Publication trends of clinical trials performed in South Africa

Background. Investigators and sponsors of clinical trials have an ethical obligation to disseminate clinical trial results, whether positive or negative, in a timely manner.Objectives. To determine the publication rate and average time to reporting for clinical trials carried out in South Africa (SA) and to explore factors indicating whether a study is published or not.Methods. A registry-based quantitative retrospective analysis of 79 SA clinical trials for new medicines registered between January 2008 and December 2010 was performed. The relevant trial identification number in the register was used to track all peer-reviewed publications subsequent to registration. Tracking of clinical trials was done through a systematic literature search of the electronic journal databases of the South African Medical Journal (SAMJ), the Cochrane Library, Public Library of Science Medical Journal (PLoS Medicine) and BioMed Central, all of which are indexed on MEDLINE via PubMed. In addition, a manual search of the Open Access Journal of Clinical Trials databases and reference lists on articles related to the trial medicine was performed.Results. Of the 79 clinical trials surveyed, 72 were concluded by December 2014. Only 35 (48.6%) of them had the results published in a peer-reviewed journal, the current benchmark for dissemination of trial results. The majority (82.9%) of those published had a positive outcome. Of the 35 trials that were published, 77.1% were published within 2 years. The average time from completion to initial reporting was 22 months. Fewer than half (40.5%) of the clinical trials surveyed were placebo controlled.Conclusion. The absence of complete outcomes data from SA clinical trials warrants utmost attention. The study puts forward a case to the regulatory body and research ethics committees to compel all data from clinical trials to be made accessible to clinicians and the public in general by being published in an easily accessible form and in a timely manner

Climate sensitivity uncertainty : When is good news bad?

Climate change is real and dangerous. Exactly how bad it will get, however, is uncertain. Uncertainty is particularly relevant for estimates of one of the key parameters: equilibrium climate sensitivity—how eventual temperatures will react as atmospheric carbon dioxide concentrations double. Despite significant advances in climate science and increased confidence in the accuracy of the range itself, the “likely” range has been 1.5-4.5°C for over three decades. In 2007, the Intergovernmental Panel on Climate Change (IPCC) narrowed it to 2-4.5°C, only to reverse its decision in 2013, reinstating the prior range. In addition, the 2013 IPCC report removed prior mention of 3°C as the “best estimate.” We interpret the implications of the 2013 IPCC decision to lower the bottom of the range and excise a best estimate. Intuitively, it might seem that a lower bottom would be good news. Here we ask: When might apparently good news about climate sensitivity in fact be bad news in the sense that it lowers societal wellbeing? The lowered bottom value also implies higher uncertainty about the temperature increase, a definite bad. Under reasonable assumptions, both the lowering of the lower bound and the removal of the “best estimate” may well be bad news

Double-peaked Lyman α emission at z = 6.803: a reionization-era galaxy self-ionizing its local H II bubble

We report the discovery of a double-peaked Lyman α profile in a galaxy at z = 6.803, A370p_z1, in the parallel Frontier Field of Abell 370. The velocity separation between the blue and red peaks of the Lyman α profile (⁠Δ v = 101^{+38}_{-19}(±48)km s^{-1}) suggests an extremely high escape fraction of ionizing photons >59(51) per cent (2σ). The spectral energy distribution indicates a young (50 Myr), star-forming (⁠12 ± 6M_{⊙}yr^{-1}) galaxy with an IRAC excess implying strong [O III] + H β emission. On the basis of the high escape fraction measured, we demonstrate that A370p_z1 was solely capable of creating an ionized bubble sufficiently large to account for the blue component of its Lyman α profile. We discuss whether A370p_z1 may be representative of a larger population of luminous z ≃ 7 double-peaked Lyman α emitting sources with high escape fractions that self-ionized their surroundings without contributions from associated ultraviolet-fainter sources

