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Human Ebola virus (EBOV) outbreaks caused by persistent EBOV infection raises questions on the role of zoonotic spillover in filovirus epidemiology. To characterise filovirus zoonotic exposure, we collected cross-sectional serum samples from bushmeat hunters ( n  = 498) in Macenta Prefecture Guinea, adjacent to the index site of the 2013 EBOV-Makona spillover event. We identified distinct immune signatures (20/498, 4.0%) to multiple EBOV antigens (GP, NP, VP40) using stepwise ELISA and Western blot analysis and, live EBOV neutralisation (5/20; 25%). Using comparative serological data from PCR-confirmed survivors of the 2013-2016 EBOV outbreak, we demonstrated that most signatures (15/20) were not plausibly explained by prior EBOV-Makona exposure. Subsequent data-driven modelling of EBOV immunological outcomes to remote-sensing environmental data also revealed consistent associations with intact closed canopy forest. Together our findings suggest exposure to other closely related filoviruses prior to the 2013-2016 West Africa epidemic and highlight future surveillance priorities. In a serological analysis, Bore et al. utilise serum samples, collected from a cohort of individuals associated with bushmeat hunting and butchering, in the forested region of Guinea, a region close to the epicentre of the 2013–2016 West Africa Ebola virus disease epidemic.

Malawi has successfully leveraged multiple delivery platforms to scale-up and sustain the implementation of preventive chemotherapy (PCT) for the control of morbidity caused by soil-transmitted helminths (STH). Sentinel monitoring demonstrates this strategy has been successful in reducing STH infection in school-age children, although our understanding of the contemporary epidemiological profile of STH across the broader community remains limited. As part of a multi-site trial evaluating the feasibility of interrupting STH transmission across three countries, this study aimed to describe the baseline demographics and the prevalence, intensity and associated risk factors of STH infection in Mangochi district, southern Malawi. Between October-December 2017, a community census was conducted across the catchment area of seven primary healthcare facilities, enumerating 131,074 individuals across 124 villages. A cross-sectional parasitological survey was then conducted between March-May 2018 in the censused area as a baseline for a cluster randomised trial. An age-stratified random sample of 6,102 individuals were assessed for helminthiasis by Kato-Katz and completed a detailed risk-factor questionnaire. The age-cluster weighted prevalence of any STH infection was 7.8% (95% C.I. 7.0%-8.6%) comprised predominantly of hookworm species and of entirely low-intensity infections. The presence and intensity of infection was significantly higher in men and in adults. Infection was negatively associated with risk factors that included increasing levels of relative household wealth, higher education levels of any adult household member, current school attendance, or recent deworming. In this setting of relatively high coverage of sanitation facilities, there was no association between hookworm and reported access to sanitation, handwashing facilities, or water facilities. These results describe a setting that has reduced the prevalence of STH to a very low level, and confirms many previously recognised risk-factors for infection. Expanding the delivery of anthelmintics to groups where STH infection persist could enable Malawi to move past the objective of elimination of morbidity, and towards the elimination of STH. Trial registration: NCT03014167 .

