Dynamical evolution of star forming regions - II. Basic kinematics

We follow the dynamical evolution of young star-forming regions with a wide range of initial conditions and examine how the radial velocity dispersion, $\sigma$, evolves over time. We compare this velocity dispersion to the theoretically expected value for the velocity dispersion if a region were in virial equilibrium, $\sigma_{\rm vir}$ and thus assess the virial state ($\sigma / \sigma_{\rm vir}$) of these systems. We find that in regions that are initially subvirial, or in global virial equilibrium but subvirial on local scales, the system relaxes to virial equilibrium within several million years, or roughly 25 - 50 crossing times, according to the measured virial ratio. However, the measured velocity dispersion, $\sigma$, appears to be a bad diagnostic of the current virial state of these systems as it suggests that they become supervirial when compared to the velocity dispersion estimated from the virial mass, $\sigma_{\rm vir}$. We suggest that this discrepancy is caused by the fact that the regions are never fully relaxed, and that the early non-equilibrium evolution is imprinted in the one-dimensional velocity dispersion at these early epochs. If measured early enough ($<$2 Myr in our simulations, or $\sim$20 crossing times), the velocity dispersion can be used to determine whether a region was highly supervirial at birth without the risk of degeneracy. We show that combining $\sigma$, or the ratio of $\sigma$ to the interquartile range (IQR) dispersion, with measures of spatial structure, places stronger constraints on the dynamical history of a region than using the velocity dispersion in isolation.Comment: 20 pages, 14 figures, accepted for publication in MNRA

Faecal microbiota transplantation for bipolar disorder: A detailed case study.

Faecal microbiota transplantation (FMT) has been proposed as a beneficial treatment for multiple conditions, including mood disorders. This case report (the second in the literature) provides detailed longitudinal information of successful FMT treatment for a patient with bipolar disorder. FMT may be a management option for treatment-resistant bipolar disorder

Nanopore direct RNA sequencing maps the complexity of Arabidopsis mRNA processing and m6A modification

Understanding genome organization and gene regulation requires insight into RNA transcription, processing and modification. We adapted nanopore direct RNA sequencing to examine RNA from a wild-type accession of the model plant Arabidopsis thaliana and a mutant defective in mRNA methylation (m6A). Here we show that m6A can be mapped in full-length mRNAs transcriptome-wide and reveal the combinatorial diversity of cap-associated transcription start sites, splicing events, poly(A) site choice and poly(A) tail length. Loss of m6A from 3’ untranslated regions is associated with decreased relative transcript abundance and defective RNA 30 end formation. A functional consequence of disrupted m6A is a lengthening of the circadian period. We conclude that nanopore direct RNA sequencing can reveal the complexity of mRNA processing and modification in full-length single molecule reads. These findings can refine Arabidopsis genome annotation. Further, applying this approach to less well-studied species could transform our understanding of what their genomes encode

