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Nontuberculous mycobacteria can cause disseminated infections in immunocompromised patients and are challenging to treat because of antimicrobial resistance and adverse effects of prolonged multidrug treatment. We report successful treatment with bedaquiline, a novel antimycobacterial drug, as part of combination therapy for 2 patients with disseminated nontuberculous mycobacteria co-infected with HIV.

Québécois writer Francine Noël is the author of three novels, Maryse, Myriam première and Babel, prise deux ou Nous avons tous découvert l' Amérique. In a three novels, reality and fiction intermingle and collide, creating a rich intertextual network. While few observers and experts in Québec question Francine Noël's feminist commitment, critics on the other hand do not readily see in her work a deeper quest to raise issues dealing with the gender bias in language itself. From the perspective of feminist literary criticism and the theories of Bakhtin, this thesis argues that the main insight of Francine Noël's work is the ability to grasp, assemble, and contextualise the ideas, images, and symbolic embodiment of feminist and gender thinking in Québec. Francine Noël's novels then are deeply polyphonic. In fact, it will be shown that beyond the themes, the structure of these novels, especially Maryse and Myriam première, transforms the traditional narrative from a monologic and androcentic perspective to a feminist one. By adopting a feminist approach and by drawing at the same time from Bakhtin's theories, this thesis on Francine Noël's work makes a contribution to feminist literary criticism in Québec but also, more generally, to the study of feminist narratology.

1. Hodgson et al. [Journal of Applied Ecology 46 (2009) 964] argue that connectivity is complex and uncertain, that it can be improved incidentally by increasing habitat extent, and that connectivity conservation is unlikely to be effective under climate change. 2. We believe that they have overlooked recent research on dispersal behaviour and structural connectivity, which has improved our understanding of functional connectivity and revealed that it will not necessarily increase with habitat extent. 3. New modelling techniques including least-cost path models incorporate this more detailed understanding of connectivity into conservation planning, facilitating the true aim of connectivity conservation — to ensure appropriate interactions between habitat extent, quality and connectivity. 4. Synthesis and applications. Advances in behavioural research and modelling techniques allow us to manage structural connectivity with as much certainty as we manage extent and quality of habitat. Successful landscape conservation to address both current threats and future climate change must manage these three elements in concert.

Timothy Bishop and colleagues from GenoMEL present a genome-wide association study for melanoma. They report three loci associated with susceptibility to melanoma, of which two were previously associated with pigmentation. We report a genome-wide association study of melanoma conducted by the GenoMEL consortium based on 317K tagging SNPs for 1,650 selected cases and 4,336 controls, with replication in an additional two cohorts (1,149 selected cases and 964 controls from GenoMEL, and a population-based case-control study in Leeds of 1,163 cases and 903 controls). The genome-wide screen identified five loci with genotyped or imputed SNPs reaching P < 5 × 10 −7 . Three of these loci were replicated: 16q24 encompassing MC1R (combined P = 2.54 × 10 −27 for rs258322), 11q14-q21 encompassing TYR ( P = 2.41 × 10 −14 for rs1393350) and 9p21 adjacent to MTAP and flanking CDKN2A ( P = 4.03 × 10 −7 for rs7023329). MC1R and TYR are associated with pigmentation, freckling and cutaneous sun sensitivity, well-recognized melanoma risk factors. Common variants within the 9p21 locus have not previously been associated with melanoma. Despite wide variation in allele frequency, these genetic variants show notable homogeneity of effect across populations of European ancestry living at different latitudes and show independent association to disease risk.

A safe, effective, and rapidly scalable vaccine against Zika virus infection is needed. We developed a purified formalin-inactivated Zika virus vaccine (ZPIV) candidate that showed protection in mice and non-human primates against viraemia after Zika virus challenge. Here we present the preliminary results in human beings. We did three phase 1, placebo-controlled, double-blind trials of ZPIV with aluminium hydroxide adjuvant. In all three studies, healthy adults were randomly assigned by a computer-generated list to receive 5 μg ZPIV or saline placebo, in a ratio of 4:1 at Walter Reed Army Institute of Research, Silver Spring, MD, USA, or of 5:1 at Saint Louis University, Saint Louis, MO, USA, and Beth Israel Deaconess Medical Center, Boston, MA, USA. Vaccinations were given intramuscularly on days 1 and 29. The primary objective was safety and immunogenicity of the ZPIV candidate. We recorded adverse events and Zika virus envelope microneutralisation titres up to day 57. These trials are registered at ClinicalTrials.gov, numbers NCT02963909, NCT02952833, and NCT02937233. We enrolled 68 participants between Nov 7, 2016, and Jan 25, 2017. One was excluded and 67 participants received two injections of Zika vaccine (n=55) or placebo (n=12). The vaccine caused only mild to moderate adverse events. The most frequent local effects were pain (n=40 [60%]) or tenderness (n=32 [47%]) at the injection site, and the most frequent systemic reactogenic events were fatigue (29 [43%]), headache (26 [39%]), and malaise (15 [22%]). By day 57, 52 (92%) of vaccine recipients had seroconverted (microneutralisation titre ≥1:10), with peak geometric mean titres seen at day 43 and exceeding protective thresholds seen in animal studies. The ZPIV candidate was well tolerated and elicited robust neutralising antibody titres in healthy adults. Departments of the Army and Defense and National Institute of Allergy and Infectious Diseases.

