Primaquine to reduce transmission of Plasmodium falciparum malaria in Mali : a single-blind, dose-ranging, adaptive randomised phase 2 trial

Background Single low doses of primaquine, when added to artemisinin-based combination therapy, might prevent transmission of Plasmodium falciparum malaria to mosquitoes. We aimed to establish the activity and safety of four low doses of primaquine combined with dihydroartemisinin-piperaquine in male patients in Mali. Methods In this phase 2, single-blind, dose-ranging, adaptive randomised trial, we enrolled boys and men with uncomplicated P falciparum malaria at the Malaria Research and Training Centre (MRTC) field site in Ouelessebougou, Mali. All participants were confirmed positive carriers of gametocytes through microscopy and had normal function of glucose-6-phosphate dehydrogenase (G6PD) on colorimetric quantification In the first phase, participants were randomly assigned (1:1:1) to one of three primaquine doses: 0 mg/kg (control), 0.125 mg/kg, and 0.5 mg/kg. Randomisation was done with a computer-generated randomisation list (in block sizes of six) and concealed with sealed, opaque envelopes. In the second phase, different participants were sequentially assigned (1:1) to 0.25 mg/kg primaquine or 0.0625 mg/kg primaquine. Primaquine tablets were dissolved into a solution and administered orally in a single dose. Participants were also given a 3 day course of dihydroartemisinin-piperaquine, administered by weight (320 mg dihydroartemisinin and 40 mg piperaquine per tablet). Outcome assessors were masked to treatment allocation, but participants were permitted to find out group assignment. Infectivity was assessed through membrane feeding assays, which were optimised through the beginning part of phase one. The primary efficacy endpoint was the mean within-person percentage change in mosquito infectivity 2 days after primaquine treatment in participants who completed the study after optimisation of the infectivity assay, had both a pre-treatment infectivity measurement and at least one follow-up infectivity measurement, and who were given the correct primaquine dose. The safety endpoint was the mean within-person change in haemoglobin concentration during 28 days of study follow-up in participants with at least one follow-up visit. This study is registered with ClinicalTrials.gov, number NCT01743820. Findings Between Jan 2,2013, and Nov 27,2014, we enrolled 81 participants. In the primary analysis sample (n=71), participants in the 0.25 mg/kg primaquine dose group (n=15) and 0.5 mg/kg primaquine dose group (n=14) had significantly lower mean within-person reductions in infectivity at day 2-92.6% (95% CI 78.3-100; p=0.0014) for the 0.25 mg/kg group; and 75.0% (45.7-100; p=0.014) for the 0.5 mg/kg primaquine group compared with those in the control group (n=14; 11.3% [-27.4 to 50.0]). Reductions were not significantly different from control for participants assigned to the 0.0625 mg/kg dose group (n=16; 41.9% [1.4-82.5]; p=0.16) and the 0.125 mg/kg dose group (n=12; 54.9% [13.4-96.3]; p=0.096). No clinically meaningful or statistically significant drops in haemoglobin were recorded in any individual in the haemoglobin analysis (n=70) during follow-up. No serious adverse events were reported and adverse events did not differ between treatment groups. Interpretation A single dose of 0.25 mg/kg primaquine, given alongside dihydroartemisinin-piperaquine, was safe and efficacious for the prevention of P falciparum malaria transmission in boys and men who are not deficient in G6PD. Future studies should assess the safety of single-dose primaquine in G6PD-deficient individuals to define the therapeutic range of primaquine to enable the safe roll-out of community interventions with primaquine.Peer reviewe

The potential role of long-acting injectable cabotegravir-rilpivirine in the treatment of HIV in sub-Saharan Africa : a modelling analysis

