular complexes cannot be determined by standard structural biology methods. To overcome this problem, we developed a method that uses probabilistic data analysis to combine single-molecule measurements with X-ray crystallography data. The method determines not only the most likely position of a fluorescent dye molecule attached to the domain but also the complete three-dimensional probability distribution depicting the experimental uncertainty. With this approach, single-pair fluorescence resonance energy transfer measurements can now be used as a quantitative tool for investigating the position and dynamics of flexible domains within macromolecular complexes. We applied this method to find the position of the 5' end of the nascent RNA exiting transcription elongation complexes of yeast (Saccharomyces cerevisiae) RNA polymerase II and studied the influence of transcription factor IIB on the position of the RNA.


Formation of hollow nanocrystals through the nanoscale Kirkendall effect.
Hollow nanocrystals can be synthesized through a mechanism analogous to the Kirkendall Effect, in which pores form because of the difference in diffusion rates between two components in a diffusion couple. Starting with cobalt nanocrystals, we show that their reaction in solution with oxygen and either sulfur or selenium leads to the formation of hollow nanocrystals of the resulting oxide and chalcogenides. This process provides a general route to the synthesis of hollow nanostructures of a large number of compounds. A simple extension of the process yielded platinum-cobalt oxide yolk-shell nanostructures, which may serve as nanoscale reactors in catalytic applications.


Global MYCN transcription factor binding analysis in neuroblastoma reveals association with distinct E-box motifs and regions of DNA hypermethylation.
Neuroblastoma, a cancer derived from precursor cells of the sympathetic nervous system, is a major cause of childhood cancer related deaths. The single most important prognostic indicator of poor clinical outcome in this disease is genomic amplification of MYCN, a member of a family of oncogenic transcription factors. We applied MYCN chromatin immunoprecipitation to microarrays (ChIP-chip) using MYCN amplified/non-amplified cell lines as well as a conditional knockdown cell line to determine the distribution of MYCN binding sites within all annotated promoter regions. Assessment of E-box usage within consistently positive MYCN binding sites revealed a predominance for the CATGTG motif (p<0.0016), with significant enrichment of additional motifs CATTTG, CATCTG, CAACTG in the MYCN amplified state. For cell lines over-expressing MYCN, gene ontology analysis revealed enrichment for the binding of MYCN at promoter regions of numerous molecular functional groups including DNA helicases and mRNA transcriptional regulation. In order to evaluate MYCN binding with respect to other genomic features, we determined the methylation status of all annotated CpG islands and promoter sequences using methylated DNA immunoprecipitation (MeDIP). The integration of MYCN ChIP-chip and MeDIP data revealed a highly significant positive correlation between MYCN binding and DNA hypermethylation. This association was also detected in regions of hemizygous loss, indicating that the observed association occurs on the same homologue. In summary, these findings suggest that MYCN binding occurs more commonly at CATGTG as opposed to the classic CACGTG E-box motif, and that disease associated over expression of MYCN leads to aberrant binding to additional weaker affinity E-box motifs in neuroblastoma. The co-localization of MYCN binding and DNA hypermethylation further supports the dual role of MYCN, namely that of a classical transcription factor affecting the activity of individual genes, and that of a mediator of global chromatin structure.


Extraction of oil from oil sands using thermoresponsive polymeric surfactants.
Several thermoresponsive block copolymers constituted of a poly(ethylene glycol) (PEG) and a poly(2-(2-methoxyethoxy) ethyl methacrylate) (PMEO2MA) block were prepared by atom transfer radical polymerization (ATRP) and their ability to extract oil from oil sands was evaluated. The chemical composition of the PEG113-b-PMEO2MAX block copolymers was determined by (1)H NMR and gel permeation chromatography (GPC) with X-values ranging between 48 and 80. Aqueous solutions of block copolymers showed a cloud point of 34 ± 1 °C as determined by turbidimetry and dynamic light scattering (DLS) measurements. DLS experiments indicated that these polymers formed stable block copolymer micelles due to association of the PMEO2MA blocks at temperatures greater than 45 °C with a unimodal distribution of hydrodynamic diameters. Since characterization of the block copolymer solutions as a function of temperature indicated the formation of hydrophobic domains in water for T > 45 °C, extractions of oil from oil sands with the block copolymers were conducted at T = 45 and 50 °C. At these temperatures, 15 mL of a 1 mg/mL PEG113-b-PMEO2MA77 aqueous solution extracted 100% of the oil trapped in 1 g of oil sand if 60 mg of toluene was added to the mixture. When the extraction was conducted under the same experimental conditions without block copolymer, a poor oil recovery of less than 30% was achieved. Starting with a 1 mg/mL block copolymer concentration, the block copolymer aqueous solution could be recycled up to five successive extractions while maintaining satisfying oil recovery. Each extraction cycle led to a 22% mass loss of block copolymer, certainly due to association with the toluene, oil, and sand particles. Together these experiments demonstrate that thermoresponsive block copolymers can be powerful aids to enhance the oil recovery of oil sands.


The role of transient-evoked otoacoustic emission testing in the evaluation of elderly persons.
The purposes of this study were: To determine the quantitative and qualitative changes that occur in transient-evoked otoacoustic emissions (TEOAEs) in older individuals without addressing the effect of aging alone and without correction for hearing loss of the subject selection. To investigate the clinical value of measuring TEOAEs in the routine audiological evaluation of older people reasoning that a finding of hearing loss in the presence of TEOAEs could indicate a form of presbycusis with a primary central component. Click-evoked otoacoustic emissions (CEOAEs) were measured in 201 subjects without middle ear problems aged 60 yr and older (range 60 to 97 yr) who volunteered for the study because of complaints concerning their hearing. Audiological procedures included a pure-tone audiogram, modified Speech Perception in Noise test (German version: Basler Satztest), and the Hearing Handicap Inventory for the Elderly (German version). Results from ears with a pure-tone average (PTA) at 0.5, 1, and 2 kHz of < or = 30 dB HL were further analyzed with respect to the presence or absence of CEOAEs. In addition, tone burst evoked otoacoustic emissions (TbOAEs) were tested in ears with responses to click stimuli. The test consisted of a paradigm used previously in our laboratory to assess superposition and suppression of frequency within the cochlea (see Xu, Probst, Harris, & Roede, 1994). CEOAEs were not detectable in ears with a PTA > 30 dB HL. The prevalence of CEOAEs in ears with a PTA < or = 30 dB HL was 60%. Response levels decreased as hearing thresholds became poorer, but there was no apparent influence on TEOAE level due to age alone. The audiological measures from ears with and without CEOAEs and with PTAs < or = 30 dB HL were similar with the exception of small between group differences at lower frequencies. The TbOAE results showed no differences in linear superposition and suppression when results were compared with those of younger subjects tested previously. The lower overall amplitudes of TEOAEs and the lower prevalence of 60% in comparison to results from younger subjects with normal hearing imply that cochlear changes do occur with aging. However, the preservation or loss of TEOAEs does not separate subjects with presbycusis into distinct audiological categories or handicaps. Tone burst results suggest that frequency processing within the cochlea is not affected by age alone. We conclude that TEOAEs add no relevant information in the routine clinical evaluation of elderly persons with hearing problems.


