1,273 research outputs found
Satisfactory safety and immunogenicity of MSP3 malaria vaccine candidate in Tanzanian children aged 12-24 months.
BACKGROUND: Development and deployment of an effective malaria vaccine would complement existing malaria control measures. A blood stage malaria vaccine candidate, Merozoite Surface Protein-3 (MSP3), produced as a long synthetic peptide, has been shown to be safe in non-immune and semi-immune adults. A phase Ib dose-escalating study was conducted to assess the vaccine's safety and immunogenicity in children aged 12 to 24 months in Korogwe, Tanzania (ClinicalTrials.gov number: NCT00469651). METHODS: This was a double-blind, randomized, controlled, dose escalation phase Ib trial, in which children were given one of two different doses of the MSP3 antigen (15 microg or 30 microg) or a control vaccine (Engerix B). Children were randomly allocated either to the MSP3 candidate malaria vaccine or the control vaccine administered at a schedule of 0, 1, and 2 months. Immunization with lower and higher doses was staggered for safety reasons starting with the lower dose. The primary endpoint was safety and reactogenicity within 28 days post-vaccination. Blood samples were obtained at different time points to measure immunological responses. Results are presented up to 84 days post-vaccination. RESULTS: A total of 45 children were enrolled, 15 in each of the two MSP3 dose groups and 15 in the Engerix B group. There were no important differences in reactogenicity between the two MSP3 groups and Engerix B. Grade 3 adverse events were infrequent; only five were detected throughout the study, all of which were transient and resolved without sequelae. No serious adverse event reported was considered to be related to MSP3 vaccine. Both MSP3 dose regimens elicited strong cytophilic IgG responses (subclasses IgG1 and IgG3), the isotypes involved in the monocyte-dependant mechanism of Plasmodium falciparum parasite-killing. The titers reached are similar to those from African adults having reached a state of premunition. Furthermore, vaccination induced seroconversion in all vaccinees. CONCLUSION: The MSP3 malaria vaccine candidate was safe, well tolerated and immunogenic in children aged 12-24 months living in a malaria endemic community. Given the vaccine's safety and its induction of cytophilic IgG responses, its efficacy against P. falciparum infection and disease needs to be evaluated in Phase 2 studies
How to Constrain Your M Dwarf. II. The MassâLuminosityâMetallicity Relation from 0.075 to 0.70 Solar Masse
The mass-luminosity relation for late-type stars has long been a critical
tool for estimating stellar masses. However, there is growing need for both a
higher-precision relation and a better understanding of systematic effects
(e.g., metallicity). Here we present an empirical relationship between Mks and
mass spanning . The relation is derived from 62
nearby binaries, whose orbits we determine using a combination of Keck/NIRC2
imaging, archival adaptive optics data, and literature astrometry. From their
orbital parameters, we determine the total mass of each system, with a
precision better than 1% in the best cases. We use these total masses, in
combination with resolved Ks magnitudes and system parallaxes, to calibrate the
mass-Mks relation. The result can be used to determine masses of single stars
with a precision of 2-3%, which we confirm by a comparison to dynamical masses
from the literature. The precision is limited by scatter around the best-fit
relation beyond mass uncertainties, perhaps driven by intrinsic variation in
the mass-Mks relation or underestimated measurement errors. We find the effect
of [Fe/H] on the mass-Mks relation is likely negligible for metallicities in
the Solar neighborhood (0.0+/-2.2% change in mass per dex change in [Fe/H]).
