The objective of this study was to assess the durability of response of dolutegravir (DTG) as an antiretroviral core agent by comparing its efficacy and safety with other recommended or commonly used ...core agents up to 96-weeks (W96).
A previously published systematic review was updated to identify phase 3/4 randomised controlled trials (RCTs) of core agents in treatment-naïve HIV-1 patients. Efficacy virologic suppression (VS), CD4
cell change from baseline and safety adverse events AEs, discontinuations, drug-related AEs DRAEs were analysed at W96 using Bayesian network meta-analysis (NMA) adjusting for nucleoside/nucleotide reverse transcriptase inhibitors' (NRTIs') backbone. Subgroups of patients with VL > 100,000 copies/mL or CD4
≤ 200 cells/μL at baseline were analysed separately.
The NMA included 20 studies reporting data at W96. A higher proportion of patients receiving DTG achieved VS compared to those on protease inhibitors PI:Range:8.7%(CrI:3.1,16.0)-19.9%(10.8,30.5), efavirenz EFV:6.9%(1.3,10.8) and cobicistat-boosted elvitegravir EVG/c:8.2%(0.2,17.4), and similar but numerically higher compared to rilpivirine RPV:5.0%(- 2.8,12.5), raltegravir RAL:2.9%(- 1.6,7.7) and bictegravir BIC:2.7%(- 2.7,10.6). The probability that more patients on DTG would achieve VS at W96 compared to any other core agent was greater than 80%. A higher proportion of patients on DTG achieved VS compared to PI/rs Range:33.1%(13.6,50.4)-45.3%(24.1,61.6) and RAL 16.7%(3.3,31.2) in patients with VL > 100,000 copies/mL at baseline, and similar VS was achieved in patients with CD4
≤ 200 cells/μL at baseline. DTG also achieved greater increase in CD4
cells from baseline compared to EFV 32.6(10.7,54.7), ritonavir-boosted darunavir DRV/r:25.7(3.6,48.1) and BIC 24.7(1.5,47.7). Patients receiving DTG had lower odds of discontinuing therapy by W96 compared to PI/rs, EFV, RAL and EVG/c. Patients on DTG had lower odds of experiencing an adverse event (AE) compared to patients on EFV odds ratio:0.6(0.3,0.9), ATV/r 0.4(0.3,0.6) and LPV/r 0.3(0.2,0.5). For patients on DTG, the odds of experiencing a drug-related AE were lower than the odds for patients on EFV 0.3(0.2,0.4), comparable to patients on RAL 1.1(0.8,1.4) and higher than those on BIC 1.5(1.1,2.0).
Un-boosted integrase inhibitors had better efficacy and similar safety compared to PI/rs at W96 in treatment-naïve patients with HIV-1, with DTG being among the most efficacious core agent, particularly in patients with baseline VL > 100,000 copies/mL or ≤ 200 CD4
cells/μL, who can be difficult to treat.
The mechanisms leading to latency and reactivation of human tuberculosis are still unclear, mainly due to the lack of standardized animal models for latent mycobacterial infection. In this ...longitudinal study of the progression of a mycobacterial disease in adult zebrafish, we show that an experimental intraperitoneal infection with a low dose (≈ 35 bacteria) of Mycobacterium marinum, results in the development of a latent disease in most individuals. The infection is characterized by limited mortality (25%), stable bacterial loads 4 weeks following infection and constant numbers of highly organized granulomas in few target organs. The majority of bacteria are dormant during a latent mycobacterial infection in zebrafish, and can be activated by resuscitation promoting factor ex vivo. In 5-10% of tuberculosis cases in humans, the disease is reactivated usually as a consequence of immune suppression. In our model, we are able to show that reactivation can be efficiently induced in infected zebrafish by γ-irradiation that transiently depletes granulo/monocyte and lymphocyte pools, as determined by flow cytometry. This immunosuppression causes reactivation of the dormant mycobacterial population and a rapid outgrowth of bacteria, leading to 88% mortality in four weeks. In this study, the adult zebrafish presents itself as a unique non-mammalian vertebrate model for studying the development of latency, regulation of mycobacterial dormancy, as well as reactivation of latent or subclinical tuberculosis. The possibilities for screening for host and pathogen factors affecting the disease progression, and identifying novel therapeutic agents and vaccine targets make this established model especially attractive.
Highlights • A novel vaccine is needed to relieve the global tuberculosis burden. • Adult zebrafish is a well-established non-mammalian vertebrate model for studying mycobacterial infection. • We ...show in this paper that zebrafish can be immunized against mycobacterial infection using BCG or a DNA-based vaccine. • Vaccine-induced protection in zebrafish depends on the adaptive immune response. • Zebrafish is a promising new model for tuberculosis vaccine research including preclinical vaccine antigen identification.
Motivated by the challenge of capturing complex hierarchical chemical detail in natural material from a wide range of applications, the Maia detector array and integrated realtime processor have been ...developed to acquire X-ray fluorescence images using X-ray Fluorescence Microscopy (XFM). Maia has been deployed initially at the XFM beamline at the Australian Synchrotron and more recently, demonstrating improvements in energy resolution, at the P06 beamline at Petra III in Germany. Maia captures fine detail in element images beyond 100 M pixels. It combines a large solid-angle annular energy-dispersive 384 detector array, stage encoder and flux counter inputs and dedicated FPGA-based real-time event processor with embedded spectral deconvolution. This enables high definition imaging and enhanced trace element sensitivity to capture complex trace element textures and place them in a detailed spatial context. Maia hardware and software methods provide per pixel correction for dwell, beam flux variation, dead-time and pileup, as well as off-line parallel processing for enhanced throughput. Methods have been developed for real-time display of deconvoluted SXRF element images, depth mapping of rare particles and the acquisition of 3D datasets for fluorescence tomography and XANES imaging using a spectral deconvolution method that tracks beam energy variation.
