Rationing tests for drug-resistant tuberculosis - who are we prepared to miss?

BACKGROUND: Early identification of patients with drug-resistant tuberculosis (DR-TB) increases the likelihood of treatment success and interrupts transmission. Resource-constrained settings use risk profiling to ration the use of drug susceptibility testing (DST). Nevertheless, no studies have yet quantified how many patients with DR-TB this strategy will miss. METHODS: A total of 1,545 subjects, who presented to Lima health centres with possible TB symptoms, completed a clinic-epidemiological questionnaire and provided sputum samples for TB culture and DST. The proportion of drug resistance in this population was calculated and the data was analysed to demonstrate the effect of rationing tests to patients with multidrug-resistant TB (MDR-TB) risk factors on the number of tests needed and corresponding proportion of missed patients with DR-TB. RESULTS: Overall, 147/1,545 (9.5%) subjects had culture-positive TB, of which 32 (21.8%) had DR-TB (MDR, 13.6%; isoniazid mono-resistant, 7.5%; rifampicin mono-resistant, 0.7%). A total of 553 subjects (35.8%) reported one or more MDR-TB risk factors; of these, 506 (91.5%; 95% CI, 88.9-93.7%) did not have TB, 32/553 (5.8%; 95% CI, 3.4-8.1%) had drug-susceptible TB, and only 15/553 (2.7%; 95% CI, 1.5-4.4%) had DR-TB. Rationing DST to those with an MDR-TB risk factor would have missed more than half of the DR-TB population (17/32, 53.2%; 95% CI, 34.7-70.9). CONCLUSIONS: Rationing DST based on known MDR-TB risk factors misses an unacceptable proportion of patients with drug-resistance in settings with ongoing DR-TB transmission. Investment in diagnostic services to allow universal DST for people with presumptive TB should be a high priority

Molecular design and control of fullerene-based bi-thermoelectric materials

Molecular junctions are a versatile test bed for investigating nanoscale thermoelectricity and contribute to the design of new cost-effective environmentally friendly organic thermoelectric materials. It was suggested that transport resonances associated with discrete molecular levels could play a key role in thermoelectric performance, but no direct experimental evidence has been reported. Here we study single-molecule junctions of the endohedral fullerene Sc3N@C8 connected to gold electrodes using a scanning tunnelling microscope. We find that the magnitude and sign of the thermopower depend strongly on the orientation of the molecule and on applied pressure. Our calculations show that Sc3N inside the fullerene cage creates a sharp resonance near the Fermi level, whose energetic location, and hence the thermopower, can be tuned by applying pressure. These results reveal that Sc3N@C80 is a bi-thermoelectric material, exhibiting both positive and negative thermopower, and provide an unambiguous demonstration of the importance of transport resonances in molecular junctions

Study of B0(s)→K0Sh+h′− decays with first observation of B0s→K0SK±π∓ and B0s→K0Sπ+π−

A search for charmless three-body decays of B 0 and B0s mesons with a K0S meson in the final state is performed using the pp collision data, corresponding to an integrated luminosity of 1.0 fb−1, collected at a centre-of-mass energy of 7 TeV recorded by the LHCb experiment. Branching fractions of the B0(s)→K0Sh+h′− decay modes (h (′) = π, K), relative to the well measured B0→K0Sπ+π− decay, are obtained. First observation of the decay modes B0s→K0SK±π∓ and B0s→K0Sπ+π− and confirmation of the decay B0→K0SK±π∓ are reported. The following relative branching fraction measurements or limits are obtained B(B0→K0SK±π∓)B(B0→K0Sπ+π−)=0.128±0.017(stat.)±0.009(syst.), B(B0→K0SK+K−)B(B0→K0Sπ+π−)=0.385±0.031(stat.)±0.023(syst.), B(B0s→K0Sπ+π−)B(B0→K0Sπ+π−)=0.29±0.06(stat.)±0.03(syst.)±0.02(fs/fd), B(B0s→K0SK±π∓)B(B0→K0Sπ+π−)=1.48±0.12(stat.)±0.08(syst.)±0.12(fs/fd)B(B0s→K0SK+K−)B(B0→K0Sπ+π−)∈[0.004;0.068]at90%CL

Differential branching fraction and angular analysis of Λb0→Λμ+μ−\Lambda^{0}_{b} \rightarrow \Lambda \mu^+\mu^- decays

