Optimally timing primaquine treatment to reduce Plasmodium falciparum transmission in low endemicity Thai-Myanmar border populations

<p>Abstract</p> <p>Background</p> <p>Effective malaria control has successfully reduced the malaria burden in many countries, but to eliminate malaria, these countries will need to further improve their control efforts. Here, a malaria control programme was critically evaluated in a very low-endemicity Thai-Myanmar border population, where early detection and prompt treatment have substantially reduced, though not ended, <it>Plasmodium falciparum </it>transmission, in part due to carriage of late-maturing gametocytes that remain post-treatment. To counter this effect, the WHO recommends the use of a single oral dose of primaquine along with an effective blood schizonticide. However, while the effectiveness of primaquine as a gametocidal agent is widely documented, the mismatch between primaquine's short half-life, the long-delay for gametocyte maturation and the proper timing of primaquine administration have not been studied.</p> <p>Methods</p> <p>Mathematical models were constructed to simulate 8-year surveillance data, between 1999 and 2006, of seven villages along the Thai-Myanmar border. A simple model was developed to consider primaquine pharmacokinetics and pharmacodynamics, gametocyte carriage, and infectivity.</p> <p>Results</p> <p>In these populations, transmission intensity is very low, so the <it>P. falciparum </it>parasite rate is strongly linked to imported malaria and to the fraction of cases not treated. Given a 3.6-day half-life of gametocyte, the estimated duration of infectiousness would be reduced by 10 days for every 10-fold reduction in initial gametocyte densities. Infectiousness from mature gametocytes would last two to four weeks and sustain some transmission, depending on the initial parasite densities, but the residual mature gametocytes could be eliminated by primaquine. Because of the short half-life of primaquine (approximately eight hours), it was immediately obvious that with early administration (within three days after an acute attack), primaquine would not be present when mature gametocytes emerged eight days after the appearance of asexual blood-stage parasites. A model of optimal timing suggests that primaquine follow-up approximately eight days after a clinical episode could further reduce the duration of infectiousness from two to four weeks down to a few days. The prospects of malaria elimination would be substantially improved by changing the timing of primaquine administration and combining this with effective detection and management of imported malaria cases. The value of using primaquine to reduce residual gametocyte densities and to reduce malaria transmission was considered in the context of a malaria transmission model; the added benefit of the primaquine follow-up treatment would be relatively large only if a high fraction of patients (>95%) are initially treated with schizonticidal agents.</p> <p>Conclusion</p> <p>Mathematical models have previously identified the long duration of <it>P. falciparum </it>asexual blood-stage infections as a critical point in maintaining malaria transmission, but infectiousness can persist for two to four weeks because of residual populations of mature gametocytes. Simulations from new models suggest that, in areas where a large fraction of malaria cases are treated, curing the asexual parasitaemia in a primary infection, and curing mature gametocyte infections with an eight-day follow-up treatment with primaquine have approximately the same proportional effects on reducing the infectious period. Changing the timing of primaquine administration would, in all likelihood, interrupt transmission in this area with very good health systems and with very low endemicity.</p

Factors associated with diversity, quantity and zoonotic potential of ectoparasites on urban mice and voles

Wild rodents are important hosts for tick larvae but co-infestations with other mites and insects are largely neglected. Small rodents were trapped at four study sites in Berlin, Germany, to quantify their ectoparasite diversity. Host-specific, spatial and temporal occurrence of ectoparasites was determined to assess their influence on direct and indirect zoonotic risk due to mice and voles in an urban agglomeration. Rodent-associated arthropods were diverse, including 63 species observed on six host species with an overall prevalence of 99%. The tick Ixodes ricinus was the most prevalent species, found on 56% of the rodents. The trapping location clearly affected the presence of different rodent species and, therefore, the occurrence of particular host-specific parasites. In Berlin, fewer temporary and periodic parasite species as well as non-parasitic species (fleas, chiggers and nidicolous Gamasina) were detected than reported from rural areas. In addition, abundance of parasites with low host-specificity (ticks, fleas and chiggers) apparently decreased with increasing landscape fragmentation associated with a gradient of urbanisation. In contrast, stationary ectoparasites, closely adapted to the rodent host, such as the fur mites Myobiidae and Listrophoridae, were most abundant at the two urban sites. A direct zoonotic risk of infection for people may only be posed by Nosopsyllus fasciatus fleas, which were prevalent even in the city centre. More importantly, peridomestic rodents clearly supported the life cycle of ticks in the city as hosts for their subadult stages. In addition to trapping location, season, host species, body condition and host sex, infestation with fleas, gamasid Laelapidae mites and prostigmatic Myobiidae mites were associated with significantly altered abundance of I. ricinus larvae on mice and voles. Whether this is caused by predation, grooming behaviour or interaction with the host immune system is unclear. The present study constitutes a basis to identify interactions and vector function of rodent-associated arthropods and their potential impact on zoonotic diseases

