Summary Background Our objective was to assess therapeutic non-inferiority of dual treatment with lopinavir–ritonavir and lamivudine to triple treatment with lopinavir–ritonavir plus two ...nucleos(t)ides for maintenance of HIV-1 viral suppression. Methods In this randomised, open-label, non-inferiority trial, we recruited patients from 32 HIV units in hospitals in Spain and France. Eligible patients were HIV-infected adults (aged ≥18 years) with HIV-1 RNA of less than 50 copies per mL, for at least 6 months on triple treatment with lopinavir–ritonavir (twice daily) plus lamivudine or emtricitabine and a second nucleos(t)ide, with no resistance or virological failure to these drugs, and no positive hepatitis B serum surface antigen. Investigators at each centre randomly assigned patients (1:1; block size of four; stratified by time to suppression <1 year or >1 year and nadir CD4 cell count <100 cells per μL or >100 cells per μL; computer-generated random sequence) to continue triple treatment or switch to dual treatment (oral lopinavir 400 mg and oral ritonavir 100 mg twice daily plus oral lamivudine 300 mg once daily). The primary endpoint was response to treatment in the intention-to-treat population (all randomised patients) at 48 weeks. The non-inferiority margin was 12%. This study is registered with ClinicalTrials.gov , number NCT01471821. Findings Between Oct 1, 2011, and April 1, 2013, we randomly assigned 250 participants to continue triple treatment (127 51% patients) or switch to dual treatment (123 49% patients). In the intention-to-treat population, 110 (86·6%) of 127 patients in the triple-treatment group responded to treatment versus 108 (87·8%) of 123 in the dual-treatment group (difference −1·2% 95% CI −9·6 to 7·3; p=0·92), meeting the criteria for non-inferiority. Serious adverse events occurred in eight (7%) patients in the triple-treatment group and five (4%) in the dual-treatment group (p=0·515), and study drug discontinuations due to adverse events occurred in four (3%) in the triple-treatment group and one (1%) in the dual-treatment group (p=0·223). Interpretation Dual treatment with lopinavir–ritonavir plus lamivudine has non-inferior therapeutic efficacy and is similarly tolerated to triple treatment. Funding AbbVie and Red Temática Cooperativa de Investigación en Sida.
To compare the visibility of the lamina cribrosa (LC) in optic disc images acquired from 60 glaucoma and 60 control subjects using three optical coherence tomography (OCT) devices, with and without ...enhanced depth imaging (EDI) and adaptive compensation (AC).
A horizontal B-scan was acquired through the center of the disc using two spectral-domain (Spectralis and Cirrus; with and without EDI) and a swept-source (DRI) OCT. Adaptive compensation was applied post acquisition to improve image quality. To assess LC visibility, four masked observers graded the 1200 images in a randomized sequence. The anterior LC was graded from 0 to 4, the LC insertions from 0 to 2, and the posterior LC either 0 or 1. The effect of EDI, AC, glaucoma severity, and other clinical/demographic factors on LC visibility was assessed using generalized estimating equations.
The anterior LC was the most detectable feature, followed by the LC insertions. Adaptive compensation improved anterior LC visibility independent of EDI. Cirrus+EDI+AC generated the greatest anterior LC visibility grades (2.79/4). For LC insertions visibility, DRI+AC was the best method (1.10/2). Visibility of the posterior LC was consistently poor. Neither glaucoma severity nor clinical/demographic factors consistently affected LC visibility.
Adaptive compensation is superior to EDI in improving LC visibility. Visibility of the posterior LC remains poor suggesting impracticality in using LC thickness as a glaucoma biomarker.