Perceptions of intimate relationships in partners before and after a patient's myocardial infarction.
To describe and explore how partners rate their intimate relationship before and after the patients' first myocardial infarction. A further aim was to investigate the association between partners' rating of their intimate relationship and self-rated health. To date, information on how partners experience the intimate relationship before and after a patient's myocardial infarction is sparse. A descriptive and exploratory design with longitudinal data collection. The study comprised 127 partners, aged 34-87 years. Data collection included self-reported information on socio-demographic data, intimate relationship and self-rated health one year before and one year after patients' first myocardial infarction. Intimate relationship was assessed by the Swedish version of the Relationship Assessment Scale. Self-rated health was evaluated by the EuroQoL visual analogue scale. In general, partners reported high satisfaction with their intimate relationship both before and after the patients' myocardial infarction. Women reported somewhat lower ratings in their intimate relationship than men before the myocardial infarction. Women increased their ratings after one year, while men on average decreased their ratings. Partners with higher education reported lower ratings for intimate relationship after one year. Those with children living at home rated intimate relationship lower than those without children living at home after one year. Partners' self-rated health status was stable over time. No significant association between intimate relationship and self-rated health was found. This study provides important insights regarding couples' relationships from the perspective of the partner. Socio-demographic factors such as sex, educational level, having children living at home and employment status may influence how the relationship, from the partners' perspective, is affected by a myocardial infarction event. This study provides insight into how partners rate their intimate relationship and self-rated health over time before and after patients' myocardial infarction.


The Management of Trigonoscaphocephaly as a Result of Combined Metopic and Sagittal Synostosis.
The combination of sagittal and metopic synostosis is rare, resulting in a scaphocephalic shape, but with an absence of frontal bossing and therefore varying degrees of trigonocephaly and occipital prominence. Treatment is primarily surgical, with a combination of procedures to address both the scaphocephaly and trigonocephaly required involving multiple operations. The authors discuss their experience of treating combined trigonoscaphocephaly in a single-stage procedure and propose a management strategy based on the severity of the presenting deformity. The Oxford Craniofacial Unit database was searched from inception in October of 2004 to August of 2013 to identify all patients with combined sagittal and metopic synostosis. Case notes were then manually searched to identify those patients who had true trigonoscaphocephaly. Of 2856 patients in the authors' database, a total of nine were identified as having had true trigonoscaphocephaly. Seven of these patients underwent a combined single-stage procedure with an average cephalic index of 68.7 percent preoperatively and 80.3 percent postoperatively. Management of trigonoscaphocephaly has been traditionally performed by multiple, staged surgical procedures. The authors propose that it can instead be managed in a single surgical procedure, with the choice of procedure determined by the severity of the deformity. If the deformity is mild to moderate with no occipital bullet, a combined fronto-orbital advancement remodeling and subtotal calvarial remodeling can be performed; however, if there is an occipital bullet, the authors propose the combination of fronto-orbital advancement remodeling and total calvarial remodeling performed in one operation with the patient turned from prone to supine intraoperatively. Therapeutic, IV.


Factors Driving Live Discharge From Hospice: Provider Perspectives.
The proportion of patients disenrolling from hospice before death has increased over the decade with significant variations across hospice types and regions. Such trends have raised concerns about live disenrollment's effect on care quality. Live disenrollment may be driven by factors other than patient preference and may create discontinuities in care, disrupting ongoing patient-provider relationships. Researchers have not explored when and how providers make this decision with patients. The objective of this study was to ascertain provider perspectives on key drivers of live discharge from the Medicare hospice program. We conducted semistructured telephone interviews with 18 individuals representing 14 hospice providers across the country. Transcriptions were coded and analyzed using a template analysis approach. Analysis generated four themes: 1) difficulty estimating patient prognosis, 2) fear of Centers for Medicare & Medicaid Services audits, 3) rising market competition, and 4) challenges with inpatient contracting. Participants emphasized challenges underlying each decision to discharge patients alive, stressing that there often exists a gray line between appropriate and inappropriate discharges. Discussions also focused on scenarios in which financial motivations drive enrollment and disenrollment practices. This study provides significant contributions to existing knowledge about hospice enrollment and disenrollment patterns. Results suggest that live discharge patterns are often susceptible to market and regulatory forces, which may have contributed to the rising national rate.


The Techniques for Overcoming Depression Questionnaire: Mokken Scale Analysis, Reliability, and Concurrent Validity in Depressed Cardiac Patients.
The Techniques for Overcoming Depression (TOD) questionnaire assesses the frequency with which patients being treated for depression use cognitive-behavioral techniques in daily life. This study examined its latent structure, reliability and concurrent validity in depressed cardiac patients. The TOD was administered at the initial and final treatment sessions in three trials of cognitive behavior therapy (CBT) (n = 260) for depression in cardiac patients. Mokken scaling was used to determine its dimensionality. The TOD is unidimensional in depressed cardiac patients, both at the initial evaluation (H = .46) and the end of treatment (H = .47). It is sensitive to change and the total score correlates with therapist ratings of the patient's socialization to CBT (r=.40, p<.05), homework adherence (r=0.36, p<0.05), and use of cognitive-behavioral techniques (r=.51, p<.01). TOD scores were associated with post-treatment depression scores in two of the trials (p<.01 in both analyses). The TOD is a unidimensional, reliable, valid, and clinically informative measure of self-reported use of cognitive-behavioral techniques for overcoming depression in cardiac patients. Studies of the TOD in other depressed patient populations are needed.


Is RPGR-related retinal dystrophy associated with systemic disease? A case series.
Ciliopathies responsible for retinitis pigmentosa can also cause systemic manifestations. RPGR is a ciliary gene and pathogenic variants in RPGR cause a retinal ciliopathy, the commonest cause of X-linked recessive retinitis pigmentosa. The RPGR protein interacts with numerous other ciliary proteins present in the transition zone of both motile and sensory cilia, and may play an important role in regulating ciliary protein transport. There has been a growing, putative association of RPGR variants with systemic ciliopathies: mainly sino-respiratory infections and primary ciliary dyskinesia. Retrospective case series of patients with RPGR-RP presenting to Oxford Eye Hospital with systemic disease. We report three children with RPGR-related rod-cone dystrophy, all of whom have mutations in the N-terminus of RPGR. Two cases co-presented with confirmed diagnoses of primary ciliary dyskinesia and one case with multiple sino-respiratory symptoms strongly suggestive of primary ciliary dyskinesia. These and all previously reported RPGR co-pathologies relate to ciliopathies and have no other systemic associations. The link between RPGR variants and a systemic ciliopathy remains plausible, but currently unproven.