To date, epidemiological studies at the index site of the 2013–16 west African Ebola outbreak in Meliandou, Guinea, have been restricted in their scope. We aimed to determine the occurrence of previously undocumented Ebola virus disease (EVD) cases and infections, and to reconstruct transmission events. This cross-sectional seroprevalence survey of the adult population of Meliandou used a highly specific oral fluid test and detailed interviews of all households in the village and key informants. Each household was interviewed, with all members prompted to describe the events of the outbreak, any illness within the household, and possible contact with suspected cases. Information for deceased individuals was provided by relatives living in the same household. Symptoms were based on Ebola virus Makona variant EVD case definitions (focusing on fever, vomiting, and diarrhoea). For antibody testing, we used an Ebola virus glycoprotein IgG capture enzyme immunoassay developed from a previously validated assay. A maximum exposure level was assigned to every participant using a predetermined scale. We used a generalised linear model (logit function) to estimate odds ratios for the association of sociodemographic variables and exposure level with Ebola virus infection. We adjusted estimates for age and maximum exposure, as appropriate. Between June 22, and July 9, 2017, we enrolled 237 participants from 27 households in Meliandou. Two households refused to participate and one was absent. All adults in participating households who were present for the interview provided an oral fluid swab for testing, of which 224 were suitable for analysis. In addition to the 11 EVD deaths described previously, on the basis of clinical description and oral fluid testing, we found two probable EVD deaths and eight previously unrecognised anti-Ebola virus IgG-positive survivors, including one who had mild symptoms and one who was asymptomatic, resulting in a case fatality of 55·6% (95% CI 30·8–78·5) for adults. Health-care work (adjusted odds ratio 6·64, 1·54–28·56; p=0·001) and level of exposure (odds ratio adjusted for linear trend across five levels 2·79, 1·59–4·883; p<0·0001) were independent risk factors for infection. Ebola virus infection was more widespread in this spillover population than previously recognised (21 vs 11 cases). We show the first serological evidence of survivors in this population (eight anti-Ebola virus IgG seropositive) and report a case fatality lower than previously reported (55·6% vs 100% in adults). These data show the high community coverage achievable by using a non-invasive test and, by accurately documenting the beginnings of the west African Ebola virus outbreak, reveal important insight into transmission dynamics and risk factors that underpin Ebola virus spillover events. US Food and Drug Administration, Wellcome Trust, and German Research Council.

We evaluated programmatic approaches for skin neglected tropical disease (NTD) surveillance and completed a robust estimation of the burden of skin NTDs endemic to West Africa (Buruli ulcer, leprosy, lymphatic filariasis morbidity, and yaws). In Maryland, Liberia, exhaustive case finding by community health workers of 56,285 persons across 92 clusters identified 3,241 suspected cases. A total of 236 skin NTDs (34.0 [95% CI 29.1–38.9]/10,000 persons) were confirmed by midlevel healthcare workers trained using a tailored program. Cases showed a focal and spatially heterogeneous distribution. This community health worker‒led approach showed a higher skin NTD burden than prevailing surveillance mechanisms, but also showed high (95.1%) and equitable population coverage. Specialized training and task-shifting of diagnoses to midlevel health workers led to reliable identification of skin NTDs, but reliability of individual diagnoses varied. This multifaceted evaluation of skin NTD surveillance strategies quantifies benefits and limitations of key approaches promoted by the 2030 NTD roadmap of the World Health Organization.

We confirmed endemicity and autochthonous transmission of yaws in Liberia after a population-based, community-led burden estimation (56,825 participants). Serologically confirmed yaws was rare and focal at population level (24 cases; 2.6 [95% CI 1.4-3.9] cases/10,000 population) with similar clinical epidemiology to other endemic countries in West Africa. Unsupervised classification of spatially referenced case finding data indicated that yaws was more likely to occur in hard-to-reach communities; healthcare-seeking was low among communities, and clinical awareness of yaws was low among healthcare workers. We recovered whole bacterial genomes from 12 cases and describe a monophyletic clade of Treponema pallidum subspecies pertenue, phylogenetically distinct from known TPE lineages, including those affecting neighboring nonhuman primate populations (Taï Forest, Côte d'Ivoire). Yaws is endemic in Liberia but exhibits low focal population prevalence with evidence of a historical genetic bottleneck and subsequent local expansion. Reporting gaps appear attributable to challenging epidemiology and low disease awareness.

Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the senescence-associated secretory phenotype (SASP). NAD + metabolism influences both tissue ageing and cancer. However, the role of NAD + metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD + salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest. NAMPT expression is regulated by high mobility group A (HMGA) proteins during senescence. The HMGA–NAMPT–NAD + signalling axis promotes the proinflammatory SASP by enhancing glycolysis and mitochondrial respiration. HMGA proteins and NAMPT promote the proinflammatory SASP through NAD + -mediated suppression of AMPK kinase, which suppresses the p53-mediated inhibition of p38 MAPK to enhance NF-κB activity. We conclude that NAD + metabolism governs the proinflammatory SASP. Given the tumour-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD + augmentation should be administered with precision. Nacarelli et al. show that the nicotinamide-phosphoribosyltransferase-regulated NAD + biogenesis pathway promotes the proinflammatory senescence-associated secretory phenotype by enhancing glycolysis and mitochondrial respiration during senescence.

