Quantifying HIV transmission flow between high-prevalence hotspots and surrounding communities: a population-based study in Rakai, Uganda

Background International and global organisations advocate targeting interventions to areas of high HIV prevalence (ie, hotspots). To better understand the potential benefits of geo-targeted control, we assessed the extent to which HIV hotspots along Lake Victoria sustain transmission in neighbouring populations in south-central Uganda. Methods We did a population-based survey in Rakai, Uganda, using data from the Rakai Community Cohort Study. The study surveyed all individuals aged 15–49 years in four high-prevalence Lake Victoria fishing communities and 36 neighbouring inland communities. Viral RNA was deep sequenced from participants infected with HIV who were antiretroviral therapy-naive during the observation period. Phylogenetic analysis was used to infer partial HIV transmission networks, including direction of transmission. Reconstructed networks were interpreted through data for current residence and migration history. HIV transmission flows within and between high-prevalence and low-prevalence areas were quantified adjusting for incomplete sampling of the population. Findings Between Aug 10, 2011, and Jan 30, 2015, data were collected for the Rakai Community Cohort Study. 25 882 individuals participated, including an estimated 75·7% of the lakeside population and 16·2% of the inland population in the Rakai region of Uganda. 5142 participants were HIV-positive (2703 [13·7%] in inland and 2439 [40·1%] in fishing communities). 3878 (75·4%) people who were HIV-positive did not report antiretroviral therapy use, of whom 2652 (68·4%) had virus deep-sequenced at sufficient quality for phylogenetic analysis. 446 transmission networks were reconstructed, including 293 linked pairs with inferred direction of transmission. Adjusting for incomplete sampling, an estimated 5·7% (95% credibility interval 4·4–7·3) of transmissions occurred within lakeside areas, 89·2% (86·0–91·8) within inland areas, 1·3% (0·6–2·6) from lakeside to inland areas, and 3·7% (2·3–5·8) from inland to lakeside areas. Interpretation Cross-community HIV transmissions between Lake Victoria hotspots and surrounding inland populations are infrequent and when they occur, virus more commonly flows into rather than out of hotspots. This result suggests that targeted interventions to these hotspots will not alone control the epidemic in inland populations, where most transmissions occur. Thus, geographical targeting of high prevalence areas might not be effective for broader epidemic control depending on underlying epidemic dynamics. Funding The Bill & Melinda Gates Foundation, the National Institute of Allergy and Infectious Diseases, the National Institute of Mental Health, the National Institute of Child Health and Development, the Division of Intramural Research of the National Institute for Allergy and Infectious Diseases, the World Bank, the Doris Duke Charitable Foundation, the Johns Hopkins University Center for AIDS Research, and the President's Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention

Somatic mutations affect key pathways in lung adenocarcinoma

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well- classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers - including NF1, APC, RB1 and ATM - and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.National Human Genome Research InstituteWe thank A. Lash, M.F. Zakowski, M.G. Kris and V. Rusch for intellectual contributions, and many members of the Baylor Human Genome Sequencing Center, the Broad Institute of Harvard and MIT, and the Genome Center at Washington University for support. This work was funded by grants from the National Human Genome Research Institute to E.S.L., R.A.G. and R.K.W.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62885/1/nature07423.pd

JUNO Sensitivity to Invisible Decay Modes of Neutrons

We explore the bound neutrons decay into invisible particles (e.g., $n\rightarrow 3 \nu$ or $nn \rightarrow 2 \nu$) in the JUNO liquid scintillator detector. The invisible decay includes two decay modes: $n \rightarrow { inv}$ and $nn \rightarrow { inv}$. The invisible decays of $s$-shell neutrons in $^{12}{\rm C}$ will leave a highly excited residual nucleus. Subsequently, some de-excitation modes of the excited residual nuclei can produce a time- and space-correlated triple coincidence signal in the JUNO detector. Based on a full Monte Carlo simulation informed with the latest available data, we estimate all backgrounds, including inverse beta decay events of the reactor antineutrino $\bar{\nu}_e$, natural radioactivity, cosmogenic isotopes and neutral current interactions of atmospheric neutrinos. Pulse shape discrimination and multivariate analysis techniques are employed to further suppress backgrounds. With two years of exposure, JUNO is expected to give an order of magnitude improvement compared to the current best limits. After 10 years of data taking, the JUNO expected sensitivities at a 90% confidence level are $\tau/B( n \rightarrow { inv} ) > 5.0 \times 10^{31} \, {\rm yr}$ and $\tau/B( nn \rightarrow { inv} ) > 1.4 \times 10^{32} \, {\rm yr}$.Comment: 28 pages, 7 figures, 4 table

No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing

Background: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. Methods: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. Results: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). Conclusions: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels

Reconstruction algorithm developments and study of the beam optics constraints at 4 TeV in the ATLAS/ALFA experiment

My summer student work was divided into two main projects. My first project consisted in implementing the fiber width measured from the data in the reconstruction algorithm in order to improve the detector resolution. I then performed some data analysis in order to measure the constraints on the beam optics at 4 TeV. Its main purpose was to check that the constraints deviations are the same as the 3.5 TeV run already analyzed