The differential branching fraction of the rare decay $\Lambda^{0}_{b} \rightarrow \Lambda \mu^+\mu^-$ is measured as a function of $q^{2}$, the square of the dimuon invariant mass. The analysis is performed using proton-proton collision data, corresponding to an integrated luminosity of 3.0 \mbox{ fb}^{-1}, collected by the LHCb experiment. Evidence of signal is observed in the $q^2$ region below the square of the $J/\psi$ mass. Integrating over 15 < q^{2} < 20 \mbox{ GeV}^2/c^4 the branching fraction is measured as d\mathcal{B}(\Lambda^{0}_{b} \rightarrow \Lambda \mu^+\mu^-)/dq^2 = (1.18 ^{+ 0.09} _{-0.08} \pm 0.03 \pm 0.27) \times 10^{-7} ( \mbox{GeV}^{2}/c^{4})^{-1}, where the uncertainties are statistical, systematic and due to the normalisation mode, $\Lambda^{0}_{b} \rightarrow J/\psi \Lambda$, respectively. In the $q^2$ intervals where the signal is observed, angular distributions are studied and the forward-backward asymmetries in the dimuon ($A^{l}_{\rm FB}$) and hadron ($A^{h}_{\rm FB}$) systems are measured for the first time. In the range 15 < q^2 < 20 \mbox{ GeV}^2/c^4 they are found to be A^{l}_{\rm FB} = -0.05 \pm 0.09 \mbox{ (stat)} \pm 0.03 \mbox{ (syst)} and A^{h}_{\rm FB} = -0.29 \pm 0.07 \mbox{ (stat)} \pm 0.03 \mbox{ (syst)}.Comment: 27 pages, 10 figures, Erratum adde

Variation in RNA Virus Mutation Rates across Host Cells

It is well established that RNA viruses exhibit higher rates of spontaneous mutation than DNA viruses and microorganisms. However, their mutation rates vary amply, from 10−6 to 10−4 substitutions per nucleotide per round of copying (s/n/r) and the causes of this variability remain poorly understood. In addition to differences in intrinsic fidelity or error correction capability, viral mutation rates may be dependent on host factors. Here, we assessed the effect of the cellular environment on the rate of spontaneous mutation of the vesicular stomatitis virus (VSV), which has a broad host range and cell tropism. Luria-Delbrück fluctuation tests and sequencing showed that VSV mutated similarly in baby hamster kidney, murine embryonic fibroblasts, colon cancer, and neuroblastoma cells (approx. 10−5 s/n/r). Cell immortalization through p53 inactivation and oxygen levels (1–21%) did not have a significant impact on viral replication fidelity. This shows that previously published mutation rates can be considered reliable despite being based on a narrow and artificial set of laboratory conditions. Interestingly, we also found that VSV mutated approximately four times more slowly in various insect cells compared with mammalian cells. This may contribute to explaining the relatively slow evolution of VSV and other arthropod-borne viruses in nature

Marine mammals and Good Environmental Status: Science, Policy and Society; Challenges and Opportunities

The Marine Strategy Framework Directive has become the key instrument for marine conservation in European seas. We review its implementation, focusing on cetacean biodiversity, using the examples of Spain and the Regional Seas Convention, OSPAR. The MSFD has been widely criticised for legal vagueness, lack of coordination, uncertainty about funding, and poor governance; its future role within EU Integrated Maritime Policy remains unclear. Nevertheless, the first stages of the process have run broadly to schedule: current status, environmental objectives and indicators have been described and the design of monitoring programmes is in progress, drawing on experience with other environmental legislation. The MSFD is now entering its critical phase, with lack of funding for monitoring, limited scope for management interventions, and uncertainty about how conservation objectives will be reconciled with the needs of other marine and maritime sectors, being among the main concerns. Clarity in governance, about the roles of the EU, Member States, Regional Seas Conventions and stakeholders, is needed to ensure success. However, even if (as seems likely) good environmental status cannot be achieved by 2020, significant steps will have been taken to place environmental sustainability centre-stage in the development of Integrated Maritime Policy for EU seas.Postprin

Variation in the Structure of Bird Nests between Northern Manitoba and Southeastern Ontario

Traits that converge in appearance under similar environmental conditions among phylogenetically independent lineages are thought to represent adaptations to local environments. We tested for convergence in nest morphology and composition of birds breeding in two ecologically different locations in Canada: Churchill in northern Manitoba and Elgin in southeastern Ontario. We examined nests from four families of passerine birds (Turdidae: Turdus, Parulidae: Dendroica, Emberizidae: Passerculus and Fringillidae: Carduelis) where closely related populations or species breed in both locations. Nests of American Robins, Yellow Warblers, and Carduelis finches had heavier nest masses, and tended to have thicker nest-walls, in northern Manitoba compared with conspecifics or congenerics breeding in southeastern Ontario. Together, all species showed evidence for wider internal and external nest-cup diameters in northern Manitoba, while individual species showed varying patterns for internal nest-cup and external nest depths. American Robins, Yellow Warblers, and Carduelis finches in northern Manitoba achieved heavier nest masses in different ways. American Robins increased all materials in similar proportions, and Yellow Warblers and Common Redpolls used greater amounts of select materials. While changes in nest composition vary uniquely for each species, the pattern of larger nests in northern Manitoba compared to southeastern Ontario in three of our four phylogenetically-independent comparisons suggests that birds are adapting to similar selective pressures between locations