BACKGROUND: The use of a combination of the integrase inhibitor, cabotegravir, and the non-nucleoside reverse transcriptase inhibitor, rilpivirine, in a long-acting injectable form is being considered as an antiretroviral treatment option for people with HIV in sub-Saharan Africa. We aimed to model the effects of injectable cabotegravir-rilpivirine to help to inform its potential effectiveness and cost-effectiveness under different possible policies for its introduction. METHODS: We used an existing individual-based model of HIV to predict the effects of introducing monthly injections of cabotegravir-rilpivirine for people with HIV in low-income settings in sub-Saharan Africa. We evaluated policies in the context of 1000 setting scenarios that reflected characteristics of HIV epidemics and programmes in sub-Saharan Africa. We compared three policies for introduction of injectable cabotegravir-rilpivirine with continued use of dolutegravir-based oral regimens for: all individuals on antiretroviral therapy (ART); individuals with a recently measured viral load of more than 1000 copies per mL (signifying poor adherence to oral drugs, and often associated with drug resistance); and individuals with a recently measured viral load of less than 1000 copies per mL (a group with a lower prevalence of pre-existing drug resistance). We also did cost-effectiveness analysis, taking a health system perspective over a 10 year period, with 3% discounting of disability-adjusted life-years (DALYs) and costs. A cost-effectiveness threshold of US$500 per DALY averted was used to establish if a policy was cost-effective. FINDINGS: In our model, all policies involving the introduction of injectable cabotegravir-rilpivirine were predicted to lead to an increased proportion of people with HIV on ART, increased viral load suppression, and decreased AIDS-related mortality, with lesser benefits in people with a recently measured viral load of less than 1000 copies per mL. Its introduction is also predicted to lead to increases in resistance to integrase inhibitors and non-nucleoside reverse transcriptase inhibitors if introduced in all people with HIV on ART or in those with a recently measured viral load of less than 1000 copies per mL, but to a lesser extent if introduced in people with more than 1000 copies per mL due to concentration of its use in people less adherent to oral therapy. Consistent with the effect on AIDS-related mortality, all approaches to the introduction of injectable cabotegravir-rilpivirine are predicted to avert DALYs. Assuming a cost of$120 per person per year, use of this regimen in people with a recently measured viral load of more than 1000 copies per mL was borderline cost-effective (median cost per DALY averted across setting scenarios $404). The other approaches considered for its use are unlikely to be cost-effective unless the cost per year of injectable cabotegravir-rilpivirine is considerably reduced. INTERPRETATION: Our modelling suggests that injectable cabotegravir-rilpivirine offers potential benefits; however, to be a cost-effective option, its introduction might need to be carefully targeted to individuals with HIV who might otherwise have suboptimal adherence to ART. As data accumulate from trials and implementation studies, such findings can be incorporated into the model to better inform on the full consequences of policy alternatives. FUNDING: Bill & Melinda Gates Foundation, including through the HIV Modelling Consortium (OPP1191655)

Anaerobic Decomposition of Switchgrass by Tropical Soil-Derived Feedstock-Adapted Consortia

Tropical forest soils decompose litter rapidly with frequent episodes of anoxic conditions, making it likely that bacteria using alternate terminal electron acceptors (TEAs) play a large role in decomposition. This makes these soils useful templates for improving biofuel production. To investigate how TEAs affect decomposition, we cultivated feedstock-adapted consortia (FACs) derived from two tropical forest soils collected from the ends of a rainfall gradient: organic matter-rich tropical cloud forest (CF) soils, which experience sustained low redox, and iron-rich tropical rain forest (RF) soils, which experience rapidly fluctuating redox. Communities were anaerobically passed through three transfers of 10 weeks each with switchgrass as a sole carbon (C) source; FACs were then amended with nitrate, sulfate, or iron oxide. C mineralization and cellulase activities were higher in CF-FACs than in RF-FACs. Pyrosequencing of the small-subunit rRNA revealed members of the Firmicutes, Bacteroidetes, and Alphaproteobacteria as dominant. RF- and CF-FAC communities were not different in microbial diversity or biomass. The RF-FACs, derived from fluctuating redox soils, were the most responsive to the addition of TEAs, while the CF-FACs were overall more efficient and productive, both on a per-gram switchgrass and a per-cell biomass basis. These results suggest that decomposing microbial communities in fluctuating redox environments are adapted to the presence of a diversity of TEAs and ready to take advantage of them. More importantly, these data highlight the role of local environmental conditions in shaping microbial community function that may be separate from phylogenetic structure

Using health worker opinions to assess changes in structural components of quality in a Cluster Randomized Trial.

BACKGROUND: The 'resource readiness' of health facilities to provide effective services is captured in the structure component of the classical Donabedian paradigm often used for assessment of the quality of care in the health sector. Periodic inventories are commonly used to confirm the presence (or absence) of equipment or drugs by physical observation or by asking those in charge to indicate whether an item is present or not. It is then assumed that this point observation is representative of the everyday status. However the availability of an item (consumables) may vary. Arguably therefore a more useful assessment for resources would be one that captures this fluctuation in time. Here we report an approach that may circumvent these difficulties. METHODS: We used self-administered questionnaires (SAQ) to seek health worker views of availability of key resources supporting paediatric care linked to a cluster randomized trial of a multifaceted intervention aimed at improving this care conducted in eight rural Kenyan district hospitals. Four hospitals received a full intervention and four a partial intervention. Data were collected pre-intervention and after 6 and 18 months from health workers in three clinical areas asked to score item availability using an 11-point scale. Mean scores for items common to all 3 areas and mean scores for items allocated to domains identified using exploratory factor analysis (EFA) were used to describe availability and explore changes over time. RESULTS: SAQ were collected from 1,156 health workers. EFA identified 11 item domains across the three departments. Mean availability scores for these domains were often <5/10 at baseline reflecting lack of basic resources such as oxygen, nutrition and second line drugs. An improvement in mean scores occurred in 8 out of 11 domains in both control and intervention groups. A calculation of difference in difference of means for intervention vs. control suggested an intervention effect resulting in greater changes in 5 out of 11 domains. CONCLUSION: Using SAQ data to assess resource availability experienced by health workers provides an alternative to direct observations that provide point prevalence estimates. Further the approach was able to demonstrate poor access to resources, change over time and variability across place