Evaluation and Characterization of Bacterial Metabolic Dynamics with a Novel Profiling Technique, Real-Time Metabolotyping

BACKGROUND: Environmental processes in ecosystems are dynamically altered by several metabolic responses in microorganisms, including intracellular sensing and pumping, battle for survival, and supply of or competition for nutrients. Notably, intestinal bacteria maintain homeostatic balance in mammals via multiple dynamic biochemical reactions to produce several metabolites from undigested food, and those metabolites exert various effects on mammalian cells in a time-dependent manner. We have established a method for the analysis of bacterial metabolic dynamics in real time and used it in combination with statistical NMR procedures. METHODOLOGY/PRINCIPAL FINDINGS: We developed a novel method called real-time metabolotyping (RT-MT), which performs sequential (1)H-NMR profiling and two-dimensional (2D) (1)H, (13)C-HSQC (heteronuclear single quantum coherence) profiling during bacterial growth in an NMR tube. The profiles were evaluated with such statistical methods as Z-score analysis, principal components analysis, and time series of statistical TOtal Correlation SpectroScopY (TOCSY). In addition, using 2D (1)H, (13)C-HSQC with the stable isotope labeling technique, we observed the metabolic kinetics of specific biochemical reactions based on time-dependent 2D kinetic profiles. Using these methods, we clarified the pathway for linolenic acid hydrogenation by a gastrointestinal bacterium, Butyrivibrio fibrisolvens. We identified trans11, cis13 conjugated linoleic acid as the intermediate of linolenic acid hydrogenation by B. fibrisolvens, based on the results of (13)C-labeling RT-MT experiments. In addition, we showed that the biohydrogenation of polyunsaturated fatty acids serves as a defense mechanism against their toxic effects. CONCLUSIONS: RT-MT is useful for the characterization of beneficial bacterium that shows potential for use as probiotic by producing bioactive compounds

Search for anomalous couplings in the W tb vertex from the measurement of double differential angular decay rates of single top quarks produced in the t-channel with the ATLAS detector

The electroweak production and subsequent decay of single top quarks is determined by the properties of the Wtb vertex. This vertex can be described by the complex parameters of an effective Lagrangian. An analysis of angular distributions of the decay products of single top quarks produced in the t -channel constrains these parameters simultaneously. The analysis described in this paper uses 4.6 fb−1 of proton-proton collision data at √s =7 TeV collected with the ATLAS detector at the LHC. Two parameters are measured simultaneously in this analysis. The fraction f 1 of decays containing transversely polarised W bosons is measured to be 0.37 ± 0.07 (stat.⊕syst.). The phase δ − between amplitudes for transversely and longitudinally polarised W bosons recoiling against left-handed b-quarks is measured to be −0.014π ± 0.036π (stat.⊕syst.). The correlation in the measurement of these parameters is 0.15. These values result in two-dimensional limits at the 95% confidence level on the ratio of the complex coupling parameters g R and V L, yielding Re[g R /V L] ∈ [−0.36, 0.10] and Im[g R /V L] ∈ [−0.17, 0.23] with a correlation of 0.11. The results are in good agreement with the predictions of the Standard Model

