CONSORT 2010 statement: extension to randomised crossover trials.

Evidence shows the quality of reporting of randomised controlled trials is not optimal. The lack of transparent reporting impedes readers from judging the reliability and validity of trial findings, prevents researchers from extracting information for systematic reviews, and results in research waste. The Consolidated Standards of Reporting Trials (CONSORT) statement was developed to improve the reporting of randomised controlled trials. The primary focus of the statement was on parallel group trials with two treatment groups. Crossover trials are a particular type of trial for chronic conditions in which participants are randomised to a sequence of interventions. They are a useful and efficient design because participants act as their own control. However, the reporting of crossover trials has been variable and incomplete, which hinders their use in clinical decision making and by future researchers. We present the CONSORT extension to randomised crossover trials, which aims to facilitate better reporting of crossover trials. The CONSORT 2010 checklist is revised for crossover designs, and introduces a modified flowchart and baseline table to enhance transparency. Examples of good reporting and evidence based rationale for CONSORT crossover checklist items are provided

3-(6-Phenylimidazo [2,1-b][1,3,4]thiadiazol-2-yl)-1HIndole derivatives as new anticancer agents in the treatment of pancreatic ductal adenocarcinoma

A new series of imidazo[2,1-b][1,3,4]thiadiazole derivatives was efficiently synthesized and screened for their in vitro antiproliferative activity on a panel of pancreatic ductal adenocarcinoma (PDAC) cells, including SUIT-2, Capan-1 and Panc-1. Compounds 9c and 9l, showed relevant in vitro antiproliferative activity on all three pre-clinical models with half maximal inhibitory concentration (IC50) ranging from 5.11 to 10.8 μM, while the compounds 9e and 9n were active in at least one cell line. In addition, compound 9c significantly inhibited the migration rate of SUIT-2 and Capan-1 cells in the scratch wound-healing assay. In conclusion, our results will support further studies to increase the library of imidazo [2,1-b][1,3,4] thiadiazole derivatives for deeper understanding of the relationship between biological activity of the compounds and their structures in the development of new antitumor compounds against pancreatic diseases

Bubbling AdS and droplet descriptions of BPS geometries in IIB supergravity

This paper focuses on supergravity duals of BPS states in N=4 super Yang-Mills. In order to describe these duals, we begin with a sequence of breathing mode reductions of IIB supergravity: first on S^3, then S^3 x S^1, and finally on S^3 x S^1 x CP^1. We then follow with a complete supersymmetry analysis, yielding 1/8, 1/4 and 1/2 BPS configurations, respectively (where in the last step we take the Hopf fibration of S^3). The 1/8 BPS geometries, which have an S^3 isometry and are time-fibered over a six-dimensional base, are determined by solving a non-linear equation for the Kahler metric on the base. Similarly, the 1/4 BPS configurations have an S^3 x S^1 isometry and a four-dimensional base, whose Kahler metric obeys another non-linear, Monge-Ampere type equation. Despite the non-linearity of the problem, we develop a universal bubbling AdS description of these geometries by focusing on the boundary conditions which ensure their regularity. In the 1/8 BPS case, we find that the S^3 cycle shrinks to zero size on a five-dimensional locus inside the six-dimensional base. Enforcing regularity of the full solution requires that the interior of a smooth, generally disconnected five-dimensional surface be removed from the base. The AdS_5 x S^5 ground state corresponds to excising the interior of an S^5, while the 1/8 BPS excitations correspond to deformations (including topology change) of the S^5 and/or the excision of additional droplets from the base. In the case of 1/4 BPS configurations, by enforcing regularity conditions, we identify three-dimensional surfaces inside the four-dimensional base which separate the regions where the S^3 shrinks to zero size from those where the S^1 shrinks.Comment: 94 pages, 6 figures, latex, typos corrected, references added, one new Appendi

Perivascular macrophages in the neonatal macaque brain undergo massive necroptosis after simian immunodeficiency virus infection

We previously showed that rhesus macaques neonatally infected with simian immunodeficiency virus (SIV) do not develop SIV encephalitis (SIVE) and maintain low brain viral loads despite having similar plasma viral loads compared to SIV-infected adults. We hypothesize that differences in myeloid cell populations that are the known target of SIV and HIV in the brain contribute to the lack of neonatal susceptibility to lentivirus-induced encephalitis. Using immunohistochemistry and immunofluorescence microscopy, we examined the frontal cortices from uninfected and SIV-infected infant and adult macaques (n = 8/ea) as well as adults with SIVE (n = 4) to determine differences in myeloid cell populations. The number of CD206+ brain perivascular macrophages (PVMs) was significantly greater in uninfected infants than in uninfected adults and was markedly lower in SIV-infected infants while microglia numbers were unchanged across groups. CD206+ PVMs, which proliferate after infection in SIV infected adults, did not undergo proliferation in infants. While virtually all CD206+ cells in adults are also CD163+, infants have a distinct CD206 single-positive population in addition to the double-positive population commonly seen in adults. Notably, we found that more than 60% of these unique CD206+CD163− PVMs in SIV-infected infants were positive for cleaved caspase-3, an indicator of apoptosis, and that nearly 100% of this subset were concomitantly positive for the necroptosis marker receptor interacting protein kinase-3 (RIP3). These findings show that distinct subpopulations of PVMs found in infants undergo programmed cell death instead of proliferation following SIV infection, which may lead to the absence of PVM-dependent SIVE and the limited size of the virus reservoir in the infant brain. Includes Supplementary Material