Three Lyα Emitting Galaxies within a Quasar Proximity Zone at z ~ 5.8

Quasar proximity zones at z > 5.5 correspond to overdense and overionized environments. Galaxies found inside proximity zones can therefore display features that would otherwise be masked by absorption in the intergalactic medium. We demonstrate the utility of this quasar-galaxy synergy by reporting the discovery of the first three “proximate Lyα emitters” (LAEs) within the proximity zone of quasar J0836+0054 at z = 5.795 (Aerith A, B, and C). Aerith A, located behind the quasar with an impact parameter D^{\perp} = 278 \pm 8 pkpc, provides the first detection of an Lyα transverse proximity effect. We model the transmission and show that it constrains the onset of J0836ʼs quasar phase to 0.2Myr < 28Myr < t in the past. The second object, Aerith B at a distance D < 912 pkpc from the quasar, displays a bright and broad double-peaked Lyα emission line. The peak separation implies a low ionizing f_{esc} \leqslant 1%. We fit the Lyα line with an outflowing shell model, finding a typical central density log N_{HI}/cm^{-2} = 19.3_{-0.2}^{+0.8}, outflow velocity v_{out} = 16_{-11}^{+4}km s^{-1}, and gas temperature log T/K = 3.8_{-0.7}^{+0.8} compared to 2 < z < 3 analog LAEs. We detect object Aerith C via an Lyα emission line at z = 5.726. This corresponds with the edge of the quasar’s proximity zone (Dz < 0.02), suggesting that the proximity zone is truncated by a density fluctuation. Via the analyses conducted here, we illustrate how proximate LAEs offer unique insight into the ionizing properties of both quasars and galaxies during hydrogen reionization

New constraints on quasar evolution: broad-line velocity shifts over 1.5 ≲ z ≲ 7.5

We present the results of a model-independent investigation of the rest-frame UV spectra from a comprehensive sample of $394$ quasars in the redshift range $1.5\leq z \leq 7.5$. We fit the main Broad Emission Lines (BELs) in the rest-frame range $1280 \text{\AA} \leq \lambda \leq 3000 \text{\AA}$ (O I, C II, Si IV, C III, C IV and Mg II) with a lightly-supervised spline fitting technique. Redshifts are derived from the peaks of each fitted BEL and used to compute relative velocity shifts. We show that our method gives unbiased velocity shifts and is insensitive to spectral resolution and instrumental parameters. It is found that the average blueshift of the \cfour\, line with respect to several low-ionisation lines in luminosity-matched samples does not significantly evolve over $1.5\gtrsim z\gtrsim6$. However, the average blueshift increases significantly by a factor $\sim 2.5$ at $z\gtrsim 6$. We propose that this redshift evolution can be explained by \cfour\, winds launched perpendicularly to an accretion disk with increased torus opacity at high-redshift, coupled with a potential orientation-driven selection bias. Our results open new exciting avenues of investigation into young quasars in the reionisation epoch

The role of galaxies and AGNs in reionizing the IGM – II. Metal-tracing the faint sources of reionization at 5 ≲ z ≲ 6

We present a new method to study the contribution of faint sources to the ultraviolet background using the 1D correlation of metal absorbers with the intergalactic medium transmission in a quasi-stellar object (QSO) sightline. We take advantage of a sample of 25 high signal-to-noise ratio QSO spectra to retrieve 150 triply-ionized carbon (C IV) absorbers at 4.5 ≲ z ≲ 6.2, of which 37 systems whose expected H I absorption lie in the Lyman-α forest. We derive improved constraints on the cosmic density of C IV at 4.3 < z < 6.2 and infer from abundance matching that C IV absorbers trace MUV ≲ −16 galaxies. Correlation with the Lyman-α forest of the QSOs indicates that these objects are surrounded by a highly opaque region at r ≲ 5 cMpc h−1 followed by an excess of transmission at r ≳ 10 cMpc h−1 detected at 2.7σ. This is in contrast to equivalent measurements at lower redshifts where only the opaque trough is detected. We interpret this excess as a statistical enhancement of the local photoionization rate due to clustered faint galaxies around the C IV absorbers. Using the analytical framework described in Paper I of this series, we derive a constraint on the average product of the escape fraction and the Lyman continuum photon production efficiency of the galaxy population clustered around the C IV absorbers, log⟨fescξion⟩/[erg−1Hz]=25.01+0.30−0.19⁠. This implies that faint galaxies beyond the reach of current facilities may have harder radiation fields and/or larger escape fractions than currently detected objects at the end of the reionization epoch

Utilization of a deoxynucleoside diphosphate substrate by HIV reverse transcriptase

