Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis

Supported by the Global Alliance for TB Drug Development with support from the Bill and Melinda Gates Foundation, the European and Developing Countries Clinical Trials Partnership, U.S. Agency for International Development, U.K. Department for International Development, Directorate General for International Cooperation of the Netherlands, Irish Aid, Australia Department of Foreign Affairs and Trade, and National Institutes of Health, AIDS Clinical Trials Group and by grants from the National Institute of Allergy and Infectious Diseases (NIAID) (UM1AI068634, UM1 AI068636, and UM1AI106701) and by NIAID grants to the University of KwaZulu Natal, South Africa, AIDS Clinical Trials Group (ACTG) site 31422 (1U01AI069469); to the Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, South Africa, ACTG site 12301 (1U01AI069453); and to the Durban International Clinical Trials Unit, South Africa, ACTG site 11201 (1U01AI069426); Bayer Healthcare for the donation of moxifloxacin; and Sanofi for the donation of rifampin.Background: Early-phase and preclinical studies suggest that moxifloxacin-containing regimens could allow for effective 4-month treatment of uncomplicated, smear-positive pulmonary tuberculosis. Methods: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to test the noninferiority of two moxifloxacin-containing regimens as compared with a control regimen. One group of patients received isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid and rifampin (control group). In the second group, we replaced ethambutol with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (isoniazid group), and in the third group, we replaced isoniazid with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (ethambutol group). The primary end point was treatment failure or relapse within 18 months after randomization. Results: Of the 1931 patients who underwent randomization, in the per-protocol analysis, a favorable outcome was reported in fewer patients in the isoniazid group (85%) and the ethambutol group (80%) than in the control group (92%), for a difference favoring the control group of 6.1 percentage points (97.5% confidence interval [CI], 1.7 to 10.5) versus the isoniazid group and 11.4 percentage points (97.5% CI, 6.7 to 16.1) versus the ethambutol group. Results were consistent in the modified intention-to-treat analysis and all sensitivity analyses. The hazard ratios for the time to culture negativity in both solid and liquid mediums for the isoniazid and ethambutol groups, as compared with the control group, ranged from 1.17 to 1.25, indicating a shorter duration, with the lower bounds of the 95% confidence intervals exceeding 1.00 in all cases. There was no significant difference in the incidence of grade 3 or 4 adverse events, with events reported in 127 patients (19%) in the isoniazid group, 111 (17%) in the ethambutol group, and 123 (19%) in the control group. Conclusions: The two moxifloxacin-containing regimens produced a more rapid initial decline in bacterial load, as compared with the control group. However, noninferiority for these regimens was not shown, which indicates that shortening treatment to 4 months was not effective in this setting. (Funded by the Global Alliance for TB Drug Development and others; REMoxTB ClinicalTrials.gov number, NCT00864383.)Publisher PDFPeer reviewe

Longitudinal optical imaging technique to visualize progressive axonal damage after brain injury in mice reveals responses to different minocycline treatments

A high-resolution, three-dimensional, optical imaging technique for the murine brain was developed to identify the effects of different therapeutic windows for preclinical brain research. This technique tracks the same cells over several weeks. We conducted a pilot study of a promising drug to treat diffuse axonal injury (DAI) caused by traumatic brain injury, using two different therapeutic windows, as a means to demonstrate the utility of this novel longitudinal imaging technique. DAI causes immediate, sporadic axon damage followed by progressive secondary axon damage. We administered minocycline for three days commencing one hour after injury in one treatment group and beginning 72 hours after injury in another group to demonstrate the method’s ability to show how and when the therapeutic drug exerts protective and/or healing effects. Fewer varicosities developed in acutely treated mice while more varicosities resolved in mice with delayed treatment. For both treatments, the drug arrested development of new axonal damage by 30 days. In addition to evaluation of therapeutics for traumatic brain injury, this hybrid microlens imaging method should be useful to study other types of brain injury and neurodegeneration and cellular responses to treatment

The splice site variant rs11078928 may be associated with a genotype-dependent alteration in expression of GSDMB transcripts.

