The undetectable hypnozoite reservoir for relapsing Plasmodium vivax and P. ovale malarias presents a major challenge for malaria control and elimination in endemic countries. This study aims to ...directly determine the contribution of relapses to the burden of P. vivax and P. ovale infection, illness, and transmission in Papua New Guinean children.
From 17 August 2009 to 20 May 2010, 524 children aged 5-10 y from East Sepik Province in Papua New Guinea (PNG) participated in a randomised double-blind placebo-controlled trial of blood- plus liver-stage drugs (chloroquine CQ, 3 d; artemether-lumefantrine AL, 3 d; and primaquine PQ, 20 d, 10 mg/kg total dose) (261 children) or blood-stage drugs only (CQ, 3 d; AL, 3 d; and placebo PL, 20 d) (263 children). Participants, study staff, and investigators were blinded to the treatment allocation. Twenty children were excluded during the treatment phase (PQ arm: 14, PL arm: 6), and 504 were followed actively for 9 mo. During the follow-up time, 18 children (PQ arm: 7, PL arm: 11) were lost to follow-up. Main primary and secondary outcome measures were time to first P. vivax infection (by qPCR), time to first clinical episode, force of infection, gametocyte positivity, and time to first P. ovale infection (by PCR). A basic stochastic transmission model was developed to estimate the potential effect of mass drug administration (MDA) for the prevention of recurrent P. vivax infections. Targeting hypnozoites through PQ treatment reduced the risk of having at least one qPCR-detectable P. vivax or P. ovale infection during 8 mo of follow-up (P. vivax: PQ arm 0.63/y versus PL arm 2.62/y, HR = 0.18 95% CI 0.14, 0.25, p < 0.001; P. ovale: 0.06 versus 0.14, HR = 0.31 95% CI 0.13, 0.77, p = 0.011) and the risk of having at least one clinical P. vivax episode (HR = 0.25 95% CI 0.11, 0.61, p = 0.002). PQ also reduced the molecular force of P. vivax blood-stage infection in the first 3 mo of follow-up (PQ arm 1.90/y versus PL arm 7.75/y, incidence rate ratio IRR = 0.21 95% CI 0.15, 0.28, p < 0.001). Children who received PQ were less likely to carry P. vivax gametocytes (IRR = 0.27 95% CI 0.19, 0.38, p < 0.001). PQ had a comparable effect irrespective of the presence of P. vivax blood-stage infection at the time of treatment (p = 0.14). Modelling revealed that mass screening and treatment with highly sensitive quantitative real-time PCR, or MDA with blood-stage treatment alone, would have only a transient effect on P. vivax transmission levels, while MDA that includes liver-stage treatment is predicted to be a highly effective strategy for P. vivax elimination. The inclusion of a directly observed 20-d treatment regime maximises the efficiency of hypnozoite clearance but limits the generalisability of results to real-world MDA programmes.
These results suggest that relapses cause approximately four of every five P. vivax infections and at least three of every five P. ovale infections in PNG children and are important in sustaining transmission. MDA campaigns combining blood- and liver-stage treatment are predicted to be a highly efficacious intervention for reducing P. vivax and P. ovale transmission.