Background: Deoxynucleoside triphosphates (dNTPs) are the normal substrates for DNA sysnthesis is catalyzed by polymerases such as HIV-1 reverse transcriptase (RT). However, substantial amounts of deoxynucleoside diphosphates (dNDPs) are also present in the cell. Use of dNDPs in HIV-1 DNA sysnthesis could have significant implications for the efficacy of nucleoside RT inhibitors such as AZT which are first line therapeutics fro treatment of HIV infection. Our earlier work on HIV-1 reverse transcriptase (RT) suggested that the interaction between the γ phosphate of the incoming dNTP and RT residue K65 in the active site is not essential for dNTP insertion, implying that this polymerase may be able to insert dNPs in addition to dNTPs. Methodology/Principal Findings: We examined the ability of recombinant wild type (wt) and mutant RTs with substitutions at residue K65 to utilize a dNDP substrate in primer extension reactions. We found that wild type HIV-1 RT indeed catalyzes incorporation of dNDP substrates whereas RT with mutations of residue K645 were unable to catalyze this reaction. Wild type HIV-1 RT also catalyzed the reverse reaction, inorganic phosphate-dependent phosphorolysis. Nucleotide-mediated phosphorolytic removal of chain-terminating 3′-terminal nucleoside inhibitors such as AZT forms the basis of HIV-1 resistance to such drugs, and this removal is enhanced by thymidine analog mutations (TAMs). We found that both wt and TAM-containing RTs were able to catalyze Pi-mediated phosphorolysis of 3′-terminal AZT at physiological levels of Pi with an efficacy similar to that for ATP-dependent AZT-excision. Conclusion: We have identified two new catalytic function of HIV-1 RT, the use of dNDPs as substrates for DNA synthesis, and the use of Pi as substrate for phosphorolytic removal of primer 3′-terminal nucleotides. The ability to insert dNDPs has been documented for only one other DNA polymerase The RB69 DNA polymerase and the reverse reaction employing inorganic phosphate has not been documented for any DNA polymerase. Importantly, our results show that Pi-mediated phosphorolysis can contribute to AZT resistance and indicates that factors that influence HIV resistance to AZT are more complex than previously appreciated. © 2008 Garforth et al

The role of galaxies and AGN in reionising the IGM -- III : IGM-galaxy cross-correlations at z~6 from 8 quasar fields with DEIMOS and MUSE

We present improved results of the measurement of the correlation between galaxies and the intergalactic medium transmission at the end of reionization. We have gathered a sample of 13 spectroscopically confirmed Lyman-break galaxies (LBGs) and 21 Lyman-α emitters (LAEs) at angular separations 20 arcsec ≲ θ ≲ 10 arcmin (∼0.1–4 pMpc at z ∼ 6) from the sightlines to eight background z ≳ 6 quasars. We report for the first time the detection of an excess of Lyman-α transmission spikes at ∼10–60 cMpc from LAEs (3.2σ) and LBGs (1.9σ). We interpret the data with an improved model of the galaxy–Lyman-α transmission and two-point cross-correlations, which includes the enhanced photoionization due to clustered faint sources, enhanced gas densities around the central bright objects and spatial variations of the mean free path. The observed LAE(LBG)–Lyman-α transmission spike two-point cross-correlation function (2PCCF) constrains the luminosity-averaged escape fraction of all galaxies contributing to reionization to ⟨fesc⟩MUV−20(2σ)⁠) is necessary to reproduce the observed 2PCCF and that reionization might be driven by different sub-populations around LBGs and LAEs at z ∼ 6

Solving the Uncapacitated Single Allocation p-Hub Median Problem on GPU

A parallel genetic algorithm (GA) implemented on GPU clusters is proposed to solve the Uncapacitated Single Allocation p-Hub Median problem. The GA uses binary and integer encoding and genetic operators adapted to this problem. Our GA is improved by generated initial solution with hubs located at middle nodes. The obtained experimental results are compared with the best known solutions on all benchmarks on instances up to 1000 nodes. Furthermore, we solve our own randomly generated instances up to 6000 nodes. Our approach outperforms most well-known heuristics in terms of solution quality and time execution and it allows hitherto unsolved problems to be solved