CD103
CD11b
dendritic cells (DCs) are unique to the intestine, but the factors governing their differentiation are unclear. Here we show that transforming growth factor receptor 1 (TGFβR1) has an ...indispensable, cell intrinsic role in the development of these cells. Deletion of Tgfbr1 results in markedly fewer intestinal CD103
CD11b
DCs and a reciprocal increase in the CD103
CD11b
dendritic cell subset. Transcriptional profiling identifies markers that define the CD103
CD11b
DC lineage, including CD101, TREM1 and Siglec-F, and shows that the absence of CD103
CD11b
DCs in CD11c-Cre.Tgfbr1
mice reflects defective differentiation from CD103
CD11b
intermediaries, rather than an isolated loss of CD103 expression. The defect in CD103
CD11b
DCs is accompanied by reduced generation of antigen-specific, inducible FoxP3
regulatory T cells in vitro and in vivo, and by reduced numbers of endogenous Th17 cells in the intestinal mucosa. Thus, TGFβR1-mediated signalling may explain the tissue-specific development of these unique DCs.Developmental cues for the different dendritic cell (DC) subsets in the intestine are yet to be defined. Here the authors show that TGFβR1 signalling is needed for development of CD103
CD11b
intestinal DCs from CD103
CD11b
cells and that they contribute to the generation of Th17 and regulatory T cells.
Antiretroviral preexposure prophylaxis has been shown to reduce the risk of human immunodeficiency virus type 1 (HIV-1) infection in some studies, but conflicting results have been reported among ...studies, probably due to challenges of adherence to a daily regimen.
We conducted a double-blind, randomized trial of antiretroviral therapy for preexposure HIV-1 prophylaxis among men who have unprotected anal sex with men. Participants were randomly assigned to take a combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) or placebo before and after sexual activity. All participants received risk-reduction counseling and condoms and were regularly tested for HIV-1 and HIV-2 and other sexually transmitted infections.
Of the 414 participants who underwent randomization, 400 who did not have HIV infection were enrolled (199 in the TDF-FTC group and 201 in the placebo group). All participants were followed for a median of 9.3 months (interquartile range, 4.9 to 20.6). A total of 16 HIV-1 infections occurred during follow-up, 2 in the TDF-FTC group (incidence, 0.91 per 100 person-years) and 14 in the placebo group (incidence, 6.60 per 100 person-years), a relative reduction in the TDF-FTC group of 86% (95% confidence interval, 40 to 98; P=0.002). Participants took a median of 15 pills of TDF-FTC or placebo per month (P=0.57). The rates of serious adverse events were similar in the two study groups. In the TDF-FTC group, as compared with the placebo group, there were higher rates of gastrointestinal adverse events (14% vs. 5%, P=0.002) and renal adverse events (18% vs. 10%, P=0.03).
The use of TDF-FTC before and after sexual activity provided protection against HIV-1 infection in men who have sex with men. The treatment was associated with increased rates of gastrointestinal and renal adverse events. (Funded by the National Agency of Research on AIDS and Viral Hepatitis ANRS and others; ClinicalTrials.gov number, NCT01473472.).
Delirium, a syndrome characterized by an acute change in attention, awareness and cognition, is caused by a medical condition that cannot be better explained by a pre-existing neurocognitive ...disorder. Multiple predisposing factors (for example, pre-existing cognitive impairment) and precipitating factors (for example, urinary tract infection) for delirium have been described, with most patients having both types. Because multiple factors are implicated in the aetiology of delirium, there are likely several neurobiological processes that contribute to delirium pathogenesis, including neuroinflammation, brain vascular dysfunction, altered brain metabolism, neurotransmitter imbalance and impaired neuronal network connectivity. The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) is the most commonly used diagnostic system upon which a reference standard diagnosis is made, although many other delirium screening tools have been developed given the impracticality of using the DSM-5 in many settings. Pharmacological treatments for delirium (such as antipsychotic drugs) are not effective, reflecting substantial gaps in our understanding of its pathophysiology. Currently, the best management strategies are multidomain interventions that focus on treating precipitating conditions, medication review, managing distress, mitigating complications and maintaining engagement to environmental issues. The effective implementation of delirium detection, treatment and prevention strategies remains a major challenge for health-care organizations globally.