U–Pb Zircon geochronology of the Cambro-Ordovician metagranites and metavolcanic rocks of central and NW Iberia

New U–Pb zircon data from metagranites and metavolcanic rocks of the Schist-Graywacke Complex Domain and the Schistose Domain of Galicia Tras-os-Montes Zone from central and NW Iberia contribute to constrain the timing of the Cambro-Ordovician magmatism from Central Iberian and Galicia Tras-os-Montes Zones which occurred between 498 and 462 Ma. The crystallization ages of the metagranites and metavolcanic rocks from the northern Schist-Graywacke Complex Domain are as follows: (a) in west Salamanca, 489 ± 5 Ma for Vitigudino, 486 ± 6 Ma for Fermoselle and 471 ± 7 Ma for Ledesma; (b) in northern Gredos, 498 ± 4 Ma for Castellanos, 492 ± 4 Ma for San Pelayo and 488 ± 3 Ma for Bercimuelle; (c) in Guadarrama, 490 ± 5 Ma for La Estacion I, 489 ± 9 Ma for La Canada, 484 ± 6 Ma for Vegas de Matute (leucocratic), 483 ± 6 Ma for El Cardoso, 482 ± 8 Ma for La Morcuera, 481 ± 9 Ma for Buitrago de Lozoya, 478 ± 7 Ma for La Hoya, 476 ± 5 Ma for Vegas de Matute (melanocratic), 475 ± 5 Ma for Riaza, 473 ± 8 Ma for La Estacion II and 462 ± 11 Ma for La Berzosa; and (d) in Toledo, 489 ± 7 Ma for Mohares and 480 ± 8 Ma for Polan. The crystallization ages of the metagranites from the Schistose Domain of Galicia Tras-os-Montes Zone are 497 ± 6 Ma for Laxe, 486 ± 8 Ma for San Mamede, 482 ± 7 Ma for Bangueses, 481 ± 5 Ma for Noia, 480 ± 10 for Rial de Sabucedo, 476 ± 9 Ma for Vilanova, 475 ± 6 Ma for Pontevedra, 470 ± 6 Ma for Cherpa and 462 ± 8 Ma for Bande.This magmatism is characterized by an average isotopic composition of (87Sr/86Sr)485Ma ≈ 0.712, (eNd)485Ma ≈ -4.1 and (TDM) ≈ 1.62 Ga, and a high zircon inheritance, composed of Ediacaran–Early Cambrian (65 %) and, to a lesser extent, Cryogenian, Tonian, Mesoproterozoic, Orosirian and Archean pre-magmatic cores. Combining our geochronological and isotopic data with others of similar rocks from the European Variscan Belt, it may be deduced that Cambro-Ordovician magmas from this belt were mainly generated by partial melting of Ediacaran–Early Cambrian igneous rocks

Endothelial Cells Support Persistent Gammaherpesvirus 68 Infection

A variety of human diseases are associated with gammaherpesviruses, including neoplasms of lymphocytes (e.g. Burkitt's lymphoma) and endothelial cells (e.g. Kaposi's sarcoma). Gammaherpesvirus infections usually result in either a productive lytic infection, characterized by expression of all viral genes and rapid cell lysis, or latent infection, characterized by limited viral gene expression and no cell lysis. Here, we report characterization of endothelial cell infection with murine gammaherpesvirus 68 (γHV68), a virus phylogenetically related and biologically similar to the human gammaherpesviruses. Endothelial cells supported γHV68 replication in vitro, but were unique in that a significant proportion of the cells escaped lysis, proliferated, and remained viable in culture for an extended time. Upon infection, endothelial cells became non-adherent and altered in size, complexity, and cell-surface protein expression. These cells were uniformly infected and expressed the lytic transcription program based on detection of abundant viral gene transcripts, GFP fluorescence from the viral genome, and viral surface protein expression. Additionally, endothelial cells continued to produce new infectious virions as late as 30 days post-infection. The outcome of this long-term infection was promoted by the γHV68 v-cyclin, because in the absence of the v-cyclin, viability was significantly reduced following infection. Importantly, infected primary endothelial cells also demonstrated increased viability relative to infected primary fibroblasts, and this increased viability was dependent on the v-cyclin. Finally, we provide evidence for infection of endothelial cells in vivo in immune-deficient mice. The extended viability and virus production of infected endothelial cells indicated that endothelial cells provided a source of prolonged virus production and identify a cell-type specific adaptation of gammaherpesvirus replication. While infected endothelial cells would likely be cleared in a healthy individual, persistently infected endothelial cells could provide a source of continued virus replication in immune-compromised individuals, a context in which gammaherpesvirus-associated pathology frequently occurs