This weak effect is consistent with predictions from the Dartmouth Stellar
Evolution Database, but inconsistent with those from MESA Isochrones and
Stellar Tracks. A sample of binaries with a wider range of abundances will be
required to discern the importance of metallicity in extreme populations (e.g.,
in the Galactic Halo or thick disk).Comment: Published in ApJ/AAS Journals. Comments welcome. Code for computing
mass posteriors from Ks+distance at https://github.com/awmann/M_-M_K
Wind-driven ventilation improvement with plan typology alteration: a CFD case study of traditional Turkish architecture
Aligned with achieving the goal of net-zero buildings, the implementation of energy-saving techniques in minimizing energy demands is proving more vital than at any time. As practical and economic options, passive strategies in ventilation developed over thousands of years have shown great potential for the reduction of residential energy demands, which are often underestimated in modern buildingâs construction. In particular, as a cost-effective passive strategy, wind-driven ventilation via windows has huge potential in the enhancement of the indoor air quality (IAQ) of buildings while simultaneously reducing their cooling load. This study aims to investigate the functionality and applicability of a common historical Turkish architectural element called âCumbaâ to improve the wind-driven ventilation in modern buildings. A case study building with an archetypal plan and parameters was defined as a result of a survey over 111 existing traditional samples across Turkey. Buildings with and without Cumba were compared in different scenarios by the development of a validated CFD microclimate model. The results of simulations clearly demonstrate that Cumba can enhance the roomâs ventilation rate by more than two times while harvesting wind from different directions. It was also found that a flexible window opening strategy can help to increase the mean ventilation rate by 276%. Moreover, the roomâs mean air velocity and ventilation rate could be adjusted to a broad range of values with the existence of Cumba. Thus, this study presents important findings about the importance of plan typology in the effectiveness of wind-driven ventilation strategies in modern dwellings
Characteristics of outdoor falls among older people: A qualitative study
Background Falls are a major threat to older peopleâs health and wellbeing. Approximately half of falls occur in outdoor environments but little is known about the circumstances in which they occur. We conducted a qualitative study to explore older peopleâs experiences of outdoor falls to develop understanding of how they may be prevented. Methods We conducted nine focus groups across the UK (England, Wales, and Scotland). Our sample was from urban and rural settings and different environmental landscapes. Participants were aged 65+ and had at least one outdoor fall in the past year. We analysed the data using framework and content analyses. Results Forty-four adults aged 65 â 92 took part and reported their experience of 88 outdoor falls. Outdoor falls occurred in a variety of contexts, though reports suggested the following scenarios may have been more frequent: when crossing a road, in a familiar area, when bystanders were around, and with an unreported or unknown attribution. Most frequently, falls resulted in either minor or moderate injury, feeling embarrassed at the time of the fall, and anxiety about falling again. Ten falls resulted in fracture, but no strong pattern emerged in regard to the contexts of these falls. Anxiety about falling again appeared more prevalent among those that fell in urban settings and who made more visits into their neighbourhood in a typical week. Conclusions This exploratory study has highlighted several aspects of the outdoor environment that may represent risk factors for outdoor falls and associated fear of falling. Health professionals are recommended to consider outdoor environments as well as the home setting when working to prevent falls and increase mobility among older people
Hypoglycaemia in severe malaria, clinical associations and relationship to quinine dosage
<p>Abstract</p> <p>Background</p> <p>Hypoglycaemia is an independent risk factor for death in severe malaria and a recognized adverse treatment effect of parenteral quinine. In 2006 our hospital changed quinine treatment policy from 15 mg/kg loading (plus 10 mg/kg 12-hourly) to 20 mg/kg loading (plus 10 mg/kg 8-hourly) to comply with new WHO guidelines. This presented us with the opportunity to examine whether there was any dose relationship of quinine and hypoglycaemia occurrence.</p> <p>Methods</p> <p>Retrospective case notes review of all children admitted to hospital with severe falciparum malaria between April 2002 - July 2009, before and after the introduction of the new WHO quinine regimen. Four-hourly bedside glucose levels were measured until intravenous quinine was discontinued. Clinical events immediately preceding or concurrent with each episode of hypoglycaemia (glucose < = 3.0 mmol/l) were recorded.