Gamma-tracking and sensitivity to gamma-emitting backgrounds in SuperNEMO

International audienceSuperNEMO, successor to the NEMO3 experiment, is looking for the neutrinoless double beta decay. Its unique design, combining both tracking and calorimetry techniques, provides essential topological informations. Indeed, fully reconstructing the event kinematics allows a powerful background discrimination, would discriminate between the several hypothesized underlying mechanisms, but also gives access to a variety of event topologies which can be used to measure the different background contributions. The SuperNEMO software relies on a range of algorithms to ensure a faithful event reconstruction. The improved detector performance for γ detection coupled to new γ-reconstruction algorithms, based on geometrical and Time-of-Flight criteria, will not only improve the measurements of the γ-emitter backgrounds ((208)Tl, (214)Bi...) but also increase the sensitivity for the search of ββ-decays to the excited states

Neutrino oscillation physics in JUNO

International audienceThe Jiangmen Underground Neutrino Observatory (JUNO) is a multipurpose neutrino detector under construction in China. It is located 700 m underground, 53 km away from eight nuclear reactors. It will use 20 kt of liquid scintillator surrounded by 17,612 20" photomultipliers and 25,600 3" photomultipliers to detect neutrino interactions with a 3% energy resolution at 1MeV. JUNO's main physics goals are the determination of the neutrino mass ordering and the high-precision measurement of $\Delta m^2_{21}$, $\sin^2\theta_{12}$, and $\Delta m^2_{31}$.I will present how JUNO can measure the reactor antineutrino oscillations to reach a $3\sigma$ sensitivity to the neutrino mass ordering with 6 years of data. JUNO can also measure atmospheric neutrino oscillations to enhance this sensitivity. After 6 years, JUNO will improve the current precision on $\Delta m^2_{21}$, $\sin^2\theta_{12}$, and $\Delta m^2_{31}$ by an order of magnitude, achieving precision well below the sub-percent level

0νββ0 \nu \beta\beta sensitivity with the SuperNEMO demonstrator

International audienceThe SuperNEMO demonstrator 1 , which is the first module of the SuperNEMOexperiment, is looking for the neutrinoless double beta decay 0νββ in order tounveil the nature of the neutrino. Its unique design, combining both trackingand calorimetry techniques, provides essential topological information. Indeed,fully reconstructing the event kinematics gives access to a variety of eventtopologies which can be used to measure the different background contributionsas well as look for new processes such as the double beta decays to the excitedstates of the daughter nuclei. Using this information in a multivariate analysiscan improve the background discrimination power and further increase thedetector sensitivity. The commissioning of the demonstrator is ongoing and thedata taking should start in Summer 2017

Développement d'outils de reconstruction et sensibilité du démonstrateur SuperNEMO

SuperNEMO is an experiment looking for the neutrinoless double beta decay in an effort to unveil the Majorana nature of the neutrino. The first module, called the demonstrator, is under construction and commissioning in the Laboratoire Souterrain de Modane. Its unique design combines tracking and calorimetry techniques. The demonstrator can study 7 kg of ⁸²Se, shaped in thin source foils. These source foils are surrounded by a wire chamber, thus allowing a 3-dimensional reconstruction of the charged particles tracks. The individual particles energies are then measured by a segmented calorimeter, composed of plastic scintillators coupled with photomultipliers. A magnetic field can be applied to the tracking volume in order to identify the charge of the particles. SuperNEMO is thus able to perform a full reconstruction of the events kinematics and to identify the nature of the particles involved: electrons, positrons, α particles or γ particles. In practice, the particle and event reconstruction relies on a variety of algorithms, implemented in the dedicated SuperNEMO simulation and reconstruction software. The γ reconstruction is particularly challenging since γ particles do not leave tracks in the wire chamber and are only detected by the calorimeter, sometimes multiple times. Several γ reconstruction approaches were explored during this thesis. This work lead to the creation of a new algorithm optimizing the γ reconstruction efficiency and improving the γ energy reconstruction. Other programs allowing the particle identification and performing the topological measurements relevant to an event were also developed. The value of the magnetic field was optimized for the 0νββ decay search, based on Monte-Carlo simulations. The magnetic shieldings performances and their impact on the shape of the magnetic field were estimated with measurements performed on small scale magnetic coils. The SuperNEMO demonstrator is able to measure its own background contamination thanks to dedicated analysis channels. At the end of the first 2.5 years data taking phase, the main backgrounds target activities should be measured accurately. The ⁸²Se 2νββ half-life should be known with a 0.3 % total uncertainty. Unlike other double beta decay experiments relying solely on the two electrons energy sum, SuperNEMO has access to the full events kinematics and thus to more topological information. A multivariate analysis based on Boosted Decision Trees was shown to guarantee at least a 10 % increase of the sensitivity of the 0νββ decay search. After 2.5 years, and if no excess of 0νββ events is observed, the SuperNEMO demonstrator should be able to set a limit on the 0νββ half-life of T > 5.85 10²⁴ y, translating into a limit on the effective Majorana neutrino mass mββ 10²⁶ y or mββ 5.85 10²⁴ ans, équivalant à une limite supérieure sur la masse effective du neutrino mββ 10²⁶ ans et mββ < 40 − 110 meV