Anatomy of the sign-problem in heavy-dense QCD

QCD at finite densities of heavy quarks is investigated using the density-of-states method. The phase factor expectation value of the quark determinant is calculated to unprecedented precision as a function of the chemical potential. Results are validated using those from a reweighting approach where the latter can produce a significant signalto-noise ratio. We confirm the particle–hole symmetry at low temperatures, find a strong sign problem at intermediate values of the chemical potential, and an inverse Silver Blaze feature for chemical potentials close to the onset value: here, the phase-quenched theory underestimates the density of the full theory

Reconstruction of hadronic decay products of tau leptons with the ATLAS experiment

This paper presents a new method of reconstructing the individual charged and neutral hadrons in tau decays with the ATLAS detector. The reconstructed hadrons are used to classify the decay mode and to calculate the visible four-momentum of reconstructed tau candidates, significantly improving the resolution with respect to the calibration in the existing tau reconstruction. The performance of the reconstruction algorithm is optimised and evaluated using simulation and validated using samples of Z→ττ and Z(→μμ)+jets events selected from proton–proton collisions at a centre-of-mass energy √s=8TeV, corresponding to an integrated luminosity of 5 fb−1.- We thank CERN for the very successful operation of the LHC, as well as the support staff from our institutions without whom ATLAS could not be operated efficiently. We acknowledge the support of ANPCyT, Argentina; YerPhI, Armenia; ARC, Australia; BMWFW and FWF, Austria; ANAS, Azerbaijan; SSTC, Belarus; CNPq and FAPESP, Brazil; NSERC, NRC and CFI, Canada; CERN; CONICYT, Chile; CAS, MOST and NSFC, China; COLCIENCIAS, Colombia; MSMT CR, MPO CR and VSC CR, Czech Republic; DNRF and DNSRC, Denmark; IN2P3-CNRS, CEA-DSM/IRFU, France; GNSF, Georgia; BMBF, HGF, and MPG, Germany; GSRT, Greece; RGC, Hong Kong SAR, China; ISF, I-CORE and Benoziyo Center, Israel; INFN, Italy; MEXT and JSPS, Japan; CNRST, Morocco; FOM and NWO, Netherlands; RCN, Norway; MNiSW and NCN, Poland; FCT, Portugal; MNE/IFA, Romania; MES of Russia and NRC KI, Russian Federation; JINR; MESTD, Serbia; MSSR, Slovakia; ARRS and MIZS, Slovenia; DST/NRF, South Africa; MINECO, Spain; SRC and Wallenberg Foundation, Sweden; SERI, SNSF and Cantons of Bern and Geneva, Switzerland; MOST, Taiwan; TAEK, Turkey; STFC, United Kingdom; DOE and NSF, United States of America. In addition, individual groups and members have received support from BCKDF, the Canada Council, CANARIE, CRC, Compute Canada, FQRNT, and the Ontario Innovation Trust, Canada; EPLANET, ERC, FP7, Horizon 2020 and Marie Sklodowska-Curie Actions, European Union; Investissements d'Avenir Labex and Idex, ANR, Region Auvergne and Fondation Partager le Savoir, France; DFG and AvH Foundation, Germany; Herakleitos, Thales and Aristeia programmes co-financed by EU-ESF and the Greek NSRF; BSF, GIF and Minerva, Israel; BRF, Norway; the Royal Society and Leverhulme Trust, United Kingdom. The crucial computing support from all WLCG partners is acknowledged gratefully, in particular from CERN and the ATLAS Tier-1 facilities at TRIUMF (Canada), NDGF (Denmark, Norway, Sweden), CC-IN2P3 (France), KIT/GridKA (Germany), INFN-CNAF (Italy), NL-T1 (Netherlands), PIC (Spain), ASGC (Taiwan), RAL (UK) and BNL (USA) and in th

Measurement of the tt̄W and tt̄Z production cross sections in pp collisions at √s = 8 TeV with the ATLAS detector