</p> <p>Results</p> <p>954 children received the old quinine regime and 283 received the new regime. We found no evidence of an increased prevalence of hypoglycaemia (< = 3.0 mmol/L) on the new regime compared to former (15% vs. 15%); similar findings were noted for profound hypoglycaemia (< 2.2 mmols/L) 8% v 5%, P = 0.07. Episodes were co-incident with disease severity markers: coma (57%), circulatory failure (38%) and respiratory distress (21%) but less commonly with seizures (10%). Disruption of maintenance fluids and/or blood transfusion concurred with 42% of the hypoglycaemia episodes. Post admission hypoglycaemia increased odds of fatal outcome (24%) compared to euglycaemic counterparts (8%), odds ratio = 3.45 (95% confidence interval = 2.30-5.16) P < 0.01.</p> <p>Conclusion</p> <p>There was no evidence to indicate a dose relationship between quinine and occurrence of hypoglycaemia. Hypoglycaemia concurred with severity features, disruption of glucose infusion and transfusion. Careful glucose monitoring should be targeted to these complications where resources are limited.</p
A novel malaria vaccine candidate antigen expressed in Tetrahymena thermophila
Development of effective malaria vaccines is hampered by the problem of producing correctly folded Plasmodium proteins for use as vaccine components. We have investigated the use of a novel ciliate expression system, Tetrahymena thermophila, as a P. falciparum vaccine antigen platform. A synthetic vaccine antigen composed of N-terminal and C-terminal regions of merozoite surface protein-1 (MSP-1) was expressed in Tetrahymena thermophila. The recombinant antigen was secreted into the culture medium and purified by monoclonal antibody (mAb) affinity chromatography. The vaccine was immunogenic in MF1 mice, eliciting high antibody titers against both N- and C-terminal components. Sera from immunized animals reacted strongly with P. falciparum parasites from three antigenically different strains by immunofluorescence assays, confirming that the antibodies produced are able to recognize parasite antigens in their native form. Epitope mapping of serum reactivity with a peptide library derived from all three MSP-1 Block 2 serotypes confirmed that the MSP-1 Block 2 hybrid component of the vaccine had effectively targeted all three serotypes of this polymorphic region of MSP-1. This study has successfully demonstrated the use of Tetrahymena thermophila as a recombinant protein expression platform for the production of malaria vaccine antigens
Characterizing, modelling and understanding the climate variability of the deep water formation in the North-Western Mediterranean Sea
Observing, modelling and understanding the climate-scale variability of the deep water formation (DWF) in the North-Western Mediterranean Sea remains today very challenging. In this study, we first characterize the interannual variability of this phenomenon by a thorough reanalysis of observations in order to establish reference time series. These quantitative indicators include 31 observed years for the yearly maximum mixed layer depth over the period 1980â2013 and a detailed multi-indicator description of the period 2007â2013. Then a 1980â2013 hindcast simulation is performed with a fully-coupled regional climate system model including the high-resolution representation of the regional atmosphere, ocean, land-surface and rivers. The simulation reproduces quantitatively well the mean behaviour and the large interannual variability of the DWF phenomenon. The model shows convection deeper than 1000 m in 2/3 of the modelled winters, a mean DWF rate equal to 0.35 Sv with maximum values of 1.7 (resp. 1.6) Sv in 2013 (resp. 2005). Using the model results, the winter-integrated buoyancy loss over the Gulf of Lions is identified as the primary driving factor of the DWF interannual variability and explains, alone, around 50 % of its variance. It is itself explained by the occurrence of few stormy days during winter. At daily scale, the Atlantic ridge weather regime is identified as favourable to strong buoyancy losses and therefore DWF, whereas the positive phase of the North Atlantic oscillation is unfavourable. The driving role of the vertical stratification in autumn, a measure of the water column inhibition to mixing, has also been analyzed. Combining both driving factors allows to explain more than 70 % of the interannual variance of the phenomenon and in particular the occurrence of the five strongest convective years of the model (1981, 1999, 2005, 2009, 2013). The model simulates qualitatively well the trends in the deep waters (warming, saltening, increase in the dense water volume, increase in the bottom water density) despite an underestimation of the salinity and density trends. These deep trends come from a heat and salt accumulation during the 1980s and the 1990s in the surface and intermediate layers of the Gulf of Lions before being transferred stepwise towards the deep layers when very convective years occur in 1999 and later. The salinity increase in the near Atlantic Ocean surface layers seems to be the external forcing that finally leads to these deep trends. In the future, our results may allow to better understand the behaviour of the DWF phenomenon in Mediterranean Sea simulations in hindcast, forecast, reanalysis or future climate change scenario modes. The robustness of the obtained results must be however confirmed in multi-model studies
Non-motor predictors of 36-month quality of life after subthalamic stimulation in Parkinson disease.