CD8+ T-Cell Interleukin-7 Receptor Alpha Expression as a Potential Indicator of Disease Status in HIV-Infected Children

Background: Initiation and modification of antiretroviral therapy in HIV-infected children depend on viral load and CD4+ T-cell count. However, these surrogates have limitations, and complementary immunological markers to assess therapeutic response are needed. Our aim was to evaluate CD8+ T-cell expression of CD127 as a marker of disease status in HIV-infected children, based on adult data suggesting its usefulness. We hypothesized that CD127 expression on CD8+ T-cells is lower in children with more advanced disease. Methods: In a cross-sectional evaluation, we used flow cytometry to measure CD127+ expression on CD8+ T-cells in whole blood from HIV-infected children with varying disease status. This was compared with expression of CD38 on this subset, currently used in clinical practice as a marker of disease status. Results: 51 HIV-infected children were enrolled. There was a strong positive correlation between CD127 expression on CD8+ T-cells and CD4+ T-cell count, and height and weight z-scores, and a strong negative correlation between CD127 expression and viral load. In contrast, we found no association between CD38 expression and these disease status markers. Conclusions: CD8+ T-cell CD127 expression is significantly higher in children with better HIV disease control, and may have a role as an immunologic indicator of disease status. Longitudinal studies are needed to determine the utility of this marker as a potential indicator of HIV disease progression

Characterization of Trapped Lignin-Degrading Microbes in Tropical Forest Soil

Lignin is often the most difficult portion of plant biomass to degrade, with fungi generally thought to dominate during late stage decomposition. Lignin in feedstock plant material represents a barrier to more efficient plant biomass conversion and can also hinder enzymatic access to cellulose, which is critical for biofuels production. Tropical rain forest soils in Puerto Rico are characterized by frequent anoxic conditions and fluctuating redox, suggesting the presence of lignin-degrading organisms and mechanisms that are different from known fungal decomposers and oxygen-dependent enzyme activities. We explored microbial lignin-degraders by burying bio-traps containing lignin-amended and unamended biosep beads in the soil for 1, 4, 13 and 30 weeks. At each time point, phenol oxidase and peroxidase enzyme activity was found to be elevated in the lignin-amended versus the unamended beads, while cellulolytic enzyme activities were significantly depressed in lignin-amended beads. Quantitative PCR of bacterial communities showed more bacterial colonization in the lignin-amended compared to the unamended beads after one and four weeks, suggesting that the lignin supported increased bacterial abundance. The microbial community was analyzed by small subunit 16S ribosomal RNA genes using microarray (PhyloChip) and by high-throughput amplicon pyrosequencing based on universal primers targeting bacterial, archaeal, and eukaryotic communities. Community trends were significantly affected by time and the presence of lignin on the beads. Lignin-amended beads have higher relative abundances of representatives from the phyla Actinobacteria, Firmicutes, Acidobacteria and Proteobacteria compared to unamended beads. This study suggests that in low and fluctuating redox soils, bacteria could play a role in anaerobic lignin decomposition

CHOMPTT (CubeSat Handling of Multisystem Precision Timing Transfer): From Concept to Launch Pad

Here we present the evolution of a student satellite mission: CHOMPTT (CubeSat Handling of Multisystem Precision Time Transfer), from its original concept as a candidate for the University NanoSatellite Program 8 (UNP8), to a spacecraft ready for launch in Fall of 2017 on ELaNa XIX (Educational Launch of Nanosatellites). The 3U CubeSat houses a 1 kg, 1U OPTI (Optical Precision Timing Instrument) payload, designed and built at the University of Florida, and a 1.5U EDSNNODeS-derived bus from NASA Ames Research Center. The OPTI payload comprises of: 1) a supervisor board that handles payload data, power regulation, and mode settings, 2) an optics assembly of six 1 cm retroreflectors and four laser beacon diodes for ground-tracking; and 3) two fully redundant timing channels, each consisting of: a chip-scale atomic clock, a microprocessor with clock counter, a picosecond event timer, and an avalanche photodetector (APD) with band-pass filter. Several iterations of OPTI have been developed, tested, and designed to achieve its current functionality and design a laboratory breadboard design, a 1.5U high altitude balloon design, engineering unit design, and its current flight unit design. In-lab testing of the current OPTI design indicates a short-term precision of 100 ps, equivalent to a range accuracy of 3 cm necessary to achieve our primary objective of 200 ps time transfer error, and a long-term timing accuracy of 20 ns over one orbit (1.5 hours). After the spacecraft reaches its nominal 500 km orbit at a 85 degree inclination, an experimental laser ranging facility at Kennedy Space Center in Florida, will track and emit 1064 nm nanosecond optical pulses at the CHOMPTT spacecraft. The laser pulses will then reflect off the retroreflector array mounted on the nadir face of CHOMPTT, and return the pulse to the laser ranging facility where the laser ranging facility will record the round-trip duration of the laser pulses. At the same time the pulse arrives at the spacecraft and is reflected by the array, an APD will record the arrival time of the pulses at the nanosatellite. By comparing the arrival of the pulse at the CubeSat and the duration of the round-trip of the laser pulse, the clock discrepancy between the ground and CubeSat atomic clocks can be determined, in addition to the CubeSats range from the facility. The design and verification of the flight version of CHOMPTT will be reviewed and an overview of the lifetime development and progression of CHOMPTT from the inception to launch pad will be presented