ABSTRACT
We present radio observations of the most slowly rotating known radio pulsar PSR J0250+5854. With a 23.5-s period, it is close, or even beyond, the P-$\dot{P}$ diagram region thought to be ...occupied by active pulsars. The simultaneous observations with the Five-hundred-metre Aperture Spherical radio Telescope (FAST), the Chilbolton and Effelsberg Low Frequency Array (LOFAR) international stations, and New Extension in Nançay Upgrading loFAR (NenuFAR) represent a five-fold increase in the spectral coverage of this object, with the detections at 1250 (FAST) and 57 MHz (NenuFAR) being the highest and lowest frequency published, respectively, to date. We measure a flux density of 4 ± 2 $\mu$Jy at 1250 MHz and an exceptionally steep spectral index of $-3.5^{+0.2}_{-1.5}$, with a turnover below ∼95 MHz. In conjunction with observations of this pulsar with the Green Bank Telescope and the LOFAR Core, we show that the intrinsic profile width increases drastically towards higher frequencies, contrary to the predictions of conventional radius-to-frequency mapping. We examine polarimetric data from FAST and the LOFAR Core and conclude that its polar cap radio emission is produced at an absolute height of several hundreds of kilometres around 1.5 GHz, similar to other rotation-powered pulsars across the population. Its beam is significantly underfilled at lower frequencies, or it narrows because of the disappearance of conal outriders. Finally, the results for PSR J0250+5854 and other slowly spinning rotation-powered pulsars are contrasted with the radio-detected magnetars. We conclude that magnetars have intrinsically wider radio beams than the slow rotation-powered pulsars, and that consequently the latter’s lower beaming fraction is what makes objects such as PSR J0250+5854 so scarce.
Key Uncertainties in the Recent Air‐Sea Flux of CO2 Woolf, D.K.; Shutler, J.D.; Goddijn‐Murphy, L. ...
Global biogeochemical cycles,
December 2019, 20191201, 2019-12, Letnik:
33, Številka:
12
Journal Article
Recenzirano
Odprti dostop
The contemporary air‐sea flux of CO2 is investigated by the use of an air‐sea flux equation, with particular attention to the uncertainties in global values and their origin with respect to that ...equation. In particular, uncertainties deriving from the transfer velocity and from sparse upper ocean sampling are investigated. Eight formulations of air‐sea gas transfer velocity are used to evaluate the combined standard uncertainty resulting from several sources of error. Depending on expert opinion, a standard uncertainty in transfer velocity of either ~5% or ~10% can be argued and that will contribute a proportional error in air‐sea flux. The limited sampling of upper ocean fCO2 is readily apparent in the Surface Ocean CO2 Atlas databases. The effect of sparse sampling on the calculated fluxes was investigated by a bootstrap method, that is, treating each ship cruise to an oceanic region as a random episode and creating 10 synthetic data sets by randomly selecting episodes with replacement. Convincing values of global net air‐sea flux can only be achieved using upper ocean data collected over several decades but referenced to a standard year. The global annual referenced values are robust to sparse sampling, but seasonal and regional values exhibit more sampling uncertainty. Additional uncertainties are related to thermal and haline effects and to aspects of air‐sea gas exchange not captured by standard models. An estimate of global net CO2 exchange referenced to 2010 of −3.0 ± 0.6 Pg C/year is proposed, where the uncertainty derives primarily from uncertainty in the transfer velocity.
Plain Language Summary
The oceanic carbon sink reduces the rate of accumulation of CO2 in the atmosphere but is also responsible for the acidification of the ocean. One method of estimating the size of the oceanic carbon sink depends on a calculation of upward and downward flows of CO2 at the sea surface. This study revisits this calculation using updated knowledge of the transfer processes at the sea surface and the results of a large international collaborative effort (Surface Ocean CO2 Atlas) to collect and compile measurements of CO2 in the upper ocean. Greater sampling of the oceans improves estimates, but direct calculation in each year is not practical. Instead, we calculate fluxes in a recent year (2010) using upper ocean measurements of CO2 over many years. The remaining uncertainty is dominated by limited knowledge of the efficiency of stirring of gas across the sea surface, the air‐sea transfer velocity. The study suggests a relatively large downward flow of CO2 into the ocean compared to previous applications of this method and other methods to estimate the oceanic carbon sink. Increased knowledge is rewarded by reduced uncertainty in the net global flux; that flux is estimated at −3.0 ± 0.6 Pg C/year. Further understanding of transfer velocities and better sampling may reduce the uncertainty in the future.