Chemotactic response and adaptation dynamics in Escherichia coli

Adaptation of the chemotaxis sensory pathway of the bacterium Escherichia coli is integral for detecting chemicals over a wide range of background concentrations, ultimately allowing cells to swim towards sources of attractant and away from repellents. Its biochemical mechanism based on methylation and demethylation of chemoreceptors has long been known. Despite the importance of adaptation for cell memory and behavior, the dynamics of adaptation are difficult to reconcile with current models of precise adaptation. Here, we follow time courses of signaling in response to concentration step changes of attractant using in vivo fluorescence resonance energy transfer measurements. Specifically, we use a condensed representation of adaptation time courses for efficient evaluation of different adaptation models. To quantitatively explain the data, we finally develop a dynamic model for signaling and adaptation based on the attractant flow in the experiment, signaling by cooperative receptor complexes, and multiple layers of feedback regulation for adaptation. We experimentally confirm the predicted effects of changing the enzyme-expression level and bypassing the negative feedback for demethylation. Our data analysis suggests significant imprecision in adaptation for large additions. Furthermore, our model predicts highly regulated, ultrafast adaptation in response to removal of attractant, which may be useful for fast reorientation of the cell and noise reduction in adaptation.Comment: accepted for publication in PLoS Computational Biology; manuscript (19 pages, 5 figures) and supplementary information; added additional clarification on alternative adaptation models in supplementary informatio

Relationships of physical activity and sedentary time in obese parent-child dyads: a cross-sectional study

Abstract Background Research suggests physical activity is linked to obesity. Further, the physical activity of healthy parents and their children is associated with each other. However, this relationship has not been examined in obese parents and their obese children. Methods The purpose of this study was to compare the physical activity and sedentary time of obese, low-income, ethnic minority parents and their children on weekdays and weekend days using accelerometry. Data were obtained from eight rural sites in the middle and eastern part of North Carolina (N.C.), United States (U.S.) from 2007-2010 using a rolling enrollment. One hundred and ninety-nine obese parents (94 % female) and their obese children (54 % female) wore accelerometers simultaneously for three weekdays and one weekend day. Total physical activity, moderate-to-vigorous physical activity (MVPA) and sedentary time and proportions were determined. Results Parents’ and children’s total physical activity and MVPA levels were lower on weekend days than weekdays. Total counts per minute for children on weekdays and weekend days were greater than for parents (p  0.13). Discussion Since physical activity levels of obese parents and their obese child are somewhat related, especially on weekend days, combined parent-child obesity programs focused on reducing sedentary time could be beneficial, particularly for the child. Conclusion In conclusion, this study of the physical activity levels of obese parents and their obese children found some relationships between the parents’ and children’s physical activity and sedentary behavior patterns, especially on weekend days. Trial registration NCT01378806

On Horizons and Plane Waves

We investigate the possibility of having an event horizon within several classes of metrics that asymptote to the maximally supersymmetric IIB plane wave. We show that the presence of a null Killing vector (not necessarily covariantly constant) implies an effective separation of the Einstein equations into a standard and a wave component. This feature may be used to generate new supergravity solutions asymptotic to the maximally supersymmetric IIB plane wave, starting from standard seed solutions such as branes or intersecting branes in flat space. We find that in many cases it is possible to preserve the extremal horizon of the seed solution. On the other hand, non-extremal deformations of the plane wave solution result in naked singularities. More generally, we prove a no-go theorem against the existence of horizons for backgrounds with a null Killing vector and which contain at most null matter fields. Further attempts at turning on a nonzero Hawking temperature by introducing additional matter have proven unsuccessful. This suggests that one must remove the null Killing vector in order to obtain a horizon. We provide a perturbative argument indicating that this is in fact possible.Comment: 46 pp, 1 figur

A Terminal Velocity on the Landscape: Particle Production near Extra Species Loci in Higher Dimensions

We investigate particle production near extra species loci (ESL) in a higher dimensional field space and derive a speed limit in moduli space at weak coupling. This terminal velocity is set by the characteristic ESL-separation and the coupling of the extra degrees of freedom to the moduli, but it is independent of the moduli's potential if the dimensionality of the field space is considerably larger than the dimensionality of the loci, D >> d. Once the terminal velocity is approached, particles are produced at a plethora of nearby ESLs, preventing a further increase in speed via their backreaction. It is possible to drive inflation at the terminal velocity, providing a generalization of trapped inflation with attractive features: we find that more than sixty e-folds of inflation for sub-Planckian excursions in field space are possible if ESLs are ubiquitous, without fine tuning of initial conditions and less tuned potentials. We construct a simple, observationally viable model with a slightly red scalar power-spectrum and suppressed gravitational waves; we comment on the presence of additional observational signatures originating from IR-cascading and individual massive particles. We also show that moduli-trapping at an ESL is suppressed for D >> d, hindering dynamical selection of high-symmetry vacua on the landscape based on this mechanism.Comment: 46 pages, 6 figures. V3: typos corrected compared to JHEP version, conclusions unchange