Published onlineJournal ArticleResearch Support, Non-U.S. Gov'tBACKGROUND: Many genetic variants have been associated with susceptibility to complex traits by genome wide association studies (GWAS), but for most, causal genes and mechanisms of action have yet to be elucidated. Using bioinformatics, we identified index and proxy variants associated with autoimmune disease susceptibility, with the potential to affect splicing of candidate genes. PCR and sequence analysis of whole blood RNA samples from population controls was then carried out for the 8 most promising variants to determine the effect of genetic variation on splicing of target genes. RESULTS: We identified 31 splice site SNPs with the potential to affect splicing, and prioritised 8 to determine the effect of genotype on candidate gene splicing. We identified that variants rs11078928 and rs2014886 were associated with altered splicing of the GSDMB and TSFM genes respectively. rs11078928, present in the asthma and autoimmune disease susceptibility locus on chromosome 17q12-21, was associated with the production of a novel Δ exon5-8 transcript of the GSDMB gene, and a separate decrease in the percentage of transcripts with inclusion of exon 6, whereas the multiple sclerosis susceptibility variant rs2014886, was associated with an alternative TFSM transcript encompassing a short cryptic exon within intron 2. CONCLUSIONS: Our findings demonstrate the utility of a bioinformatic approach in identification and prioritisation of genetic variants effecting splicing of their host genes, and suggest that rs11078928 and rs2014886 may affect the splicing of the GSDMB and TSFM genes respectively.Mendip Golf ClubNIHR Exeter Clinical Research Facilit

Tidally Forced Internal Waves and Overturns Observed on a Slope: Results from HOME

Tidal mixing over a slope was explored using moored time series observations on Kaena Ridge extending northwest from Oahu, Hawaii, during the Survey component of the Hawaii Ocean Mixing Experiment (HOME). A mooring was instrumented to sample the velocity and density field of the lower 500 m of the water column to look for indirect evidence of tidally induced mixing and was deployed on a slope in 1453-m water depth for 2 months beginning in November 2000. The semidiurnal barotropic tidal currents at this site have a significant cross-ridge component, favorable for exciting an internal tidal response. A large-amplitude response is expected, given that the slope of the topography (4.5°) is nearly the same as the slope of the internal wave group velocity at semidiurnal frequency. Density overturns were inferred from temperature profiles measured every 2 min. The number and strength of the overturns are greater in the 200 m nearest the bottom, with overturns exceeding 24 m present at any depth nearly 10% of the time. Estimates of turbulent dissipation rate ε were made for each overturn by associating the measured Thorpe scale with the Ozmidov scale. The average ε between 1300 and 1450 m for the entire experiment is about 10⁻⁸ m² s⁻³, corresponding to an average K[subscript]ρ of 10⁻³ m² s⁻1. Both ε and K[subscript]ρ decrease by about an order of magnitude by 1200 m. The occurrence of overturns and the magnitude of ε are both highly correlated with the tide: both with the spring–neap cycle as well as the phase of the semidiurnal tide itself. Dissipation rate varies by at least an order of magnitude over the spring–neap cycle. It appears that tidal frequency vertical shear within 200 m of the boundary leads to significant strain (vertical divergence). Most of the overturns occur during the few hours when the vertical strain is greatest. The buoyancy frequency N calculated from reordering these overturns is a factor of 3 lower than the background N[with line above]. This is consistent with the following kinematic description: the internal tide first strains the mean density field, leading to regions of low N that subsequently overturn. Less regularly, overturns also occur when the internal tide strain has created relatively high stratification within 200 m of the bottom

Are any coastal internal tides predictable?

Author Posting. © The Oceanography Society, 2012. This article is posted here by permission of The Oceanography Society for personal use, not for redistribution. The definitive version was published in Oceanography 25, No. 2 (2012): 80-95, doi:10.5670/oceanog.2012.44.Surface tides are the heartbeat of the ocean. Because they are controlled by Earth's motion relative to other astronomical objects in our solar system, surface tides act like clockwork and generate highly deterministic ebb and flow familiar to all mariners. In contrast, baroclinic motions at tidal frequencies are much more stochastic, owing to complexities in how these internal motions are generated and propagate. Here, we present analysis of current records from continental margins worldwide to illustrate that coastal internal tides are largely unpredictable. This conclusion has numerous implications for coastal processes, as across-shelf exchange and vertical mixing are, in many cases, strongly influenced by the internal wave field.This work was supported through grants from the US Office of Naval Research and NSF (Nash, Shroyer, Musgrave, Levine, and Duda), by NERC (grant NE/IO30224/1 FASTNEt; Inall), and by AIMS/CSIRO (Kelly and Jones)

DNA replication initiation in Bacillus subtilis: Structural and functional characterization of the essential DnaA-DnaD interaction