Identification of the OXA-48 Carbapenemase Family by Use of Tryptic Peptides and Liquid Chromatography-Tandem Mass Spectrometry.
Phenotypic detection of the OXA-48-type class D β-lactamases in Enterobacteriaceae is challenging. We describe a rapid (less than 90 min) assay for the identification of OXA-48 family carbapenemases in subcultured bacterial isolates based on a genoproteomic approach. Following in silico trypsin digestion to ascertain theoretical core peptides common to the OXA-48 family, liquid chromatography-tandem mass spectrometry (LC-MS/MS) data-dependent acquisition was used to identify candidate peptide markers. Two peptides were selected based on performance characteristics: ANQAFLPASTFK, a core peptide common to all 12 OXA-48 family β-lactamase members, and YSVVPVYQEFAR, a highly specific peptide common to 11 of 12 OXA-48 family proteins providing the basis for an LC-MS/MS multiple reaction monitoring assay. An accuracy assessment was performed that included 98 isolates, 26 of which were OXA-48 positive. Two additional specificity assessments were performed including a mixture of isolates positive for OXA-48, KPC, NDM, VIM, and IMP carbapenemases. A combination of expert rules and expert judgment was applied by blinded operators to identify positive isolates. All isolates containing an OXA-48 family carbapenemase across all three test sets were correctly identified with no false positives, demonstrating 100% sensitivity (95% confidence interval [CI], 91.2% to 100%) and 100% specificity (95% CI, 96.2% to 100%) for the assay. These findings provide a framework for an LC-MS/MS-based method for the direct detection of OXA-48 family carbapenemases from cultured isolates that may have utility in predicting carbapenem resistance and tracking hospital outbreaks of OXA-48-carrying organisms.


Penalized unsupervised learning with outliers.
We consider the problem of performing unsupervised learning in the presence of outliers - that is, observations that do not come from the same distribution as the rest of the data. It is known that in this setting, standard approaches for unsupervised learning can yield unsatisfactory results. For instance, in the presence of severe outliers, K-means clustering will often assign each outlier to its own cluster, or alternatively may yield distorted clusters in order to accommodate the outliers. In this paper, we take a new approach to extending existing unsupervised learning techniques to accommodate outliers. Our approach is an extension of a recent proposal for outlier detection in the regression setting. We allow each observation to take on an "error" term, and we penalize the errors using a group lasso penalty in order to encourage most of the observations' errors to exactly equal zero. We show that this approach can be used in order to develop extensions of K-means clustering and principal components analysis that result in accurate outlier detection, as well as improved performance in the presence of outliers. These methods are illustrated in a simulation study and on two gene expression data sets, and connections with M-estimation are explored.


Connexin-36 gap junctions regulate in vivo first- and second-phase insulin secretion dynamics and glucose tolerance in the conscious mouse.
Insulin is secreted from the islets of Langerhans in coordinated pulses. These pulses are thought to lead to plasma insulin oscillations, which are putatively more effective in lowering blood glucose than continuous levels of insulin. Gap-junction coupling of β-cells by connexin-36 coordinates intracellular free calcium oscillations and pulsatile insulin release in isolated islets, however a role in vivo has not been shown. We test whether loss of gap-junction coupling disrupts plasma insulin oscillations and whether this impacts glucose tolerance. We characterized the connexin-36 knockout (Cx36(-/-)) mouse phenotype and performed hyperglycemic clamps with rapid sampling of insulin in Cx36(-/-) and control mice. Our results show that Cx36(-/-) mice are glucose intolerant, despite normal plasma insulin levels and insulin sensitivity. However, Cx36(-/-) mice exhibit reduced insulin pulse amplitudes and a reduction in first-phase insulin secretion. These changes are similarly found in isolated Cx36(-/-) islets. We conclude that Cx36 gap junctions regulate the in vivo dynamics of insulin secretion, which in turn is important for glucose homeostasis. Coordinated pulsatility of individual islets enhances the first-phase elevation and second-phase pulses of insulin. Because these dynamics are disrupted in the early stages of type 2 diabetes, dysregulation of gap-junction coupling could be an important factor in the development of this disease.


Clinical outcomes following early versus late pharmacologic thromboprophylaxis in patients with traumatic intracranial hemorrhage: a systematic review and meta-analysis.
Venous thromboembolism (VTE) after traumatic brain injury (TBI) with intracranial hemorrhage (ICH) presents a serious yet manageable morbidity and mortality risk. This systematic review and meta-analysis aimed to pool the current literature to evaluate whether or not pharmacologic thromboprophylaxis (PTP) administered early after traumatic ICH significantly changes incidence of VTE or hemorrhagic progression when compared to late administration. Systematic searches of seven electronic databases from their inception to July 2018 were conducted following the appropriate guidelines. One thousand four hundred ninety articles were identified for screening. Outcomes of interest were pooled as odd ratios (ORs) and analyzed using a random-effects model. Eleven comparative studies satisfied selection criteria, yielding a total of 5036 cases. Overall, mean age was 47.6 years and 36% patients were female. PTP was administered early (≤ 72 h from admission) in 2106 (42%) patients and late (> 72 h from admission) in 2922 (58%) cases. There was no statistically significant difference in the incidence of hemorrhagic progression (OR, 0.86; P = 0.450) or all-cause mortality (OR, 0.83; P = 0.347) between the early versus late PTP patient groups. However, incidence of VTE was significantly less in the early PTP patient group (OR, 0.58; P = 0.008). The early administration of PTP after traumatic ICH does not appear to confer a worse prognosis in terms of hemorrhagic progression. However, it seems to confer superior VTE prophylaxis, when compared to late PTP administration. We suggest that early PTP should not be prematurely discounted for patients with ICH in TBI on the assumption of aggravating hemorrhagic progression alone.


Renal scar formation and kidney function following antibiotic-treated murine pyelonephritis.
We present a new preclinical model to study treatment, resolution and sequelae of severe ascending pyelonephritis. Urinary tract infection (UTI), primarily caused by uropathogenic Escherichia coli (UPEC), is a common disease in children. Severe pyelonephritis is the primary cause of acquired renal scarring in childhood, which may eventually lead to hypertension and chronic kidney disease in a small but important fraction of patients. Preclinical modeling of UTI utilizes almost exclusively females, which (in most mouse strains) exhibit inherent resistance to severe ascending kidney infection; consequently, no existing preclinical model has assessed the consequences of recovery from pyelonephritis following antibiotic treatment. We recently published a novel mini-surgical bladder inoculation technique, with which male C3H/HeN mice develop robust ascending pyelonephritis, highly prevalent renal abscesses and evidence of fibrosis. Here, we devised and optimized an antibiotic treatment strategy within this male model to more closely reflect the clinical course of pyelonephritis. A 5-day ceftriaxone regimen initiated at the onset of abscess development achieved resolution of bladder and kidney infection. A minority of treated mice displayed persistent histological abscess at the end of treatment, despite microbiological cure of pyelonephritis; a matching fraction of mice 1 month later exhibited renal scars featuring fibrosis and ongoing inflammatory infiltrates. Successful antibiotic treatment preserved renal function in almost all infected mice, as assessed by biochemical markers 1 and 5 months post-treatment; hydronephrosis was observed as a late effect of treated pyelonephritis. An occasional mouse developed chronic kidney disease, generally reflecting the incidence of this late sequela in humans. In total, this model offers a platform to study the molecular pathogenesis of pyelonephritis, response to antibiotic therapy and emergence of sequelae, including fibrosis and renal scarring. Future studies in this system may inform adjunctive therapies that may reduce the long-term complications of this very common bacterial infection.