ClinicalTrials.gov NCT02143934.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Plasmodium vivax remains an important cause of malaria in South America and the Asia-Pacific. Naturally acquired antibody responses against multiple P. vivax proteins have been described in numerous ...countries, however, direct comparison of these responses has been difficult with different methodologies employed. We measured antibody responses against 307 P. vivax proteins at the time of P. vivax infection, and at 2-3 later time-points in three countries. We observed that seropositivity rates at the time of infection were highest in Thailand, followed by Brazil then PNG, reflecting the level of antigenic input. The majority of sero-reactive antigens in all sites induced short-lived antibody responses with estimated half-lives of less than 6 months, although there was a trend towards longer-lived responses in PNG children. Despite these differences, IgG seropositivity rates, magnitude and longevity were highly and significantly rank-correlated between the different regions, suggesting such features are reflective of the individual protein.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The thermochemical structure of lithospheric and asthenospheric mantle exert primary controls on surface topography and volcanic activity. Volcanic rock compositions and mantle seismic velocities ...provide indirect observations of this structure. Here, we compile and analyze a global database of the distribution and composition of Neogene-Quaternary intraplate volcanic rocks. By integrating this database with seismic tomographic models, we show that intraplate volcanism is concentrated in regions characterized by slow upper mantle shear-wave velocities and by thin lithosphere (i.e. <100 km). We observe a negative correlation between shear-wave velocities at depths of 125-175 km and melt fractions inferred from volcanic rock compositions. Furthermore, mantle temperature and lithospheric thickness estimates obtained by geochemical modeling broadly agree with values determined from tomographic models that have been converted into temperature. Intraplate volcanism often occurs in regions where uplifted (but undeformed) marine sedimentary rocks are exposed. Regional elevation of these rocks can be generated by a combination of hotter asthenosphere and lithospheric thinning. Therefore, the distribution and composition of intraplate volcanic rocks through geologic time will help to probe past mantle conditions and surface processes.
Severe falciparum malaria is a major cause of preventable child mortality in sub-Saharan Africa. Plasma concentrations of P. falciparum Histidine-Rich Protein 2 (PfHRP2) have diagnostic and ...prognostic value in severe malaria. We investigate the potential use of plasma PfHRP2 and the sequestration index (the ratio of PfHRP2 to parasite density) as quantitative traits for case-only genetic association studies of severe malaria. Data from 2198 Kenyan children diagnosed with severe malaria, genotyped for 14 major candidate genes, show that polymorphisms in four major red cell genes that lead to hemoglobin S, O blood group, α-thalassemia, and the Dantu blood group, are associated with substantially lower admission plasma PfHRP2 concentrations, consistent with protective effects against extensive parasitized erythrocyte sequestration. In contrast the known protective ATP2B4 polymorphism is associated with higher plasma PfHRP2 concentrations, lower parasite densities and a higher sequestration index. We provide testable hypotheses for the mechanism of protection of ATP2B4.
Cenozoic Dynamic Topography of Madagascar Stephenson, S. N.; White, N. J.; Carter, A. ...
Geochemistry, geophysics, geosystems : G3,
June 2021, 2021-06-00, 20210601, 2021-06-01, Letnik:
22, Številka:
6
Journal Article
Recenzirano
Odprti dostop
It has been proposed that Oligo‐Miocene regional uplift of Madagascar was generated and is maintained by mantle dynamical processes. Expressions of regional uplift include flat‐lying Upper ...Cretaceous‐Paleogene marine limestones that crop out at elevations of hundreds of meters along the western seaboard and emergent Quaternary coral‐rich terraces that rim the coastline. Here, we explore the history of subcrustal topographic support through a combined analysis of four sets of observational constraints. First, we exploit published receiver function estimates of crustal thickness and spectral admittance between gravity and topography. An admittance value of ∼+40 ± 10 mGal km−1 at wavelengths >500 km implies that ∼1 km of topography is supported by subcrustal processes. Secondly, new apatite fission‐track and helium measurements from 18 basement samples are inverted, constraining temperature and denudation histories. Results suggest that 0.5–1.6 km of regional uplift occurred after ∼30 Ma. Thirdly, we calculate a history of regional uplift by minimizing the misfit between observed and calculated longitudinal river profiles. Results suggest that topography was generated during Neogene times. Finally, inverse modeling of rare earth element concentrations in Neogene mafic rocks indicates that melting of the asthenospheric source occurred at depths of ≤65 km with potential temperatures of 1300–1370 °C. Melting occurred at higher temperatures beneath Réunion Island and northern Madagascar and at lower temperatures beneath the Comores and southern Madagascar. These inferences are consistent with shear wave velocities obtained from tomographic models. We conclude that Madagascar is underlain by thinned lithospheric mantle and that a thermal anomaly lies within an asthenospheric layer beneath northern Madagascar.