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP , PLA2G6 , and IRF4 , and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1 , PPARGC1B , HDAC4 , FAM208B, DOCK8 , and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk ( KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis. Melanocytic nevus count is associated with melanoma risk. In this study, a meta-analysis of 11 nevus GWAS studies identifies novel SNPs in KITLG and 9q32, and bivariate analysis with melanoma GWAS meta-analysis reveals that most nevus genes affect melanoma risk, while melanoma risk loci do not alter the nevus count.

Coal-fired power plants release substantial air pollution, which included over 60% of US sulfur dioxide emissions in 2014. Such air pollution may exacerbate asthma, but direct studies of the health impacts linked to power plant air pollution are rare. Here we take advantage of a natural experiment in Louisville, Kentucky, where one coal-fired power plant was retired and converted to natural gas, and three others installed SO 2 emission control systems between 2013 and 2016. Dispersion modelling indicated that exposure to SO 2 emissions from these power plants decreased after the energy transitions. We used several analysis strategies, which include difference-in-differences, first-difference and interrupted time-series modelling to show that the emissions control installations and plant retirements are associated with a reduced asthma disease burden related to hospitalizations and emergency room visits at the ZIP-code level, and to individual-level medication use as measured by digital medication sensors. Transition from coal to gas, retrofitting and retirement of coal power plants are expected to reduce air pollution and therefore have positive health effects. Casey et al. present direct evidence of this phenomenon by reporting improved asthma outcomes in the wake of coal plant closure and retrofit in Louisville, Kentucky.

Sterol 14-[alpha]-demethylase (C14DM) is a key enzyme in the biosynthesis of sterols and the primary target of azoles. In Leishmania major, genetic or chemical inactivation of C14DM leads to accumulation of 14-methylated sterol intermediates and profound plasma membrane abnormalities including increased fluidity and failure to maintain ordered membrane microdomains. These defects likely contribute to the hypersensitivity to heat and severely reduced virulence displayed by the C14DM-null mutants (c14dm). In addition to plasma membrane, sterols are present in intracellular organelles. In this study, we investigated the impact of C14DM ablation on mitochondria. Our results demonstrate that c14dm mutants have significantly higher mitochondrial membrane potential than wild type parasites. Such high potential leads to the buildup of reactive oxygen species in the mitochondria, especially under nutrient-limiting conditions. Consistent with these mitochondrial alterations, c14dm mutants show impairment in respiration and are heavily dependent on glucose uptake and glycolysis to generate energy. Consequently, these mutants are extremely sensitive to glucose deprivation and such vulnerability can be rescued through the supplementation of glucose or glycerol. In addition, the accumulation of oxidants may also contribute to the heat sensitivity exhibited by c14dm. Finally, genetic or chemical ablation of C14DM causes increased susceptibility to pentamidine, an antimicrobial agent with activity against trypanosomatids. In summary, our investigation reveals that alteration of sterol synthesis can negatively affect multiple cellular processes in Leishmania parasites and make them vulnerable to clinically relevant stress conditions.

We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10(-5) and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10(-3): an SNP in ATM (rs1801516, overall P = 3.4 x 10(-9)), an SNP in MX2 (rs45430, P = 2.9 x 10-9) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 x 10(-10)). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 x 10(-7) under a fixed-effects model and P = 1.2 x 10(-3) under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.

Cross-sector partnerships benefit public health by leveraging ideas, resources, and expertise from a wide range of partners. In this study we documented the process and impact of AIR Louisville (a collaboration forged among the Louisville Metro Government, a nonprofit institute, and a technology company) in successfully tackling a complex public health challenge: asthma. We enrolled residents of Louisville, Kentucky, with asthma and used electronic inhaler sensors to monitor where and when they used medication. We found that the use of the digital health platform achieved positive clinical outcomes, including a 78 percent reduction in rescue inhaler use and a 48 percent improvement in symptom-free days. Moreover, the crowdsourced real-world data on inhaler use, combined with environmental data, led to policy recommendations including enhancing tree canopy, tree removal mitigation, zoning for air pollution emission buffers, recommended truck routes, and developing a community asthma notification system. AIR Louisville represents a model that can be replicated to address many public health challenges by simultaneously guiding individual, clinical, and policy decisions.