Effect of coconut oil on weight loss and metabolic parameters in men with obesity: a randomized controlled clinical trial.
Coconut oil appears to help in weight loss and improve metabolic parameters associated with obesity. We evaluate the influence of coconut oil on the body composition, lipid profile and glycemia in men with obesity. A controlled, randomized clinical trial was performed with 29 adult men affected by obesity. They were randomized between two groups receiving a daily intake of 1 tablespoon (12 mL) of extra virgin coconut oil (CO, n = 15) or soybean oil (SO, n = 14), and an isoenergetic balanced diet. The anthropometric profile, lipid profile and glycaemia were evaluated at the baseline and 45 days after intervention. The Mann-Whitney test was performed to compare the groups, and the Wilcoxon test was performed to compare the times. We considered a value of p < 0.05 as significant. There was no difference in anthropometric variables between the groups before and after intervention. The level of HDL cholesterol increased (3.67 ± 8.08 versus-3.79 ± 10.98, p = 0.02) and the TC/HDL cholesterol ratio decreased (-0.63 ± 0.82 versus 0.23 ± 0.80, p = 0.03) in the CO group, compared to the SO group. Coconut oil included in the isoenergetic balanced diet could increase HDL cholesterol and decrease the TC/HDL cholesterol ratio in men with obesity.


Discovery of a Potent Adenine-Benzyltriazolo-Pleuromutilin Conjugate with Pronounced Antibacterial Activity against MRSA.
Conjugation of pleuromutilin is an attractive strategy for the development of novel antibiotics and the fight against multiresistant bacteria as the class is associated with low rates of resistance and cross-resistance development. Herein, the preparation of 35 novel (+)-pleuromutilin conjugates is reported. Their design was based on a synthetically more efficient benzyl adaption of a potent lead but still relied on the Cu(I)-catalyzed alkyne-azide [3 + 2] cycloaddition for conjugation onto pleuromutilin. Their antibacterial activity was evaluated against the multiresistant Staphylococcus aureus strain USA300 for which they displayed moderate to excellent activity. Compound 35, bearing a para-benzyladenine substituent, proved particularly potent against USA300 and additional strains of MRSA and displayed as importantly no cytotoxicity in four mammalian cell lines. Structure-activity relationship analysis revealed that the purine 6-amino is essential for high potency, likely because of strong hydrogen bonding with the RNA backbone of C2469, as suggested by a molecular model based on the MM-GBSA approach.


Modeling the impact on virus transmission of Wolbachia-mediated blocking of dengue virus infection of Aedes aegypti.
Dengue is the most common arboviral infection of humans and is a public health burden in more than 100 countries. Aedes aegypti mosquitoes stably infected with strains of the intracellular bacterium Wolbachia are resistant to dengue virus (DENV) infection and are being tested in field trials. To mimic field conditions, we experimentally assessed the vector competence of A. aegypti carrying the Wolbachia strains wMel and wMelPop after challenge with viremic blood from dengue patients. We found that wMelPop conferred strong resistance to DENV infection of mosquito abdomen tissue and largely prevented disseminated infection. wMel conferred less resistance to infection of mosquito abdomen tissue, but it did reduce the prevalence of mosquitoes with infectious saliva. A mathematical model of DENV transmission incorporating the dynamics of viral infection in humans and mosquitoes was fitted to the data collected. Model predictions suggested that wMel would reduce the basic reproduction number, R0, of DENV transmission by 66 to 75%. Our results suggest that establishment of wMelPop-infected A. aegypti at a high frequency in a dengue-endemic setting would result in the complete abatement of DENV transmission. Establishment of wMel-infected A. aegypti is also predicted to have a substantial effect on transmission that would be sufficient to eliminate dengue in low or moderate transmission settings but may be insufficient to achieve complete control in settings where R0 is high. These findings develop a framework for selecting Wolbachia strains for field releases and for calculating their likely impact.


Childbirth preferences after cesarean birth: a review of the evidence.
Conflicting evidence on maternal and fetal safety of vaginal and cesarean childbirth after a previous cesarean makes patients and practitioners uncertain about pursuing a trial of labor or an elective repeat cesarean delivery. This review systematically evaluated and summarized the evidence related to women's preference for delivery. The Cochrane Database of Systematic Reviews and Registry of Controlled Trials and the MEDLINE, HealthSTAR, PsycINFO, and CINAHL databases were searched from 1980 to August 2002. We reviewed controlled trials, case-control studies, and observational studies that contained original patient data on preference for women with a previous cesarean delivery and that were of "good" or "fair" quality. Women with a previous vaginal delivery were more likely to select trial of labor than women who did not have one. The most commonly cited reason for selecting trial of labor was ease of recovery and desire to return quickly to caring for other children (reported in 6 of 7 studies). Safety for the mother and/or infant was cited as an important reason for delivery choice in 4 of 11 studies. Important ethnic differences were reported. Nonwhite women were more likely to identify their provider as an important influence (39% vs 19%), and perceived labor as something to be avoided if another option resulted in a healthy baby compared with white women, who perceived labor as a challenge and an experience not to be missed. A woman's choice for delivery was often based on family obligations, such as the need for a shorter recovery so that she could care for her infant and children at home, rather than the safety of herself or her infant. It remains unclear if education on vaginal birth after cesarean increases the proportion of women who choose trial of labor. Future studies should evaluate the impact of education and timing of education on patient preference.


Assessing care integration for dual-eligible beneficiaries: a review of quality measures chosen by states in the financial alignment initiative.
Caring for the 9 million low-income elderly or disabled adults who are eligible for full benefits under both Medicare and Medicaid can be extremely costly. As part of the federal Financial Alignment Initiative, states have the opportunity to test care models for dual-eligibles that integrate acute care, behavioral health and mental health services, and long-term services and supports, with the goals of enhancing access to services, improving care quality, containing costs, and reducing administrative barriers. One of the challenges in designing these demonstrations is choosing and applying measures that accurately track changes in quality over time—essential for the rapid identification of effective innovations. This brief reviews the quality measures chosen by eight demonstration states as of December 2013. The authors find that while some quality domains are well represented, others are not. Quality-of-life measures are notably lacking, as are informative, standardized measures of long-term services and supports.


Evaluating use of higher dose oxybutynin in combination with desmopressin for refractory nocturnal enuresis.
Nocturnal enuresis is a common pediatric condition with limited treatment options. In older children, pharmacologic therapy is often the preferred treatment. Pharmacologic therapies including desmopressin (DDAVP) or imipramine are effective in 40-50% of children. However, imipramine has serious safety concerns. Desmopressin in combination with a fixed dose anticholinergic has been shown to be useful in individuals who fail desmopressin monotherapy, but still fails to achieve success rates greater than 60%. The goal was to explore the efficacy and safety of using combination therapy desmopressin plus oxybutynin with increasing dose of oxybutynin in patients refractory to standard combination therapy. This was a single institution, IRB-approved, retrospective chart review of 61 patients (ages 7-18 years) including those with monosymptomatic primary nocturnal enuresis and non-monosymptomatic enuresis with controlled daytime voiding symptoms (CDVS) treated initially with desmopressin. All patients who failed initial therapy with desmopressin were started on combination therapy desmopressin (0.6 mg) plus standard dose (5 mg) oxybutynin. In patients who failed standard combination therapy, the dose of oxybutynin was titrated upwards until a response or the maximum dose of 10 mg was achieved. Demographic and medical history data were evaluated to determine predictive factors associated with response/failure to different therapy groups. The use of escalating doses of oxybutynin in combination with desmopressin achieved an overall response rate of 96.7% defined as a 2-week period without any enuretic events following initiation of treatment. Low-dose combination therapy (LDCT) (0.6 mg of desmopressin+5 mg of oxybutynin) had a response rate of 68% (Table). Advanced dose combination therapy (ADCT) (0.6 mg of desmopressin+7.5-10 mg of oxybutynin) had a response rate of 75.0%. A statistically significant relationship was found correlating both attention deficit disorder/attention-deficit hyperactivity disorder(ADD/ADHD) and CDVS with failure on monotherapy. No patients in the study reported any adverse events or side effects from the medications. The overall success rate of 96.7% with titrated doses of oxybutynin in combination with desmopressin is considerably higher than the response rates on fixed dose combination therapy quoted in the literature and supports the need for further evaluation in larger studies. Additionally, we found a statistically significant association between monotherapy failure and children with either ADD/ADHD or controlled daytime voiding symptoms. Our study is limited by small numbers and larger studies are needed to confirm these results. Our results suggest that ADCT is a safe and effective treatment option for primary nocturnal enuresis refractory to standard and low-dose combination therapy.