© 2018 The Author(s). The homotetrameric DnaD protein is essential in low G+C content gram positive bacteria and is involved in replication initiation at oriC and re-start of collapsed replication forks. It interacts with the ubiquitously conserved bacterial master replication initiation protein DnaA at the oriC but structural and functional details of this interaction are lacking, thus contributing to our incomplete understanding of the molecular details that underpin replication initiation in bacteria. DnaD comprises N-terminal (DDBH1) and C-terminal (DDBH2) domains, with contradicting bacterial two-hybrid and yeast two-hybrid studies suggesting that either the former or the latter interact with DnaA, respectively. Using Nuclear Magnetic Resonance (NMR) we showed that both DDBH1 and DDBH2 interact with the N-terminal domain I of DnaA and studied the DDBH2 interaction in structural detail. We revealed two families of conformations for the DDBH2-DnaA domain I complex and showed that the DnaA-interaction patch of DnaD is distinct from the DNA-interaction patch, suggesting that DnaD can bind simultaneously DNA and DnaA. Using sensitive single-molecule FRET techniques we revealed that DnaD remodels DnaA-DNA filaments consistent with stretching and/or untwisting. Furthermore, the DNA binding activity of DnaD is redundant for this filament remodelling. This in turn suggests that DnaA and DnaD are working collaboratively in the oriC to locally melt the DNA duplex during replication initiation

The enigmatic multiple star VV Ori

New photometry, including TESS data, have been combined with recent spectroscopic observations of the Orion Ib pulsating triple-star system VV Ori. This yields a revised set of absolute parameters with increased precision. Two different programs were utilized for the light curve analysis, with results in predictably close agreement. The agreement promotes confidence in the analysis procedures. The spectra were analysed using the {\sc FDBinary} program. The main parameters are as follows: $M_1 = 11.6 \pm 0.14$ and $M_2 = 4.8 \pm 0.06$ (M$_\odot$). We estimate an approximate mass of the wide companion as $M_3 = 2.0 \pm 0.3$ M$_\odot$. Similarly, $R_{1} = 5.11 \pm 0.03$, $R_2 = 2.51 \pm 0.02$, $R_3 = 1.8 \pm 0.1$ (R$_\odot$); $T_{\rm e 1} = 26600 \pm 300$, $T_{\rm e 2} = 16300 \pm 400$ and $T_{\rm e 3} = 10000 \pm 1000$ (K). The close binary's orbital separation is $a= 13.91$ (R$_\odot$); its age is $8 \pm 2$ (Myr) and its photometric distance is $396 \pm 7$ pc. The primary's $\beta$ Cep type oscillations support these properties and confirm our understanding of its evolutionary status. Examination of the well-defined $\lambda$6678 He I profiles reveals the primary to have a significantly low projected rotation: some 80\% of the synchronous value. This can be explained on the basis of the precession of an unaligned spin axis. This proposal can resolve also observed variations of the apparent inclination and address other longer-term irregularities of the system reported in the literature. This topic invites further observations and follow-up theoretical study of the dynamics of this intriguing young multiple star.Comment: 17 pages, 15 figures, 14 tables, accepted by MNRA

Probing for Exoplanets Hiding in Dusty Debris Disks: Disk Imaging, Characterization, and Exploration with HST/STIS Multi-Roll Coronagraphy

Spatially resolved scattered-light images of circumstellar (CS) debris in exoplanetary systems constrain the physical properties and orbits of the dust particles in these systems. They also inform on co-orbiting (but unseen) planets, systemic architectures, and forces perturbing starlight-scattering CS material. Using HST/STIS optical coronagraphy, we have completed the observational phase of a program to study the spatial distribution of dust in ten CS debris systems, and one "mature" protoplanetrary disk all with HST pedigree, using PSF-subtracted multi-roll coronagraphy. These observations probe stellocentric distances > 5 AU for the nearest stars, and simultaneously resolve disk substructures well beyond, corresponding to the giant planet and Kuiper belt regions in our Solar System. They also disclose diffuse very low-surface brightness dust at larger stellocentric distances. We present new results inclusive of fainter disks such as HD92945 confirming, and better revealing, the existence of a narrow inner debris ring within a larger diffuse dust disk. Other disks with ring-like sub-structures, significant asymmetries and complex morphologies include: HD181327 with a posited spray of ejecta from a recent massive collision in an exo-Kuiper belt; HD61005 suggested interacting with the local ISM; HD15115 & HD32297, discussed also in the context of environmental interactions. These disks, and HD15745, suggest debris system evolution cannot be treated in isolation. For AU Mic's edge-on disk, out-of-plane surface brightness asymmetries at > 5 AU may implicate one or more planetary perturbers. Time resolved images of the MP Mus proto-planetary disk provide spatially resolved temporal variability in the disk illumination. These and other new images from our program enable direct inter-comparison of the architectures of these exoplanetary debris systems in the context of our own Solar System.Comment: 109 pages, 43 figures, accepted for publication in the Astronomical Journa

