Ruth Harrell

BACKGROUND: Tuberculosis incidence in the UK has risen in the past decade. Disease control depends on epidemiological data, which can be difficult to obtain. Whole-genome sequencing can detect microevolution within Mycobacterium tuberculosis strains. We aimed to estimate the genetic diversity of related M tuberculosis strains in the UK Midlands and to investigate how this measurement might be used to investigate community outbreaks. METHODS: In a retrospective observational study, we used Illumina technology to sequence M tuberculosis genomes from an archive of frozen cultures. We characterised isolates into four groups: cross-sectional, longitudinal, household, and community. We measured pairwise nucleotide differences within hosts and between hosts in household outbreaks and estimated the rate of change in DNA sequences. We used the findings to interpret network diagrams constructed from 11 community clusters derived from mycobacterial interspersed repetitive-unit-variable-number tandem-repeat data. FINDINGS: We sequenced 390 separate isolates from 254 patients, including representatives from all five major lineages of M tuberculosis. The estimated rate of change in DNA sequences was 0.5 single nucleotide polymorphisms (SNPs) per genome per year (95% CI 0.3-0.7) in longitudinal isolates from 30 individuals and 25 families. Divergence is rarely higher than five SNPs in 3 years. 109 (96%) of 114 paired isolates from individuals and households differed by five or fewer SNPs. More than five SNPs separated isolates from none of 69 epidemiologically linked patients, two (15%) of 13 possibly linked patients, and 13 (17%) of 75 epidemiologically unlinked patients (three-way comparison exact p<0.0001). Genetic trees and clinical and epidemiological data suggest that super-spreaders were present in two community clusters. INTERPRETATION: Whole-genome sequencing can delineate outbreaks of tuberculosis and allows inference about direction of transmission between cases. The technique could identify super-spreaders and predict the existence of undiagnosed cases, potentially leading to early treatment of infectious patients and their contacts. FUNDING: Medical Research Council, Wellcome Trust, National Institute for Health Research, and the Health Protection Agency.

BACKGROUND: Winter deaths are a known health and social care challenge for many countries. A previous international comparison showed significant differences in excess winter deaths across Europe in the 1990s, with the northern countries having lower excess winter mortality than those in southern Europe. METHODS: The Excess Winter Deaths Index (EWDI) is the ratio of deaths in the winter period (December to March) compared with deaths in the non-winter period. Data from the Eurostat database and national registries were used to calculate the EWDI for 31 countries in Europe across the time period 2002/2003 to 2010/2011. RESULTS: National EWDI values show heterogeneity, with a broad pattern of increasing EWDI values from northern to southern Europe and increasing mean winter temperature (r(2) = 0.50, P > 0.0001). Malta, Portugal, Spain, Cyprus and Belgium all had an EWDI that was statistically significantly higher than the average EWDI for the other 30 European countries. There was no clear association between country-level EWDI and the level of inter-annual variability in winter temperature across Europe. DISCUSSION: This article demonstrates the differences in EWDI that exist between European countries with implications for both research and policy. Many deaths may be avoidable as environmental, social and personal factors are known to contribute to winter mortality. We now need to work to better understand the causes of inter-country differences.

In February 2013, novel coronavirus (nCoV) infection was diagnosed in an adult male in the United Kingdom with severe respiratory illness, who had travelled to Pakistan and Saudi Arabia 10 days before symptom onset. Contact tracing identified two secondary cases among family members without recent travel: one developed severe respiratory illness and died, the other an influenza-like illness. No other severe cases were identified or nCoV detected in respiratory samples among 135 contacts followed for 10 days.

We have studied the transport properties of a high quality one-dimensional constriction formed in an undoped ${\mathrm{G}\mathrm{a}\mathrm{A}\mathrm{s}/\mathrm{A}\mathrm{l}}_{x}{\mathrm{Ga}}_{1\ensuremath{-}x}\mathrm{As}$ heterostructure and therefore largely free of the random potential of ionized donors. We induce an electron gas electrostatically and are able to vary the sheet carrier density ${(n}_{2\mathrm{D}})$ by a factor of at least seven. The constriction shows resonance-free integer conductance plateaus and the additional ``0.7 structure,'' a plateaulike feature, the conductance of which decreases from about 0.80 towards $0.5\ifmmode\times\else\texttimes\fi{}{2e}^{2}/h$ at low and high ${n}_{2\mathrm{D}}.$ This low value is unaffected by a high in-plane magnetic field, supporting previous evidence and theories that the breaking of the spin degeneracy at high fields persists in some form, even at zero field. The height of the feature generally seen at a conductance of about $0.85\ifmmode\times\else\texttimes\fi{}{2e}^{2}/h$ at high dc bias also varies, and we show that this is in reasonable agreement with a simple relation linking the conductances of the two features. We use a source-drain bias to study the spin splitting of the lowest one-dimensional subbands, and find a spin gap that is independent of ${n}_{2\mathrm{D}}$ for the first subband. We discuss possible reasons for the splitting, and show how various models for the 0.7 structure can be applied in the finite bias regime.

We have developed a technique for the fabrication of high-mobility electron gases formed in undoped GaAs/AlGaAs heterostructures. The use of an insulated gate allows independent control over the carrier density in the Hall bar and ohmic contact regions of the device. This unique design eliminates difficulties in obtaining reliable ohmic contacts, particularly in the low carrier density regime. In the absence of remote ionized impurity scattering, extremely high transport mobilities are obtained at low carrier densities (1×106 cm2 V−1 s−1 at 1×1010 cm−2). This design has been adapted to the formation of undoped one-dimensional electron gases that show clean and reproducible conductance plateau at 1.5 K.