Key Points
Increased understanding of air‐sea gas transfer processes and better sampling of the upper ocean enables higher confidence in calculations of air‐sea CO2 fluxes
The calculations imply a relatively large global net air‐to‐sea flux of −3.0 Pg C/year (referenced to 2010)
This flux is known within 0.6 Pg C/year, where uncertainty in air‐sea transfer velocity is the largest contribution to the combined uncertainty
We investigate the beaming of 11 Io‐Jupiter decametric (Io‐DAM) emissions observed by Juno/Waves, the Nançay Decameter Array, and NenuFAR. Using an up‐to‐date magnetic field model and three methods ...to position the active Io Flux Tube (IFT), we accurately locate the radiosources and determine their emission angle θ from the local magnetic field vector. These methods use (a) updated models of the IFT equatorial lead angle, (b) ultraviolet (UV) images of Jupiter's aurorae, and (c) multi‐point radio measurements. The kinetic energy Ee− of source electrons is then inferred from θ in the framework of the Cyclotron Maser Instability. The precise position of the active IFT achieved from methods (b and c) can be used to test the effective plasma density of the Io torus. Simultaneous radio/UV observations reveal that multiple Io‐DAM arcs are associated with multiple UV spots and provide the first direct evidence of an Io‐DAM arc associated with a trans‐hemispheric beam UV spot. Multi‐point radio observations probe the Io‐DAM sources at various altitudes, times and hemispheres. Overall, θ varies a function of frequency (altitude), by decreasing from 75°−80° to 70°−75° over 10−40 MHz with slightly larger values in the northern hemisphere, and independently varies as a function of time (or longitude of Io). Its uncertainty of a few degrees is dominated by the error on the longitude of the active IFT. The inferred values of Ee− also vary as a function of altitude and time. For the 11 investigated cases, they range from 3 to 16 keV, with a 6.6 ± 2.7 keV average.
Plain Language Summary
The auroral decametric emissions of Jupiter induced by Io (Io‐DAM) are radiated along high latitude magnetic field lines at large aperture angles from the local magnetic field vector, forming a thin hollow cone. In this study, we determine the emission angle θ of 11 cases of Io‐DAM emissions observed by Juno/Waves, the Nançay Decameter Array and the NenuFAR radiotelescope with an up‐to‐date magnetic field model and three different methods aimed at minimizing the uncertainty on θ. These methods accurately position the active Io magnetic Flux Tube (IFT) which hosts the decametric radiosources by using (a) models of the active IFT, (b) ultraviolet images of Jupiter's aurorae, and (c) multi‐point radio measurements. most notably, we found that θ varies within 70°–80° as a function of the source altitude along the field line and independently as a function of time. Assuming that the Io‐DAM emissions are driven by the Cyclotron Maser Instability from energetic electrons, we infer from the measured θ the kinetic energy Ee− of the source electrons accelerated by the Io‐Jupiter interaction. The obtained values of Ee− also depend on altitude and time and vary between 3 and 16 keV, with a ∼6.5 keV average, in agreement with Juno in situ measurements.