Key Points
Oligo‐Miocene regional uplift of Madagascar appears to be generated and maintained by mantle processes
Apatite fission‐track analyses suggest Neogene denudation. Rapid uplift and exhumation are consistent with fluvial drainage evolution
Geochemical analysis of basalts implies elevated asthenospheric temperature beneath north of island and regionally thinned plate
We present first results of the H2O Southern Galactic Plane Survey (HOPS), using the Mopra Radio Telescope with a broad-band backend and a beam size of about 2 arcmin. We have observed 100 deg2 of ...the southern Galactic plane at 12 mm (19.5-27.5 GHz), including spectral line emission from H2O masers, multiple metastable transitions of ammonia, cyanoacetylene, methanol and radio recombination lines. In this paper, we report on the characteristics of the survey and H2O maser emission. We find 540 H2O masers, of which 334 are new detections. The strongest maser is 3933 Jy and the weakest is 0.7 Jy, with 62 masers over 100 Jy. In 14 maser sites, the spread in the velocity of the H2O maser emission exceeds 100 km s−1. In one region, the H2O maser velocities are separated by 351.3 km s−1. The rms noise levels are typically between 1 and 2 Jy, with 95 per cent of the survey under 2 Jy. We estimate completeness limits of 98 per cent at around 8.4 Jy and 50 per cent at around 5.5 Jy. We estimate that there are between 800 and 1500 H2O masers in the Galaxy that are detectable in a survey with similar completeness limits to HOPS. We report possible masers in NH3 (11,9) and (8,6) emission towards G19.61−0.23 and in the NH3 (3,3) line towards G23.33−0.30.
A major gap in the Plasmodium vivax elimination toolkit is the identification of individuals carrying clinically silent and undetectable liver-stage parasites, called hypnozoites. This study ...developed a panel of serological exposure markers capable of classifying individuals with recent P. vivax infections who have a high likelihood of harboring hypnozoites. We measured IgG antibody responses to 342 P. vivax proteins in longitudinal clinical cohorts conducted in Thailand and Brazil and identified candidate serological markers of exposure. Candidate markers were validated using samples from year-long observational cohorts conducted in Thailand, Brazil and the Solomon Islands and antibody responses to eight P. vivax proteins classified P. vivax infections in the previous 9 months with 80% sensitivity and specificity. Mathematical models demonstrate that a serological testing and treatment strategy could reduce P. vivax prevalence by 59-69%. These eight antibody responses can serve as a biomarker, identifying individuals who should be targeted with anti-hypnozoite therapy.
Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is ...generally referred to as 'accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. 'Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.
Elimination of Plasmodium vivax malaria would be greatly facilitated by the development of an effective vaccine. A comprehensive and systematic characterization of antibodies to P. vivax antigens in ...exposed populations is useful in guiding rational vaccine design.
In this study, we investigated antibodies to a large library of P. vivax entire ectodomain merozoite proteins in 2 Asia-Pacific populations, analysing the relationship of antibody levels with markers of current and cumulative malaria exposure, and socioeconomic and clinical indicators. 29 antigenic targets of natural immunity were identified. Of these, 12 highly-immunogenic proteins were strongly associated with age and thus cumulative lifetime exposure in Solomon Islanders (P<0.001-0.027). A subset of 6 proteins, selected on the basis of immunogenicity and expression levels, were used to examine antibody levels in plasma samples from a population of young Papua New Guinean children with well-characterized individual differences in exposure. This analysis identified a strong association between reduced risk of clinical disease and antibody levels to P12, P41, and a novel hypothetical protein that has not previously been studied, PVX_081550 (IRR 0.46-0.74; P<0.001-0.041).
These data emphasize the benefits of an unbiased screening approach in identifying novel vaccine candidate antigens. Functional studies are now required to establish whether PVX_081550 is a key component of the naturally-acquired protective immune response, a biomarker of immune status, or both.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK