203 research outputs found
Planet or brown dwarf? Inferring the companion mass in HD 100546 from the wall shape using mid-infrared interferometry
Efficacy and safety of praziquantel in preschool-aged and school-aged children infected with Schistosoma mansoni: a randomised controlled, parallel-group, dose-ranging, phase 2 trial
Background
Praziquantel has been the drug of choice for schistosomiasis control for more than 40 years, yet surprisingly, the optimal dose for children younger than 4 years is not known. We aimed to assess the efficacy and safety of escalating praziquantel dosages in preschool-aged children (PSAC).
Methods
We did a randomised controlled, parallel-group, single-blind, dose-ranging, phase 2 trial in PSAC (2â5 years) and school-aged children (SAC; aged 6â15 years) as a comparator group in southern CĂŽte d'Ivoire. Children were randomly assigned (1:1:1:1) to 20 mg/kg, 40 mg/kg, or 60 mg/kg praziquantel or placebo. Participants, investigators, and laboratory technicians were masked to group assignment, while the investigator providing treatment was aware of the treatment group. The primary objective was to estimate the nature of the doseâresponse relation in terms of cure rate using the Kato Katz technique. Doseâresponse curves were estimated using Emax models. Available case analysis was done including all participants with primary endpoint data. This trial is registered with International Standard Randomised Controlled Trial, number ISRCTN15280205.
Findings
Between Nov 11, 2014, and Feb 18, 2015, 660 PSAC and 225 SAC were assessed for eligibility; of whom 161 (24%) PSAC and 180 (80%) SAC had a detectable Schistosoma mansoni infection. 161 PSAC were randomly allocated of whom 154 received treatment: 42 were assigned to 20 mg/kg praziquantel, of whom 40 received treatment; 38 were assigned to 40 mg/kg praziquantel, of whom 38 received treatment; 41 were assigned to 60 mg/kg praziquantel, of whom 39 received treatment; and 40 were assigned to placebo, of whom 37 received placebo. 180 SAC were randomly allocated of whom 177 received treatment: 49 were assigned to 20 mg/kg praziquantel, of whom 47 received treatment; 46 were assigned to 40 mg/kg praziquantel, of whom 46 received treatment; 42 were assigned to 60 mg/kg praziquantel, of whom 42 received treatment; and 43 were assigned to placebo, of whom 43 received treatment. Follow-up (available-case) data were available for 143 PSAC and 174 SAC. In PSAC, the 20 mg/kg dose resulted in cure in 23 children (62%; 95% CI 44·8â77·5), 40 mg/kg in 26 children (72%; 54·8â85·8), 60 mg/kg in 25 children (71%; 53·7â85·4), and placebo in 13 children (37%; 21·5â55·1). In SAC, the 20 mg/kg dose resulted in cure in 14 children (30%; 95% CI 17·7â45·8), 40 mg/kg in 31 children (69%; 53·4â81·8), 60 mg/kg in 34 children (83%; 67·9â92·8), and placebo in five children (12%; 4·0â25·6). For both age groups, the number of adverse events was similar among the three praziquantel treatment groups, with fewer adverse events observed in the placebo groups. The most common adverse events in PSAC were diarrhoea (11 [9%] of 124) and stomach ache (ten [8%]) and in SAC were diarrhoea (50 [28%] of 177), stomach ache (66 [37%]), and vomiting (26 [15%]) 3 h post treatment. No serious adverse events were reported.