Key Points
We derive the Io‐decametric emission angle θ from Juno, Nançay Decameter Array, and NenuFAR data using 3 methods to locate the radio sources
θ(f) decreases from 75°−80° to 70°−75° over 10–40 MHz and varies both as a function of frequency (or altitude) and time (or longitude of Io)
The inferred electron energies amplifying Io‐decametric waves range from 3 to 16 keV also vary as a function of altitude and time
In this placebo-controlled phase II randomized clinical trial, 103 human immunodeficiency virus type 1 (HIV-1)-infected patients under cART (combined antiretroviral treatment) were randomized 2:1 to ...receive either 3 doses of DNA GTU-MultiHIV B (coding for Rev, Nef, Tat, Gag, and gp160) at week 0 (W0), W4, and W12, followed by 2 doses of LIPO-5 vaccine containing long peptides from Gag, Pol, and Nef at W20 and W24, or placebo. Analytical treatment interruption (ATI) was performed between W36 to W48. At W28, vaccinees experienced an increase in functional CD4
T-cell responses (
< 0.001 for each cytokine compared to W0) measured, predominantly against Gag and Pol/Env, and an increase in HIV-specific CD8
T cells producing interleukin 2 (IL-2) and tumor necrosis factor alpha (TNF-α) (
= 0.001 and 0.013, respectively), predominantly against Pol/Env and Nef. However, analysis of T-cell subsets by mass cytometry in a subpopulation showed an increase in the W28/W0 ratio for memory CD8
T cells coexpressing exhaustion and senescence markers such as PD-1/TIGIT (
= 0.004) and CD27/CD57 (
= 0.044) in vaccinees compared to the placebo group. During ATI, all patients experienced viral rebound, with the maximum observed HIV RNA level at W42 (median, 4.63 log
copies cp/ml; interquartile range IQR, 4.00 to 5.09), without any difference between arms. No patient resumed cART for CD4 cell count drop. Globally, the vaccine strategy was safe. However, a secondary HIV transmission during ATI was observed. These data show that the prime-boost combination of DNA and LIPO-5 vaccines elicited broad and polyfunctional T cells. The contrast between the quality of immune responses and the lack of potent viral control underscores the need for combined immunomodulatory strategies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01492985.)
In this placebo-controlled phase II randomized clinical trial, we evaluated the safety and immunogenicity of a therapeutic prime-boost vaccine strategy using a recombinant DNA vaccine (GTU-MultiHIV B clade) followed by a boost vaccination with a lipopeptide vaccine (HIV-LIPO-5) in HIV-infected patients on combined antiretroviral therapy. We show here that this prime-boost strategy is well tolerated, consistently with previous studies in HIV-1-infected individuals and healthy volunteers who received each vaccine component individually. Compared to the placebo group, vaccinees elicited strong and polyfunctional HIV-specific CD4
and CD8
T-cell responses. However, these immune responses presented some qualitative defects and were not able to control viremia following antiretroviral treatment interruption, as no difference in HIV viral rebound was observed in the vaccine and placebo groups. Several lessons were learned from these results, pointing out the urgent need to combine vaccine strategies with other immune-based interventions.
LOFAR sparse image reconstruction Garsden, H.; Girard, J. N.; Starck, J. L. ...
Astronomy and astrophysics (Berlin),
03/2015, Letnik:
575, Številka:
A90
Journal Article
Recenzirano
Odprti dostop
Context. The LOw Frequency ARray (LOFAR) radio telescope is a giant digital phased array interferometer with multiple antennas distributed in Europe. It provides discrete sets of Fourier components ...of the sky brightness. Recovering the original brightness distribution with aperture synthesis forms an inverse problem that can be solved by various deconvolution and minimization methods. Aims. Recent papers have established a clear link between the discrete nature of radio interferometry measurement and the “compressed sensing” (CS) theory, which supports sparse reconstruction methods to form an image from the measured visibilities. Empowered by proximal theory, CS offers a sound framework for efficient global minimization and sparse data representation using fast algorithms. Combined with instrumental direction-dependent effects (DDE) in the scope of a real instrument, we developed and validated a new method based on this framework. Methods. We implemented a sparse reconstruction method in the standard LOFAR imaging tool and compared the photometric and resolution performance of this new imager with that of CLEAN-based methods (CLEAN and MS-CLEAN) with simulated and real LOFAR data. Results. We show that i) sparse reconstruction performs as well as CLEAN in recovering the flux of point sources; ii) performs much better on extended objects (the root mean square error is reduced by a factor of up to 10); and iii) provides a solution with an effective angular resolution 2−3 times better than the CLEAN images. Conclusions. Sparse recovery gives a correct photometry on high dynamic and wide-field images and improved realistic structures of extended sources (of simulated and real LOFAR datasets). This sparse reconstruction method is compatible with modern interferometric imagers that handle DDE corrections (A- and W-projections) required for current and future instruments such as LOFAR and SKA.
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