The production cross sections of top-quark pairs in association with massive vector bosons have been measured using data from pp collisions at s√ = 8 TeV. The dataset corresponds to an integrated luminosity of 20.3 fb−¹ collected by the ATLAS detector in 2012 at the LHC. Final states with two, three or four leptons are considered. A fit to the data considering the tt̄W and tt̄Z processes simultaneously yields a significance of 5.0σ (4.2σ) over the background-only hypothesis for tt¯Wtt¯W (tt̄Z) production. The measured cross sections are σtt̄W = 369 + 100−91 fb and σtt̄Z = 176 + 58−52 fb. The background-only hypothesis with neither tt̄W nor tt̄Z production is excluded at 7.1σ. All measurements are consistent with next-to-leading-order calculations for the tt̄W and tt̄Z processes

Searches for Higgs boson pair production in the hh→bbττ, γγWW∗, γγbb, bbbb channels with the ATLAS detector

Searches for both resonant and nonresonant Higgs boson pair production are performed in the hh→bbττ, γγWW∗ final states using 20.3  fb−1 of pp collision data at a center-of-mass energy of 8 TeV recorded with the ATLAS detector at the Large Hadron Collider. No evidence of their production is observed and 95% confidence-level upper limits on the production cross sections are set. These results are then combined with the published results of the hh→γγbb, bbbb analyses. An upper limit of 0.69 (0.47) pb on the nonresonant hh production is observed (expected), corresponding to 70 (48) times the SM gg→hh cross section. For production via narrow resonances, cross-section limits of hh production from a heavy Higgs boson decay are set as a function of the heavy Higgs boson mass. The observed (expected) limits range from 2.1 (1.1) pb at 260 GeV to 0.011 (0.018) pb at 1000 GeV. These results are interpreted in the context of two simplified scenarios of the Minimal Supersymmetric Standard Model

Search for the direct production of charginos and neutralinos in final states with tau leptons in √s=13 TeV collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with at least two hadronically decaying tau leptons is presented. The analysis uses a dataset of pp collisions corresponding to an integrated luminosity of 36.1 fb−1, recorded with the ATLAS detector at the Large Hadron Collider at a centre-of-mass energy of 13TeV.Nosignificant deviation from the expected Standard Model background is observed. Limits are derived in scenarios of ˜χ+1 ˜χ−1 pair production and of ˜χ±1 ˜χ02 and ˜χ+1 ˜χ−1 production in simplified models where the neutralinos and charginos decay solely via intermediate left-handed staus and tau sneutrinos, and the mass of the ˜ τL state is set to be halfway between the masses of the ˜χ±1 and the ˜χ01. Chargino masses up to 630 GeV are excluded at 95% confidence level in the scenario of direct production of ˜χ+1 ˜χ−1 for a massless ˜χ01. Common ˜χ±1 and ˜χ02 masses up to 760 GeV are excluded in the case of production of ˜χ±1 ˜χ02 and ˜χ+1 ˜χ−1 assuming a massless ˜χ01. Exclusion limits for additional benchmark scenarios with large and small mass-splitting between the ˜χ±1 and the ˜χ01 are also studied by varying the ˜ τL mass between the masses of the ˜χ±1 and the ˜χ01

Combined measurement of differential and total cross sections in the H → γγ and the H → ZZ* → 4ℓ decay channels at s=13 TeV with the ATLAS detector

A combined measurement of differential and inclusive total cross sections of Higgs boson production is performed using 36.1 fb−1 of 13 TeV proton–proton collision data produced by the LHC and recorded by the ATLAS detector in 2015 and 2016. Cross sections are obtained from measured H→γγ and H→ZZ*(→4ℓ event yields, which are combined taking into account detector efficiencies, resolution, acceptances and branching fractions. The total Higgs boson production cross section is measured to be 57.0−5.9 +6.0 (stat.) −3.3 +4.0 (syst.) pb, in agreement with the Standard Model prediction. Differential cross-section measurements are presented for the Higgs boson transverse momentum distribution, Higgs boson rapidity, number of jets produced together with the Higgs boson, and the transverse momentum of the leading jet. The results from the two decay channels are found to be compatible, and their combination agrees with the Standard Model predictions