The analysis of texture, major element and oxygen isotope compositions of cloudy garnet crystals from a metapelite sampled on Ikaria Island (Greece) is used to assess the model of growth and ...re‐equilibration of these garnet crystals and to reconstruct the pressure–temperature–fluid history of the sample. Garnet crystals show complex textural and chemical zoning. Garnet cores (100–200 μm) are devoid of fluid inclusions. They are characterized by growth zoning demonstrated by a bell‐shaped profile of spessartine component (7–3 mol.%), an increase in grossular from 14 to 22 mol.% and δ18O values between 9.5 ± 0.3‰ and 10.4 ± 0.2‰. Garnet inner rims (90–130 μm) are fluid inclusion‐rich and show a decreasing grossular component from 22 to 5 mol.%. The trend of the spessartine component observed in the inner rim allows two domains to be distinguished. In contrast to domain I, where the spessartine content shows the same trend as in the core, the spessartine content of domain II increases outwards from 2 to 14 mol.%. The δ18O values decrease towards the margins of the crystals to a lowest value of 7.4 ± 0.2‰. The outer rims (<10 μm) are devoid of fluid inclusions and have the same chemical composition as the outermost part of domain II of the inner rim. Garnet crystals underwent a four‐stage history. Stage 1: garnet growth during the prograde path in a closed system for oxygen. Garnet cores are remnants of this growth stage. Stage 2: garnet re‐equilibration by coupled dissolution–reprecipitation at the temperature peak (630 < T < 650 °C). This causes the creation of porosity as the coupled dissolution–reprecipitation process allows chemical (Ca) and isotopic (O) exchange between garnet inner rims and the matrix. The formation of the outer rim is related to the closure of porosity. Stage 3: garnet mode decreases during the early retrograde path, but garnet is still a stable phase. The resulting garnet composition is characterized by an increasing Mn content in the inner rim’s domain II caused by intracrystalline diffusion. Stage 4: dissolution of garnet during the late retrograde path as garnet is not a stable phase anymore. This last stage forms corroded garnet. This study shows that coupled dissolution–reprecipitation is a possible re‐equilibration process for garnet in metamorphic rocks and that intra‐mineral porosity is an efficient pathway for chemical and isotopic exchange between garnet and the matrix, even for otherwise slow diffusing elements.
Nodular chromite is a characteristic feature of ophiolitic podiform chromitite and there has been much debate about how it forms. Nodular chromite from the Troodos ophiolite in Cyprus is unusual in ...that it contains skeletal crystals enclosed within the centres of the nodules and interstitial to them. 3D imaging and electron backscatter diffraction have shown that the skeletal crystals within the nodules are single crystals that are surrounded by a rim of polycrystalline chromite. 3D analysis reveals that the skeletal crystals are partially or completely formed cage or hopper structures elongated along the axis. The rim is composed of a patchwork of chromite grains that are truncated on the outer edge of the rim. The skeletal crystals formed first from a magma supersaturated in chromite and silicate minerals crystallised from melt trapped between the chromite skeletal crystal blades as they grew. The formation of skeletal crystals was followed by a crystallisation event which formed a silicate-poor rim of chromite grains around the skeletal crystals. These crystals show a weak preferred orientation related to the orientation of the core skeletal crystal implying that they formed by nucleation and growth on this core, and did not form by random mechanical aggregation. Patches of equilibrium adcumulate textures within the rim attest to in situ development of such textures. The nodules were subsequently exposed to chromite undersaturated magma resulting in dissolution, recorded by truncated grain boundaries in the rim and a smooth outer surface to the nodule. None of these stages of formation require a turbulent magma. Lastly the nodules impinged on each other causing local deformation at points of contact.
Display omitted
•Troodos nodular chromite has a skeletal core that in 3D forms a hopper crystal.•EBSD reveals a polycrystalline nodule rim accreted to the core skeletal crystal.•The nodule rim contains adcumulate texture formed by primary crystallisation.•Grains on the outer edge of the nodule rim suffer dissolution and are truncated.•Nodules show evidence of chromite super-saturation followed by chromite under-saturation.
Background: Given the presence of neural progenitor cells (NPC) in the retina of other species capable of differentiating into multiple neural components, the authors report the presence of NPC in ...the adult human retina. A resident population of NPC suggests that the retina may constitutively replace neurons, photoreceptors, and glia. Methods: Adult human postmortem retinal explants and cell suspensions were used to generate cells in tissue culture that display the features of NPC. The phenotype of cells and differentiation into neurons was determined by immunocytochemistry. Dividing cells were labelled with 5-bromo-2-deoxyuridine (BrdU) and neurospheres were generated and passaged. Results: Cells labelled with nestin, neurofilament M (NFM), rhodopsin, or glial fibrillary acidic protein (GFAP) grew out from explant cultures. BrdU labelling of these cells occurred only with basic fibroblast growth factor (FGF-2). Dissociated retina and pars plana generated primary neurospheres. From primary neurospheres, NPC were passaged to generate secondary neurospheres, neurons, photoreceptors, and glia. BrdU labelling identified dividing cells from neurospheres that differentiated to express NFM and rhodopsin. Conclusion: The adult human retina contains NPC and may have the potential to replace neurons and photoreceptors. This has implications for the pathogenesis and treatment of retinal disorders and degenerations, including glaucoma, and those disorders associated with retinal scarring.
PDF