Cinnamaldehyde prevents endothelial dysfunction induced by high glucose by activating Nrf2.
It is well documented that hyperglycemia-induced oxidative stress is an important causative factor of endothelial dysfunction. Cinnamaldehyde (CA) is a key flavor compound in cinnamon essential oil that can enhance the antioxidant defense against reactive oxygen species (ROS) by activating NF-E2-related factor 2 (Nrf2), which has been shown to have a cardiovascular protective effect, but its role in endothelial dysfunction induced by high glucose is unknown. Dissected male C57BL/6J mouse aortic rings and HUVECs were cultured in normal glucose(NG 5.5 mM) or high glucose(HG 30.0 mM) DMEM treatment with or without CA (10 µM). Treatment with CA protected the endothelium relaxation, inhibited ROS generation and preserved nitric oxide (NO) levels in the endothelium of mouse aortas treated with high glucose . CA up-regulated Nrf2 expression, promoted its translocation to the nucleus'and increased HO-1, NQO1, Catalase and Gpx1 expression under high glucose condition. The increased level of nitrotyrosine in HUVECs under high glucose was also attenuated by treatment with CA. Dihydroethidium (DHE) and DAF-2DA staining indicated that CA inhibited the ROS generation and preserved the NO levels in HUVECs, but these effects were reversed by Nrf2-siRNA in high glucose conditions. Our results indicated that CA protected endothelial dysfunction under high glucose conditions and this effect was mediated by Nrf2 activation and the up-regulation of downstream target proteins. CA administration may represent a promising intervention in diabetic patients who are at risk for vascular complications.


The Abl interactor proteins localize to sites of actin polymerization at the tips of lamellipodia and filopodia.
Cell movement is mediated by the protrusion of cytoplasm in the form of sheet- and rod-like extensions, termed lamellipodia and filopodia. Protrusion is driven by actin polymerization, a process that is regulated by signaling complexes that are, as yet, poorly defined. Since actin assembly is controlled at the tips of lamellipodia and filopodia [1], these juxtamembrane sites are likely to harbor the protein complexes that control actin polymerization dynamics underlying cell motility. An understanding of the regulation of protrusion therefore requires the characterization of the molecular components recruited to these sites. The Abl interactor (Abi) proteins, targets of Abl tyrosine kinases [2-4], have been implicated in Rac-dependent cytoskeletal reorganization in response to growth factor stimulation [5]. Here, we describe the unique localization of Abi proteins in living, motile cells. We show that Abi-1 and Abi-2b fused to enhanced yellow fluorescent protein (EYFP) are recruited to the tips of lamellipodia and filopodia. We identify the targeting domain as the homologous N terminus of these two proteins. Our findings are the first to suggest a direct involvement of members of the Abi protein family in the control of actin polymerization in protrusion events, and establish the Abi proteins as potential regulators of motility.


Enacted Stigma, Mental Health, and Protective Factors Among Transgender Youth in Canada.
Purpose: We aimed to assess the Minority Stress Model which proposes that the stress of experiencing stigma leads to adverse mental health outcomes, but social supports (e.g., school and family connectedness) will reduce this negative effect. Methods: We measured stigma-related experiences, social supports, and mental health (self-injury, suicide, depression, and anxiety) among a sample of 923 Canadian transgender 14- to 25-year-old adolescents and young adults using a bilingual online survey. Logistic regression models were conducted to analyze the relationship between these risk and protective factors and dichotomous mental health outcomes among two separate age groups, 14- to 18-year-old and 19- to 25-year-old participants. Results: Experiences of discrimination, harassment, and violence (enacted stigma) were positively related to mental health problems and social support was negatively associated with mental health problems in all models among both age groups. Among 14-18 year olds, we examined school connectedness, family connectedness, and perception of friends caring separately, and family connectedness was always the strongest protective predictor in multivariate models. In all the mental health outcomes we examined, transgender youth reporting low levels of enacted stigma experiences and high levels of protective factors tended to report favorable mental health outcomes. Conversely, the majority of participants reporting high levels of enacted stigma and low levels of protective factors reported adverse mental health outcomes. Conclusion: While these findings are limited by nonprobability sampling procedures and potential additional unmeasured risk and protective factors, the results provide positive evidence for the Minority Stress Model in this population and affirm the need for policies and programs to support schools and families to support transgender youth.


Influences of prior miscarriage and weight status on perinatal psychological well-being, exercise motivation and behavior.
women who have experienced miscarriage may be at increased risk for elevated depressive and anxiety symptoms in subsequent pregnancies. Exercise may be a useful strategy for coping with these symptoms. Little is known about how miscarriage influences prenatal exercise behavior. The study purpose was to examine the influences of miscarriage history and prepregnancy weight status on pregnant women's psychological health, exercise motivation, and behavior using the Theory of Planned Behavior. Pregnant women (N=203; 41 with prior miscarriage; 72 overweight/obese; BMI > 25.0) in the northeast United States. Women prospectively reported their depressive/anxiety symptoms and exercise motivation/behavior in the 1st, 2nd, and 3rd trimesters via mailed surveys. Group differences in depressive/anxiety symptoms, exercise behavior, and its motivational determinants were examined using Chi Square analyses and Univariate and Multivariate Analyses of Covariance. Women with a history of miscarriage had higher 1st and 2nd trimester depressive/anxiety symptoms and lower 1st trimester attitudes about exercise and 1st and 2nd trimester perceived behavior control than women without a history of miscarriage. Overweight/obese women had higher 1st and 2nd trimester pregnancy depressive/anxiety symptoms, engaged in less prepregnancy exercise, and had lower levels of exercise intention, attitude, and perceived behavior control throughout pregnancy than normal weight women. Women with a history of miscarriage and overweight/obese women have poorer psychological health and lower motivation to exercise during pregnancy than women without a history of miscarriage and normal weight women. Interventions and healthcare provider communications aimed at promoting perinatal exercise behavior and psychological health should take into account pre-pregnancy weight status and pregnancy history to identify strategies to help women, particularly overweight/obese women with a history of miscarriage, to overcome exercise barriers.


The relationship between voting restrictions and COVID-19 case and mortality rates between US counties.
Since the 2010 election, the number of laws in the U.S. that create barriers to voting has increased dramatically. These laws may have spillover effects on population health by creating a disconnect between voter preferences and political representation, thereby limiting protective public health policies and funding. We examine whether voting restrictions are associated with county-level COVID-19 case and mortality rates. To obtain information on restricted access to voting, we used the Cost of Voting Index (COVI), a state-level measure of barriers to voting during a U.S. election from 1996 to 2016. COVID-19 case and mortality rates were obtained from the New York Times' GitHub database (a compilation from multiple academic sources). Multilevel modeling was used to determine whether restrictive voting laws were associated with county-level COVID-19 case and mortality rates after controlling for county-level characteristics from the County Health Rankings. We tested whether associations were heterogeneous across racial and socioeconomic groups. A significant association was observed between increasing voting restrictions and COVID-19 case (ß = 580.5, 95% CI = 3.9, 1157.2) and mortality rates (ß = 16.5, 95% CI = 0.33,32.6) when confounders were included. Restrictive voting laws were associated with higher COVID-19 case and mortality rates.


Casting light on multiple sclerosis heterogeneity: the role of HLA-DRB1 on spinal cord pathology.
Clinical heterogeneity in multiple sclerosis is the rule. Evidence suggests that HLA-DRB1*15 may play a role in clinical outcome. Spinal cord pathology is common and contributes significantly to disability in the disease. The influence of HLA-DRB1*15 on multiple sclerosis spinal cord pathology is unknown. A post-mortem cohort of pathologically confirmed cases with multiple sclerosis (n = 108, 34 males) with fresh frozen material available for genetic analyses and fixed material for pathology was used. HLA-DRB1 alleles were genotyped to select a subset of age- and sex-matched HLA-DRB1*15-positive (n = 21) and negative (n = 26) cases for detailed pathological analyses. For each case, transverse sections from three spinal cord levels (cervical, thoracic and lumbar) were stained for myelin, axons and inflammation. The influence of HLA-DRB1*15 on pathological outcome measures was evaluated. Carriage of HLA-DRB1*15 significantly increased the extent of demyelination (global measure 15+: 23.7% versus 15-: 12.16%, P = 0.004), parenchymal (cervical, P < 0.01; thoracic, P < 0.05; lumbar, P < 0.01) and lesional inflammation (border, P = 0.001; periplaque white matter, P < 0.05) in the multiple sclerosis spinal cord. HLA-DRB1*15 influenced demyelination through controlling the extent of parenchymal inflammation. Meningeal inflammation correlated significantly with small fibre axonal loss in the lumbar spinal cord (r = -0.832, P = 0.003) only in HLA-DRB1*15-positive cases. HLA-DRB1*15 significantly influences pathology in the multiple sclerosis spinal cord. This study casts light on the role of HLA-DRB1*15 in disease outcome and highlights the powerful approach of using microscopic pathology to clarify the way in which genes and clinical phenotypes of neurological diseases are linked.


Thermal, mechanical and biodegradation studies of biofiller based poly-3-hydroxybutyrate biocomposites.
Biodegradable poly-3-hydroxybutyrate [P(3HB)] and natural fillers - clay, peat, and birch wood flour - were used to prepare powdered composites to form pellets and granules. Pellets were produced by cold pressing of polymer and filler powder whereas granules were produced from the powders wetted with ethanol. Characterization techniques like IR spectroscopy, differential scanning calorimetry, X-ray analysis, mechanical analysis and electron microscopy were employed to study the properties of the initial P(3HB) and fillers and the composites. Analysis of the IR spectra of the composites showed the absence of chemical bonds between the components, i.e. the composites were physical mixtures. Young's moduli of the pellets prepared from initial materials varied considerably, and the highest value was obtained for P(3HB) pellets (350 MPa). Studies of biodegradation of composite pellets and granules in the soil for 35 days showed that the residual mass of the pellets had decreased to 68% for P(3HB); 56.4% for P(3HB)/peat; 67% for P(3HB)/wood flour, and 64% for P(3HB)/clay; granules exhibited a similar mass loss, residual mass of the granules of P(3HB) was 68.4%, P(3HB)/peat 46.4%; P(3HB)/wood flour 77%, and P(3HB)/clay 74%. This shows the significance of the material as an eco-friendly composite without sacrificing its mechanical properties.


Utility of the NEO-FFI in multi-dimensional assessment of orofacial pain conditions.
The purpose of this study was to examine the utility of using the NEO-FFI personality assessment as part of multi-dimensional psychological assessment in orofacial pain patients during the initial diagnostic visit. All patients completed an orofacial pain questionnaire and a battery of psychological questionnaires that cover a wide range of symptoms and behaviors important to developing a comprehensive treatment plan. For purposes of the present study, the NEO-FFI was included. Personality characteristics were within normal ranges compared to NEO-FFI norms. Regression analyses demonstrated higher self-reported pain severity was associated with lower openness. Higher psychological distress was associated with higher neuroticism, lower extraversion, and lower openness. In patients reporting a traumatic life experience, neuroticism and extraversion mediated the relationship between trauma-symptoms and psychological distress. The addition of a global personality measure in standard assessment batteries may help the clinician develop coping strategies and techniques based on individual characteristics of the pain patient. Greater understanding of the individual's personality characteristics will likely influence the nature of the pain management program and predict treatment outcomes.


Aerobiology Over Antarctica - A New Initiative for Atmospheric Ecology.
The role of aerial dispersal in shaping patterns of biodiversity remains poorly understood, mainly due to a lack of coordinated efforts in gathering data at appropriate temporal and spatial scales. It has been long known that the rate of dispersal to an ecosystem can significantly influence ecosystem dynamics, and that aerial transport has been identified as an important source of biological input to remote locations. With the considerable effort devoted in recent decades to understanding atmospheric circulation in the south-polar region, a unique opportunity has emerged to investigate the atmospheric ecology of Antarctica, from regional to continental scales. This concept note identifies key questions in Antarctic microbial biogeography and the need for standardized sampling and analysis protocols to address such questions. A consortium of polar aerobiologists is established to bring together researchers with a common interest in the airborne dispersion of microbes and other propagules in the Antarctic, with opportunities for comparative studies in the Arctic.


microRNAs: Master regulators as potential therapeutics in cancer.
It has been demonstrated that all the known processes involved in cancer, including apoptosis, proliferation, survival, and metastasis, are regulated by small regulatory noncoding RNAs consisting of approximately 19-25 nucleotides; these are named microRNAs (miRNAs). Both loss and gain of miRNA function contribute to cancer development through the upregulation and silencing, respectively, of different target genes. Experimental evidence indicates that the use of miRNA mimics or anti-microRNAs may represent a powerful therapeutic strategy to interfere with key molecular pathways involved in cancer. This review provides insights about how micro- RNAs act as oncogenes and tumor suppressor genes and how these findings, along with our increasing understanding of miRNA regulation, can be applied to optimize recent miRNA-based technologies and make them suitable for clinical applications.