The phyllosphere—the aerial surfaces of plants, including leaves—is a ubiquitous global habitat that harbors diverse bacterial communities. Phyllosphere bacterial communities have the potential to influence plant biogeography and ecosystem function through their influence on the fitness and function of their hosts, but the host attributes that drive community assembly in the phyllosphere are poorly understood. In this study we used high-throughput sequencing to quantify bacterial community structure on the leaves of 57 tree species in a neotropical forest in Panama. We tested for relationships between bacterial communities on tree leaves and the functional traits, taxonomy, and phylogeny of their plant hosts. Bacterial communities on tropical tree leaves were diverse; leaves from individual trees were host to more than 400 bacterial taxa. Bacterial communities in the phyllosphere were dominated by a core microbiome of taxa including Actinobacteria, Alpha-, Beta-, and Gammaproteobacteria, and Sphingobacteria. Host attributes including plant taxonomic identity, phylogeny, growth and mortality rates, wood density, leaf mass per area, and leaf nitrogen and phosphorous concentrations were correlated with bacterial community structure on leaves. The relative abundances of several bacterial taxa were correlated with suites of host plant traits related to major axes of plant trait variation, including the leaf economics spectrum and the wood density–growth/mortality tradeoff. These correlations between phyllosphere bacterial diversity and host growth, mortality, and function suggest that incorporating information on plant–microbe associations will improve our ability to understand plant functional biogeography and the drivers of variation in plant and ecosystem function. Significance In this study we sequenced bacterial communities present on tree leaves in a neotropical forest in Panama, to quantify the poorly understood relationships between bacterial biodiversity on leaves (the phyllosphere) vs. host tree attributes. Bacterial community structure on leaves was highly correlated with host evolutionary relatedness and suites of plant functional traits related to host ecological strategies for resource uptake and growth/mortality tradeoffs. The abundance of several bacterial taxa was correlated with host growth, mortality, and function. Our study quantifies the drivers of variation in plant-associated microbial biodiversity; our results suggest that incorporating information on plant-associated microbes will improve our understanding of the functional biogeography of plants and plant–microbe interactions.

TAILORx established the role of the 21-gene predictor of genetic risk in ascertaining treatment for women with hormone-receptor–positive, human epidermal growth factor receptor 2–negative breast cancer. Clinical risk factors provided additional prognostic information for women with intermediate genetic risk.

Infections in critically ill patients are associated with persistently poor clinical outcomes. These patients have severely altered and variable antibiotic pharmacokinetics and are infected by less susceptible pathogens. Antibiotic dosing that does not account for these features is likely to result in suboptimum outcomes. In this Review, we explore the challenges related to patients and pathogens that contribute to inadequate antibiotic dosing and discuss how to implement a process for individualised antibiotic therapy that increases the accuracy of dosing and optimises care for critically ill patients. To improve antibiotic dosing, any physiological changes in patients that could alter antibiotic concentrations should first be established; such changes include altered fluid status, changes in serum albumin concentrations and renal and hepatic function, and microvascular failure. Second, antibiotic susceptibility of pathogens should be confirmed with microbiological techniques. Data for bacterial susceptibility could then be combined with measured data for antibiotic concentrations (when available) in clinical dosing software, which uses pharmacokinetic/pharmacodynamic derived models from critically ill patients to predict accurately the dosing needs for individual patients. Individualisation of dosing could optimise antibiotic exposure and maximise effectiveness.

Hundreds of human genes are associated with neurological diseases, but translation into tractable biological mechanisms is lagging. Larval zebrafish are an attractive model to investigate genetic contributions to neurological diseases. However, current CRISPR-Cas9 methods are difficult to apply to large genetic screens studying behavioural phenotypes. To facilitate rapid genetic screening, we developed a simple sequencing-free tool to validate gRNAs and a highly effective CRISPR-Cas9 method capable of converting >90% of injected embryos directly into F0 biallelic knockouts. We demonstrate that F0 knockouts reliably recapitulate complex mutant phenotypes, such as altered molecular rhythms of the circadian clock, escape responses to irritants, and multi-parameter day-night locomotor behaviours. The technique is sufficiently robust to knockout multiple genes in the same animal, for example to create the transparent triple knockout crystal fish for imaging. Our F0 knockout method cuts the experimental time from gene to behavioural phenotype in zebrafish from months to one week.