Interpretation
Praziquantel shows a flat dose-response and overall lower efficacy in PSAC compared with in SAC. In the absence of treatment alternatives, a single dose of praziquantel of 40 mg/kg, recommended by the WHO for S mansoni infections in SAC can be endorsed for PSAC in preventive chemotherapy programmes
Investigations on the interplays between Schistosoma mansoni, praziquantel and the gut microbiome
Schistosomiasis is a neglected tropical disease burdening millions of people. One drug, praziquantel, is currently used for treatment and control. Clinically relevant drug resistance has not yet been described, but there is considerable heterogeneity in treatment outcomes, ranging from cure to only moderate egg reduction rates. The objectives of this study are to investigate potential worm-induced dysbacteriosis of the gut microbiota and to assess whether a specific microbiome profile could influence praziquantel response.; Using V3 and V4 regions of 16S rRNA genes, we screened the gut microbiota of 34 Schistosoma mansoni infected and uninfected children from CĂŽte d'Ivoire. From each infected child one pre-treatment, one 24-hour and one 21-day follow-up sample after administering 60 mg/kg praziquantel or placebo, were collected.; Overall taxonomic profiling and diversity indicators were found to be close to a "healthy" gut structure in all children. Slight overall compositional changes were observed between S. mansoni-infected and non-infected children. Praziquantel treatment was not linked to a major shift in the gut taxonomic profiles, thus reinforcing the good safety profile of the drug by ruling out off-targets effects on the gut microbes.16S rRNA gene of the Fusobacteriales order was significantly more abundant in cured individuals, both at baseline and 24 hours post-treatment. A real-time qPCR confirmed the over-abundance of Fusobacterium spp. in cured children. Fusobacterium spp. abundance could also be correlated with treatment induced S. mansoni egg-reduction.; Our study suggests that neither a S. mansoni infection nor praziquantel administration triggers a significant effect on the microbial composition and that a higher abundance of Fusobacterium spp., before treatment, is associated with higher efficacy of praziquantel in the treatment of S. mansoni infections.; International Standard Randomised Controlled Trial, number ISRCTN15280205
TW Hya: an old protoplanetary disc revived by its planet
Dark rings with bright rims are the indirect signposts of planets embedded in protoplanetary discs. In a recent first, an azimuthally elongated AU-scale blob, possibly a planet, was resolved with ALMA in TW Hya. The blob is at the edge of a cliff-like rollover in the dust disc rather than inside a dark ring. Here we build time-dependent models of TW Hya disc. We find that the classical paradigm cannot account for the morphology of the disc and the blob. We propose that ALMA-discovered blob hides a Neptune mass planet losing gas and dust. We show that radial drift of mm-sized dust particles naturally explains why the blob is located on the edge of the dust disc. Dust particles leaving the planet perform a characteristic U-turn relative to it, producing an azimuthally elongated blob-like emission feature. This scenario also explains why a 10âMyr old disc is so bright in dust continuum. Two scenarios for the dust-losing planet are presented. In the first, a dusty pre-runaway gas envelope of a âŒ40Mâ Core Accretion planet is disrupted, e.g. as a result of a catastrophic encounter. In the second, a massive dusty pre-collapse gas giant planet formed by Gravitational Instability is disrupted by the energy released in its massive core. Future modelling may discriminate between these scenarios and allow us to study planet formation in an entirely new way â by analysing the flows of dust and gas recently belonging to planets, informing us about the structure of pre-disruption planetary envelopes
Evaluation of the ClinitekÂź, a point-of-care urinalysis system for the measurement of clinically significant urinary metabolites and detection of haematuria in Schistosoma haematobium infected children in southern CĂŽte d'Ivoire
Urinary schistosomiasis, caused by Schistosoma haematobium, remains a significant public health problem worldwide, despite years of efforts to control it. Haematuria is one of the notable indirect indicators of S. haematobium infection and is commonly assessed along with other routine screens using a urinary dipstick test. A portable "field friendly" electronic analyser would offer an automated and thus more objective read-out compared to visual-read dipstick methods.; Within the framework of a Phase 2 praziquantel dose finding study in preschool- and school-aged children infected with S. haematobium, in southern CĂŽte d'Ivoire, we compared a visual-read of the urine dipstick strips (Multistix PRO, Siemens Healthcare Diagnostics) to an automated reader (CLINITEK Status+ analysertm Siemens Healthcare Diagnostics). Urine samples were collected from 148 pre-school aged and 152 school-aged children for urinalysis. Values were compared using a linear weighted kappa statistic and Bland-Altman analysis.; A very good correlation between the two methods for nitrites and haematuria was observed (Îș coefficient of 0.88 and 0.82, respectively), while a good correlation was observed for leukocytes (Îș coefficient of 0.63) A moderate to fair correlation was calculated (Îș coefficient â€Â 0.6) for all other parameters. When the results were stratified according to infection intensity, the agreements were stronger from the high infection intensity sample measurements, for most of the parameters.; Our results demonstrate the device's utility in detecting haematuria and nitrites but underline the need for further development of this tool in order to improve its performance in the field
Orally active antischistosomal early leads identified from the open access malaria box.