Magnetic Susceptibility Instrument for Magnetically Inhomogeneous Granular Mixtures

A Digilent Analogue Discovery 2 (AD2) was used in conjunction with the Digilent WaveForm software Network Analyzer to find the resonance frequency of our LRC circuit. The resonnance frequency was used to calculate inductance. We used the measured inductance to calculate the permeability of granular mixture relative to air to solve for the magnetic susceptibility of the mixture.We introduce an instrument and novel method for characterizing the bulk magnetic susceptibility of granular mixtures by submerging an inductor coil in a bed of metallic beads and gauging changes in self-inductance. The resonance frequency of the coil was measured to determine its inductance and evaluate the magnetic permeability of ferrous mixtures relative to air. In air, our coil was accurate to within 3% of the permeability of free space. The range of magnetic susceptibility values for magnetically inhomogeneous granular mixtures is poorly constrained, but our coil uniquely quantifies bulk effects that other surface meters are not designed to resolve. Compared to both a commercial Terraplus Inc. KT-10 meter and theoretical approximations, we report similar trends in susceptibility values measured as a function of mass of ferromagnetic material per volume

Experimental Demonstration and Quantification of Electrostatic Lofting of Dust Clumps

A PCO Dimax CS3 was used to take high-speed images at 945 frames per second of electrostatically lofted clumps of zirconia-silica microspheres. The images were processed and analyzed in Matlab using Matlab built-in functions. The two-dimensional centroid positions of lofted objects of interest were identified and their trajectories were tracked. The velocity and accelerations of tracked objects were then numerically calculated in order to solve for the cohesion, and compared to other independent methods.Electrostatic lofting of individual regolith grains on the Moon and asteroids has been investigated extensively. However, motion of clumps has been mentioned only anecdotally. For the first time, we electrostatically lofted clumps of 200-300 micrometer zirconia-silica microspheres in vacuum and quantitatively analyzed their trajectories. The microspheres were charged by an emissive filament. A biased plate produced an electric field of 870 kV/m that attracted sufficiently charged clumps from the surface. A high-speed camera imaged the lofted clumps at 945 fps in order to obtain their size and centroid positions over time. Using the centroids from the initial clump detachment, we numerically calculated an initial acceleration to solve for the cohesion that had been restraining the clump. These experimental results show that the detachment of clumps of particles are a non-negligible portion of the lofted object population for cohesive powders. Thus, if electrostatic lofting occurs on small airless bodies, we will likely see clumps lofted.NASA PICASSO Grant 80NSSC18K093

Public Engagement Through Online TV Channels: A Way Forward For The Audiovisual Communication Of Archaeology?

This paper assesses the relationship between the public and archaeology within a rapidly evolving world of communication, where the increasingly dominant position of the Internet is changing the role of television. The first part of the paper examines the ways in which digital technologies have changed the media environment and, in particular, the televisual communication of archaeology, over the past decade, in Britain. The analysis is based on audience figures of archaeology-themed TV series and one-off programmes, and on other statistics regarding the use of digital and online platforms and of mobile technology. It is argued that, in the United Kingdom, opportunities for screening archaeology on both terrestrial and digital channels have diminished. Such opportunities will be likely to decrease even further in the future, due to increasing competition that is affecting the TV world and is diversifying its (once) mass audiences. In this scenario, however, the Internet opens up new possibilities for engagement. The second section of this paper compares two different forms of online audio-visual communication: 1) that of strongly-branded online TV channels and 2) the one of shorter-term and/or more discontinuous web-based video communication. The discussion is based on the analysis of specific case studies, investigating the ways in which they have been designed and used. The conclusion highlights that strongly-branded online TV channels are more visible and effective, not only in terms of public engagement (audience attraction and provision of satisfying experiences), but also their contribution towards a more sustainable future for the archaeological sector