Assessment of the Nanodropper Eye Drop Adaptor for Glaucoma Medications

Assessment of the Nanodropper Eye Drop Adaptor for Glaucoma Medications Nicholas Pryde, BS1; Parker J. Williams, DO 1; John-Michael Guest, MD1; Bret A. Hughes, MD1; Faisal Ridha MD1 1Kresge Eye Institute and Wayne State University Department of Ophthalmology, Detroit, MI, USA Purpose: To determine the dispensed volume change for seven medications with and without the Nanodropper adaptor. Methods: Sequentially, 100 µL of each medication was dispensed by micropipette into a 1.5 mL Eppendorf tube, and mass without the tube was determined with a precision balance (Practum, Germany). The mean mass was calculated following five serial measurements of 100 µL, and density was calculated by dividing mean mass (mg) by 100 µL. This procedure was repeated with and without the Nanodropper adaptor to provide the mean volume per drop. The means and standard deviations were calculated, with and without the adaptor. An unpaired student T-test was used for statistical analysis. Tested medications included brimonidine tartrate 0.2% (Alphagan P, Allergan), dorzolamide HCL (Hi-Tech), travoprost (Travatan Z, Alcon) timolol malate (Sandoz), netarsudil/latanoprost (Rocklatan, Aerie), netarsudil (Rhopressa, Aerie), and pilocarpine 1.25% (Vuity, Allergan). Results: The mean volume reduction across all medications was 62.3% (range 55.2% - 69.7%). The volume of Alphagan P decreased from 43.2 ±1.6 µL to 17.1 ±1.8 µL (60.4% reduction) with the adaptor. The volume of dorzolamide HCL decreased from 39.9 ±1.6 µL to 14.2 ±1.1 µL (64.4% reduction). The volume of Travatan Z decreased from 30.8 ±1.6 µL to 12.3 ±1.4 µL (60.1% reduction). The volume of timolol malate decreased from 28.6 ±2.2 µL to 12.8 ±1.6 µL (55.2% reduction). The volume of Rocklatan decreased from 40.2 ±2.2 µL to 12.2 ±1.1 µL (69.7% reduction). The volume of Rhopressa decreased from 33.5 ±1.4 µL to 12.2 ±1.3 µL (63.6% reduction). The volume of Vuity decreased from 32.1±1.08 µL to 11.9 ± 0.9 µL (62.9% reduction). All p-values were less than 0.0001. Discussion: It is reported that the optimal eye drop volume is between 5-15 µL.1 The Nanodropper adaptor produced statistically significant volume reductions near this range for all tested medications with excellent reproducibility. All drop volumes measured between 10-20 µL with the adaptor. Conclusions: The novel eye drop adaptor reliably reduced eye drop volumes to a level between 10.0-20.0 µL. The mean volume reduction across all medications was 62.3% (range 55.2% - 69.7%). This may decrease the financial burden on patients and reduce the risk of systemic side effects, as long as efficacy is maintained. Future studies could target differences in the reduced final volumes and the clinical efficacy of volume reduction for various medications. References: Van Santvliet, L., & Ludwig, A. (2004). Determinants of eye drop size. Survey of ophthalmology, 49(2), 197-213

Time domain computational modelling of 1D arterial networks in monochorionic placentas

Published versio

Divergent confidence intervals among pre-specified analyses in the HiSTORIC stepped wedge trial:an exploratory post-hoc investigation

BACKGROUND: The high-sensitivity cardiac troponin on presentation to rule out myocardial infarction (HiSTORIC) study was a stepped-wedge cluster randomised trial with long before-and-after periods, involving seven hospitals across Scotland. Results were divergent for the binary safety endpoint (type 1 or type 4b myocardial infarction or cardiac death) across certain pre-specified analyses, which warranted further investigation. In particular, the calendar-matched analysis produced an odds ratio in the opposite direction to the primary logistic mixed-effects model analysis. METHODS: Several post-hoc statistical models were fitted to each of the co-primary outcomes of length of hospital stay and safety events, which included adjusting for exposure time, incorporating splines, and fitting a random time effect. We improved control of patient characteristics over time by adjusting for multiple additional covariates using different methods: direct inclusion, regression adjustment for propensity score, and weighting. A data augmentation approach was also conducted aiming to reduce the effect of sparse data bias. Finally, the raw data was examined. RESULTS: The new statistical models confirmed the results of the pre-specified trial analysis. In particular, the observed divergence between the calendar-matched and other analyses remained, even after performing the covariate adjustment methods, and after using data augmentation. Divergence was particularly acute for the safety endpoint, which had an event rate of 0.36% overall. Examining the raw data was particularly helpful to assess the sensitivity of the results to small changes in event rates and identify patterns in the data. CONCLUSIONS: Our experience reveals the importance of conducting multiple pre-specified sensitivity analyses and examining the raw data, particularly for stepped wedge trials with low event rates or with a small number of sites. Before-and-after analytical approaches that adjust for differences in patient populations but avoid direct modelling of the time trend should be considered in future stepped wedge trials with similar designs