Prevalence of Sleep Disorders in Children with Cerebral Palsy; A Questionnaire-based Observational Study.
Cerebral palsy (CP), the most common developmental disorder, has many comorbidities (epilepsy and behavioral issues). Sleep disturbances are common complaints of parents and are usually neglected in pediatric populations in comparison to other well-documented co-morbidities of CP but may have a significant effect on the quality of life of children and their parents. To study the prevalence and pattern of sleep disorders (SD) in children with CP. Questionnaire-based observational study. Pediatric tertiary care center. The study was done over 6 months. In total, 200 children with CP between the ages of 1 year to 14 years were included in the study by convenience sampling. Co-morbid health problems involving cardiorespiratory system, other illness (e.g. epilepsy and gastroesophageal reflux disease), or children on anticonvulsant medications altering sleep patterns were excluded. The Sleep Disturbance Scale for Children (SDSC) was administered to assess the presence of pathological sleep and type of SD ranging between Disorders of Initiation and Maintenance of Sleep (DIMS), Sleep Breathing disorders (SBD), Disorders of Arousal (DA), Sleep-Wake Transition Disorders (SWTD), Disorders of Excessive Somnolence (DES), and Sleep Hyperhydrosis (SHY). Sixty-two percentage of children (124) had a pathological total sleep score (score >39). DIMS are the most common, occurring in 78.2% of subjects with a pathological sleep score (score >39). Quadriplegics [n = 96, mean score = 49.86(16.38)] and GMFCS V [n = 19, mean score = 58.00(17.10)] are most severely affected. Children with CP have under-reported SD and DIMS is the most common type of SD. There is a linear correlation between the extent of topographical and motor afflictions and SD.


Split-cre complementation indicates coincident activity of different genes in vivo.
Cre/LoxP recombination is the gold standard for conditional gene regulation in mice in vivo. However, promoters driving the expression of Cre recombinase are often active in a wide range of cell types and therefore unsuited to target more specific subsets of cells. To overcome this limitation, we designed inactive "split-Cre" fragments that regain Cre activity when overlapping co-expression is controlled by two different promoters. Using transgenic mice and virus-mediated expression of split-Cre, we show that efficient reporter gene activation is achieved in vivo. In the brain of transgenic mice, we genetically defined a subgroup of glial progenitor cells in which the Plp1- and the Gfap-promoter are simultaneously active, giving rise to both astrocytes and NG2-positive glia. Similarly, a subset of interneurons was labelled after viral transfection using Gad67- and Cck1 promoters to express split-Cre. Thus, split-Cre mediated genomic recombination constitutes a powerful spatial and temporal coincidence detector for in vivo targeting.


Precise switching of DNA replication timing in the GC content transition area in the human major histocompatibility complex.
The human genome is composed of long-range G+C% (GC%) mosaic structures thought to be related to chromosome bands. We previously reported a boundary of megabase-sized GC% mosaic domains at the junction area between major histocompatibility complex (MHC) classes II and III, proposing it as a possible chromosome band boundary. DNA replication timing during the S phase is known to be correlated cytogenetically with chromosome band zones, and thus the band boundaries have been predicted to contain a switch point for DNA replication timing. In this study, to identify to the nucleotide sequence level the replication switch point during the S phase, we determined the precise DNA replication timing for MHC classes II and III, focusing on the junction area. To do this, we used PCR-based quantitation of nascent DNA obtained from synchronized human myeloid leukemia HL60 cells. The replication timing changed precisely in the boundary region with a 2-h difference between the two sides, supporting the prediction that this region may be a chromosome band boundary. We supposed that replication fork movement terminates (pauses) or significantly slows in the switch region, which contains dense Alu clusters; polypurine/polypyrimidine tracts; di-, tri-, or tetranucleotide repeats; and medium-reiteration-frequency sequences. Because the nascent DNA in the switch region was recovered at low efficiency, we investigated whether this region is associated with the nuclear scaffold and found three scaffold-associated regions in and around the switch region.


A comparison of statistical models in predicting violence in psychotic illness.
The application of statistical modeling techniques, including classification and regression trees, in the prediction of violence has increasingly received attention. The predictive performance of logistic regression and classification tree methods in predicting violence was explored in a sample of patients with psychotic illness. Of 2 logistic regression models, the forward stepwise method produced a simpler model than the full model, but the latter performed better. The performance of the classification tree appeared to be high before cross-validation, but reduced when cross-validated. The standard logistic model was the most robust model. A simplified tree with extra weight given to violent cases was a reasonable competitor and was simple to apply. Although classification trees can be suitable for routine clinical practice, because of the simplicity of their decision-making processes, their robustness and therefore clinical utility was problematic in this sample. Further research is required to compare such models in large prospective epidemiologic studies of other psychiatric populations.


Psychological Distress Across the Life Course and Cardiometabolic Risk: Findings From the 1958 British Birth Cohort Study.
Research suggests cardiovascular and metabolic diseases are influenced by psychological distress in adulthood; however, this research is often limited to adult populations and/or a snapshot measure of distress. Given emerging recognition that cardiometabolic diseases have childhood origins, an important question is whether psychological distress earlier in life influences disease development. This study sought to assess whether life course patterns of psychological distress assessed from childhood through adulthood predict biomarkers of cardiometabolic risk in adulthood and whether effects of sustained distress differ from more limited exposure. The sample (n = 6,714) consists of members of the 1958 British Birth Cohort Study who completed repeated measures of psychological distress and a biomedical survey at age 45 years. Psychological distress profiles over the life course (no distress, childhood only, adulthood only, or persistent distress) were identified from 6 assessments between ages 7 and 42 years. Cardiometabolic risk was assessed by combining information on 9 biomarkers of immune, cardiovascular, and metabolic system function. Covariate adjusted linear regression models were used to assess associations between distress profiles and cardiometabolic risk. Compared with those with no distress, cardiometabolic risk was higher among people with psychological distress in childhood only (β = 0.11, SE = 0.03, p = 0.0002), in adulthood only (β = 0.09, SE = 0.03, p = 0.007), and persistent across the life course (β = 0.26, SE = 0.04, p < 0.0001). Psychological distress at any point in the life course is associated with higher cardiometabolic risk. This is the first study to suggest that even if distress appears to remit by adulthood, heightened risk of cardiometabolic disease remains. Findings suggest early emotional development may be a target for primordial prevention and for promoting lifelong cardiovascular health.


Developing a tool to monitor knowledge translation in the health system: results from an international Delphi study.
It is generally accepted that evidence-informed decision making contributes to better health system performance and health outcomes, yet we are lacking benchmarks to monitor the impact of national health information systems (HIS) in policy and practice. Hence in this study, we have aimed to identify criteria for monitoring Knowledge Translation (KT) capacity within countries. We conducted a web-based Delphi with over 120 public health professionals from 45 countries to reach agreement on criteria to monitor KT at the level of national HIS. Public health professionals participated in three survey rounds, in which they ranked 85 preselected criteria and could suggest additional criteria. Experts working in national (public) health agencies and statistical offices, as well as in health policy and care agreed on 29 criteria which constitute the Health Information (HI)-Impact Index. The criteria cover four essential domains of evaluation: the production of high-quality evidence, broad access and dissemination, stakeholder engagement and knowledge integration across sectors and in civil society. The HI-Impact Index was pretested by officials working in ministries of health and public health agencies in eight countries; they found the tool acceptable and user-friendly. The HI-Impact Index provides benchmarks to monitor KT so that countries can assess whether high-quality evidence can be easily accessed and used by the relevant stakeholders in health policy and practice, by civil society and across sectors. Next steps include further refining the procedure for conducting the assessment in routine, and sharing experiences from HIS evaluations using the HI-Impact Index.