To identify predictors of 36-month follow-up quality of life (QoL) outcome after bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinsonâs disease (PD). In this ongoing, prospective, multicenter international study (Cologne, Manchester, London) including 73 patients undergoing STN-DBS, we assessed the following scales preoperatively and at 6-month and 36-month follow-up: PD Questionnaire-8 (PDQ-8), NMSScale (NMSS), Scales for Outcomes in PD (SCOPA)-motor examination, -activities of daily living, and -complications, and levodopa equivalent daily dose (LEDD). We analyzed factors associated with QoL improvement at 36-month follow-up based on (1) correlations between baseline test scores and QoL improvement, (2) step-wise linear regressions with baseline test scores as independent and QoL improvement as dependent variables, (3) logistic regressions and receiver operating characteristic curves using a dichotomized variable âQoL respondersâ/ânon-respondersâ. At both follow-ups, NMSS total score, SCOPA-motor examination, and -complications improved and LEDD was reduced significantly. PDQ-8 improved at 6-month follow-up with subsequent decrements in gains at 36-month follow-up when 61.6% of patients were categorized as âQoL non-respondersâ. Correlations, linear, and logistic regression analyses found greater PDQ-8 improvements in patients with younger age, worse PDQ-8, and worse specific NMS at baseline, such as âdifficulties experiencing pleasureâ and âproblems sustaining concentrationâ. Baseline SCOPA scores were not associated with PDQ-8 changes. Our results provide evidence that 36-month QoL changes depend on baseline neuropsychological and neuropsychiatric non-motor symptoms burden. These findings highlight the need for an assessment of a wide range of non-motor and motor symptoms when advising and selecting individuals for DBS therapy
Genome-wide analysis of ivermectin response by Onchocerca volvulus reveals that genetic drift and soft selective sweeps contribute to loss of drug sensitivity
Treatment of onchocerciasis using mass ivermectin administration has reduced morbidity and transmission throughout Africa and Central/South America. Mass drug administration is likely to exert selection pressure on parasites, and phenotypic and genetic changes in several Onchocerca volvulus populations from Cameroon and Ghana-exposed to more than a decade of regular ivermectin treatment-have raised concern that sub-optimal responses to ivermectin's anti-fecundity effect are becoming more frequent and may spread.Pooled next generation sequencing (Pool-seq) was used to characterise genetic diversity within and between 108 adult female worms differing in ivermectin treatment history and response. Genome-wide analyses revealed genetic variation that significantly differentiated good responder (GR) and sub-optimal responder (SOR) parasites. These variants were not randomly distributed but clustered in ~31 quantitative trait loci (QTLs), with little overlap in putative QTL position and gene content between the two countries. Published candidate ivermectin SOR genes were largely absent in these regions; QTLs differentiating GR and SOR worms were enriched for genes in molecular pathways associated with neurotransmission, development, and stress responses. Finally, single worm genotyping demonstrated that geographic isolation and genetic change over time (in the presence of drug exposure) had a significantly greater role in shaping genetic diversity than the evolution of SOR.This study is one of the first genome-wide association analyses in a parasitic nematode, and provides insight into the genomics of ivermectin response and population structure of O. volvulus. We argue that ivermectin response is a polygenically-determined quantitative trait (QT) whereby identical or related molecular pathways but not necessarily individual genes are likely to determine the extent of ivermectin response in different parasite populations. Furthermore, we propose that genetic drift rather than genetic selection of SOR is the underlying driver of population differentiation, which has significant implications for the emergence and potential spread of SOR within and between these parasite populations
- âŠ