Ammonia decomposition enhancement by Cs-Promoted Fe/Al2O3 catalysts

A range of Cs-doped Fe/Al2O3 catalysts were prepared for the ammonia decomposition reaction. Through time on-line studies it was shown that at all loadings of Cs investigated the activity of the Fe/Al2O3 catalysts was enhanced, with the optimum Cs:Fe being ca. 1. Initially, the rate of NH3 decomposition was low, typically < 10% equilibrium conversion (99.7%@500°C) recorded after 1 h. All catalysts exhibited an induction period (typically ca. 10 h) with the conversion reaching a high of 67% equilibrium conversion for Cs:Fe = 0.5 and 1. The highest rate of decomposition observed was attributed to the balance between increasing the concentration of Cs without blocking the active site. Analysis of H2-TPR and XPS measurements indicated that Cs acts as an electronic promoter. Previously, Cs has been shown to act as a promoter for Ru, where Cs alters the electron density of the active site, thereby facilitating the recombination of N2 which is considered the rate determining step. In addition, XRD and N2 adsorption measurements suggest that with higher Cs loadings deactivation of the catalytic activity is due to a layer of CsOH that forms on the surface and blocks active sites

Phase III Trial of PROSTVAC in Asymptomatic or Minimally Symptomatic Metastatic Castration-Resistant Prostate Cancer

Càncer de pròstata; Metàstasi neoplàsica; ImmunoteràpiaCáncer de próstata; Metástasis neoplásica; InmunoterapiaProstate cancer; Metastatic neoplasm; ImmunotherapyPURPOSE PROSTVAC, a viral vector–based immunotherapy, prolonged median overall survival (OS) by 8.5 months versus placebo in metastatic castration-resistant prostate cancer in a phase II study. This phase III study further investigated those findings. PATIENTS AND METHODS Patients were randomly assigned to PROSTVAC (Arm V; n = 432), PROSTVAC plus granulocyte-macrophage colony-stimulating factor (Arm VG; n = 432), or placebo (Arm P; n = 433), stratified by prostate-specific antigen (less than 50 ng/mL v 50 ng/mL or more) and lactate dehydrogenase (less than 200 v 200 U/L or more). Primary end point was OS. Secondary end points were patients alive without events (AWE)—namely, radiographic progression, pain progression, chemotherapy initiation, or death—at 6 months and safety. The study design was a superiority trial of PROSTVAC (Arm V or Arm VG) versus Arm P. Three interim analyses were planned. RESULTS At the third interim analysis, criteria for futility were met and the trial was stopped early. Neither active treatment had an effect on median OS (Arm V, 34.4 months; hazard ratio, 1.01; 95% CI, 0.84 to 1.20; P = .47; Arm VG, 33.2 months; hazard ratio, 1.02; 95% CI, 0.86 to 1.22; P = .59; Arm P, 34.3 months). Likewise, AWE at 6 months was similar (Arm V, 29.4%; odds ratio, 0.96; 95% CI, 0.71 to 1.29; Arm VG, 28.0%; odds ratio, 0.89; 95% CI, 0.66 to 1.20; placebo, 30.3%). Adverse events were similar for the treatment and placebo groups, with the most common being injection site reactions (62% to 72%) and fatigue (21% to 24%). Arrhythmias were the most common cardiac-related events (1.4% to 3.5%). There were no reports of either myocarditis or pericarditis. Serious treatment-related events occurred in less than 1% of all patients. CONCLUSION Whereas PROSTVAC was safe and well tolerated, it had no effect on OS or AWE in metastatic castration-resistant prostate cancer. Combination therapy is currently being explored in clinical trials.Supported by Bavarian Nordic, the National Institute for Health Research Biomedical Research Centre at the Royal Marsden National Health Service Foundation Trust, and the Institute of Cancer Research. Funded in part by National Cancer Institute Cancer Center Support Grant No. P30-CA008748 and the Center for Cancer Research, National Cancer Institute.P30 CA008748/CA/NCI NIH HHS/United States DH_/Department of Health/United Kingdo