Gastric emptying after overnight fasting and clear fluid intake: a prospective investigation using serial magnetic resonance imaging in healthy children.
Current guidelines recommend preoperative fasting of 2 h for clear fluids, which is often exceeded in routine clinical practice. Existing data on residual gastric volumes in children do not consider fluid intake within <2 h and rely on the aspiration of gastric contents via a gastric tube. This study evaluated the emptying of clear fluids from the stomach using magnetic resonance imaging (MRI). Healthy volunteers aged 6-14 years were asked to fast overnight. MRI scans to assess gastric volumes were obtained before and immediately after drinking 7 ml kg(-1) of diluted raspberry syrup and then every 30 min up to 120 min. Volumes were determined by a blinded investigator and indexed gastric fluid/air volumes (GFV(w)/GAV(w)) and half-life (t(1/2)) of GFV(w) course after clear fluid intake were calculated. Sixteen children, median age 9.2 (range 6.4-12.8) years, were investigated. Median (range) GFV(w) was 0.62 (0.15-0.97) ml kg(-1) before and 6.68 (4.77-7.78) ml kg(-1) immediately after fluid intake, and 2.92 (0.43-5.04), 1.27 (0.28-3.62), 0.42 (0.07-2.49), and 0.32 (0.04-1.13) ml kg(-1) 30, 60, 90, and 120 min thereafter. Median GFV(w) declined exponentially (t(1/2)=26.1 min). Median individual t(1/2) was 23.6 (range 17.9-47.8) min. GAV(w) showed considerable intra- and inter-individual variation. In healthy school children, gastric emptying after ingestion of clear fluid occurs with a median half-life time of <30 min but with considerable inter-individual variation.


Prevalence and risk factors of micronutrient deficiencies pre- and post-antiretroviral therapy (ART) among a diverse multicountry cohort of HIV-infected adults.
HIV-infected adults have increased risk of several individual micronutrient deficiencies. However, the prevalence and risk factors of concurrent and multiple micronutrient deficiencies and whether micronutrient concentrations change after antiretroviral therapy (ART) initiation have not been well described. The objective of this study was to determine the prevalence and risk factors of individual, concurrent and multiple micronutrient deficiencies among ART-naïve HIV-infected adults from nine countries and assess change in micronutrient status 48 weeks post-ART initiation. A random sub-cohort (n = 270) stratified by country was selected from the multinational PEARLS clinical trial (n = 1571 ART-naïve, HIV-infected adults). We measured serum concentrations of vitamins A, D (25-hydroxyvitamin), E, carotenoids and selenium pre-ART and 48 weeks post-ART initiation, and measured vitamins B6, B12, ferritin and soluble transferrin receptor at baseline only. Prevalence of single micronutrient deficiencies, concurrent (2 coexisting) or conditional (a deficiency in one micronutrient given a deficiency in another) and multiple (≥3) were determined using defined serum concentration cutoffs. We assessed mean changes in micronutrient concentrations from pre-ART to week 48 post-ART initiation using multivariable random effects models. Of 270 participants, 13.9%, 29.2%, 24.5% and 32.4% had 0, 1, 2 and multiple deficiencies, respectively. Pre-ART prevalence was the highest for single deficiencies of selenium (53.2%), vitamin D (42.4%), and B6 (37.3%) with 12.1% having concurrent deficiencies of all three micronutrients. Deficiency prevalence varied widely by country. 48 weeks post-ART initiation, mean vitamin A concentration increased (p < 0.001) corresponding to a 9% decrease in deficiency. Mean concentrations also increased for other micronutrients assessed 48 weeks post-ART (p < 0.001) but with minimal change in deficiency status. Single and multiple micronutrient deficiencies are common among HIV-infected adults pre-ART initiation but vary between countries. Importantly, despite increases in micronutrient concentrations, prevalence of individual deficiencies remains largely unchanged after 48 weeks on ART. Our results suggest that ART alone is not sufficient to improve micronutrient deficiency.


Anisotropic Photoluminescence from Isotropic Optical Transition Dipoles in Semiconductor Nanoplatelets.
Many important light-matter coupling and energy-transfer processes depend critically on the dimensionality and orientation of optical transition dipoles in emitters. We investigate individual quasi-two-dimensional nanoplatelets (NPLs) using higher-order laser scanning microscopy and find that absorption dipoles in NPLs are isotropic in three dimensions at the excitation wavelength. Correlated polarization studies of the NPLs reveal that their emission polarization is strongly dependent on the aspect ratio of the lateral dimensions. Our simulations reveal that this emission anisotropy can be readily explained by the electric field renormalization effect caused by the dielectric contrast between the NPLs and the surrounding medium, and we conclude that emission dipoles in NPLs are isotropic in the plane of the NPLs. Our study presents an approach for disentangling the effects of dipole degeneracy and electric field renormalization on emission anisotropy and can be adapted for studying the intrinsic optical transition dipoles of various nanostructures.


The effect of long timescale gas dynamics on femtosecond filamentation.
Femtosecond laser pulses filamenting in various gases are shown to generate long- lived quasi-stationary cylindrical depressions or 'holes' in the gas density. For our experimental conditions, these holes range up to several hundred microns in diameter with gas density depressions up to ~20%. The holes decay by thermal diffusion on millisecond timescales. We show that high repetition rate filamentation and supercontinuum generation can be strongly affected by these holes, which should also affect all other experiments employing intense high repetition rate laser pulses interacting with gases.


Altitude decompression sickness symptom resolution during descent to ground level.
Altitude decompression sickness (DCS) is a health risk associated with the conduct of high altitude airdrop operations, high altitude reconnaissance, future fighter operations, hypobaric chamber training, unpressurized flight, and extravehicular activity (EVA) in space. The treatment for DCS includes the provision of 100% oxygen (O2) at ground level (GLO) and/or hyperbaric oxygen therapy (HBO). In this paper we examine the effect of repressurization to ground level from hypobaric conditions on DCS symptoms. Timely recompression (descent at first recognition of any DCS symptom) may be a safe, effective treatment for the large majority of DCS symptoms. Data from altitude chamber exposures recorded in the Air Force Research Laboratory (AFRL) Altitude DCS Database were reviewed to determine the level of recompression required for complete resolution of 1,699 observed symptoms. Of the 1,699 DCS symptoms reviewed, 66 (3.9%) resolved at altitude, 117 (6.9%) resolved at ground level, and 1,433 (84.3%) resolved during descent. Increasing the pressure by 138 mmHg from the altitude of exposure where symptoms occurred resolved roughly 50% of symptoms. Little resolution of symptoms was noted with recompressions of < 50 mmHg. The greatest rate of symptom resolution occurred with recompressions of 50-250 mmHg. These findings support the concept that descent and postflight, ground-level oxygen may be sufficient to relieve the majority of altitude DCS symptoms. HBO may be reserved for serious, recurring, delayed, or refractory symptoms. The findings also suggest a need for further study of DCS symptom resolution.