Mooring observations from the Mid-Atlantic Bight, July-September 1996 : synthetic aperture sonar primer and coastal mixing & optics programs

This report documents the observations of velocity, temperature and conductivity made in the Mid-Atlantic Bight region of the NW Atlantic Ocean during the Synthetic Aperture Sonar (SAS) Primer experiment. The primary data were obtained from instruments moored in 70 in of water near 40° 30' N, 70° 30' W, from July through September 1996 (Figure 1). Vertical profiles of conductivity, temperature, light transmission and fluorescence were also made during deployment and recovery cruises. The overall goals of this PRIMER program are to assess the feasibility of the operation of an SAS on the continental shelf. A study of acoustic propagation was conducted during the period the mooring was deployed, from August 20 through August 27, by F. Henyey, T. Ewart, and K. Williams (Applied Physics Laboratory / University of Washington). The evaluation of the synthetic aperture sonar itself was performed by S. Stanic and R. Meredith (Naval Research Laboratory). This project was carried out in close cooperation with the ONR-sponsored Coastal Mixing & Optics ARE. In addition to shared logistical planning, we anticipate joint analysis and sharing of data. The specific goals of this project are to describe the internal wave field and associated sound speed fluctuations on the shelf--both statistically and by events. The sampling scheme was designed to resolve the many components of the wavefield including: near-inertial waves, internal tide, background continuum and internal solitary waves. This report is divided into two sections. The first section contains descriptions of the instrumentation deployed on the PRIMER moorings including locations, sampling rates, and calibrations. It also includes a brief description of the CTD sampling and sample profiles from the CTD stations occupied. Copies of the deployment and recovery cruise logs are appended to the first section. The second section contains plots from the mooring deployment. Several views of the time series recorded by the moorings are presented. Time series of vertically separated temperature, salinity, and velocity measurements are shown for the main, subsurface mooring. Temperature observations from sensors at the same depth on horizontally separated mooring are also shown. These data are presented as both low-pass filtered and unfiltered time series. Time is given as day of year 1996 in all of the time series plots; conversion to calendar date is provided in Table 8. The data displayed in these figures are a subset of the data collected during the mooring deployment, all of which are available on CD-ROM from the authors

Development and initial validation of the bronchiectasis exacerbation and symptom tool (BEST)

BACKGROUND: Recurrent bronchiectasis exacerbations are related to deterioration of lung function, progression of the disease, impairment of quality of life, and to an increased mortality. Improved detection of exacerbations has been accomplished in chronic obstructive pulmonary disease through the use of patient completed diaries. These tools may enhance exacerbation reporting and identification. The aim of this study was to develop a novel symptom diary for bronchiectasis symptom burden and detection of exacerbations, named the BEST diary. METHODS: Prospective observational study of patients with bronchiectasis conducted at Ninewells Hospital, Dundee. We included patients with confirmed bronchiectasis by computed tomography, who were symptomatic and had at least 1 documented exacerbation of bronchiectasis in the previous 12\u2009months to participate. Symptoms were recorded daily in a diary incorporating cough, sputum volume, sputum colour, dyspnoea, fatigue and systemic disturbance scored from 0 to 26. RESULTS: Twenty-one patients were included in the study. We identified 29 reported (treated exacerbations) and 23 unreported (untreated) exacerbations over 6-month follow-up. The BEST diary score showed a good correlation with the established and validated questionnaires and measures of health status (COPD Assessment Test, r =\u20090.61, p =\u20090.0037, Leicester Cough Questionnaire, r =\u2009-\u20090.52,p =\u20090.0015, St Georges Respiratory Questionnaire, r =\u20090.61,p <\u20090.0001 and 6\u2009min walk test, r =\u2009-\u20090.46,p =\u20090.037). The mean BEST score at baseline was 7.1 points (SD 2.2). The peak symptom score during exacerbation was a mean of 16.4 (3.1), and the change from baseline to exacerbation was a mean of 9.1 points (SD 2.5). Mean duration of exacerbations based on time for a return to baseline symptoms was 15.3\u2009days (SD 5.7). A minimum clinically important difference of 4 points is proposed. CONCLUSIONS: The BEST symptom diary has shown concurrent validity with current health questionnaires and is responsive at onset and recovery from exacerbation. The BEST diary may be useful to detect and characterise exacerbations in bronchiectasis clinical trials