BACKGROUND: Worldwide hundreds of millions of schistosomiasis patients rely on treatment with a single drug, praziquantel. Therapeutic limitations and the threat of praziquantel resistance underline the need to discover and develop next generation drugs. METHODOLOGY: We studied the antischistosomal properties of the Medicines for Malaria Venture (MMV) malaria box containing 200 diverse drug-like and 200 probe-like compounds with confirmed in vitro activity against Plasmodium falciparum. Compounds were tested against schistosomula and adult Schistosoma mansoni in vitro. Based on in vitro performance, available pharmacokinetic profiles and toxicity data, selected compounds were investigated in vivo. PRINCIPAL FINDINGS: Promising antischistosomal activity (IC50: 1.4-9.5 ”M) was observed for 34 compounds against schistosomula. Three compounds presented IC50 values between 0.8 and 1.3 ”M against adult S. mansoni. Two promising early leads were identified, namely a N,N'-diarylurea and a 2,3-dianilinoquinoxaline. Treatment of S. mansoni infected mice with a single oral 400 mg/kg dose of these drugs resulted in significant worm burden reductions of 52.5% and 40.8%, respectively. CONCLUSIONS/SIGNIFICANCE: The two candidates identified by investigating the MMV malaria box are characterized by good pharmacokinetic profiles, low cytotoxic potential and easy chemistry and therefore offer an excellent starting point for antischistosomal drug discovery and development
Constraining the Gap Size in the Disk around HD 100546 in the Mid-infrared
We refine the gap size measurements of the disk surrounding the Herbig Ae star HD 100546 in the N band. Our new mid-infrared interferometric (MIDI) data have been taken with the UT baselines and span the full range of orientations. The correlated fluxes show a wavy pattern in which the minima separation links to a geometrical structure in the disk. We fit each correlated flux measurement with a spline function, deriving the corresponding spatial scale, while assuming that the pattern arises interferometrically due to the bright emission from the inner disk and the opposing sides of the wall of the outer disk. We then fit an ellipse to the derived separations at their corresponding position angles, thereby using the observations to constrain the disk inclination to i = 47° ± 1° and the disk position angle to PA = 135â°0 ± 2â°5 east of north, both of which are consistent with the estimated values in previous studies. We also derive the radius of the ellipse to 15.7 ± 0.8 au. To confirm that the minima separations translate to a geometrical structure in the disk, we model the disk of HD 100546 using a semianalytical approach taking into account the temperature and optical depth gradients. Using this model, we simultaneously reproduce the level and the minima of the correlated fluxes and constrain the gap size of the disk for each observation. The values obtained for the projected gap size in different orientations are consistent with the separation found by the geometrical model
Asymmetric mid-plane gas in ALMA images of HD 100546
In this paper we present new ALMA observations towards the proto-planet
hosting transitional disc of Herbig Ae/Be star HD 100546. This includes
resolved 1.3 mm continuum, CO and the first detection of CO in
this disc, which displays azimuthal asymmetry in regions spatially coincident
with structures previously identified in HST images related to spiral arms. The
lower limit on the mass of the dust disc is calculated to be
9.6x10M. A firm lower-limit on the total gas mass calculated
from optically thin, mid-plane tracing CO (2-1) emission is
0.018M assuming ISM abundances. These mass estimates provide an
estimate of gas-to-dust ratio in the disc of 19, the ratio will increase if
CO is relatively under-abundant in the disc compared to CO and H2.
Through deprojection and azimuthal averaging of the image plane we detect 1.3
mm continuum emission out to 290+/-10 au,CO to 390+/-10 au and CO
to 300+/-10au. We measure a radially increasing millimetre spectral index
between wavelengths of 867m and 1.3 mm, which shows that grain sizes
increase towards the star, with solid particles growing to cm scales in the
inner disc
Sensitive limits on the abundance of cold water vapor in the DM Tau protoplanetary disk
We performed a sensitive search for the ground-state emission lines of ortho-
and para-water vapor in the DM Tau protoplanetary disk using the Herschel/HIFI
instrument. No strong lines are detected down to 3sigma levels in 0.5 km/s
channels of 4.2 mK for the 1_{10}--1_{01} line and 12.6 mK for the
1_{11}--0_{00} line. We report a very tentative detection, however, of the
1_{10}--1_{01} line in the Wide Band Spectrometer, with a strength of
T_{mb}=2.7 mK, a width of 5.6 km/s and an integrated intensity of 16.0 mK km/s.
The latter constitutes a 6sigma detection. Regardless of the reality of this
tentative detection, model calculations indicate that our sensitive limits on
the line strengths preclude efficient desorption of water in the UV illuminated
regions of the disk. We hypothesize that more than 95-99% of the water ice is
locked up in coagulated grains that have settled to the midplane.Comment: 5 pages, 3 figures. Accepted for publication in the Herschel HIFI
special issue of A&
Metabolic maturation in the first 2 years of life in resource-constrained settings and its association with postnatal growths
Funding Information: The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) is carried out as a collaborative project supported by the Bill & Melinda Gates Foundation (BMGF 47075), the Foundation for the National Institutes of Health, and the National Institutes of Health, Fogarty International Center, while additional support was obtained from BMGF for the examination of host innate factors on enteric disease risk and enteropathy (grants OPP1066146 and OPP1152146 to M.N.K.). Additional funding was obtained from the Sherrilyn and Ken Fisher Center for Environmental Infectious Diseases of the Johns Hopkins School of Medicine (to M.N.K.). Publisher Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).Peer reviewedPublisher PD
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