Ebola exposure, illness experience, and Ebola antibody prevalence in international responders to the West African Ebola epidemic 2014-2016: A cross-sectional study.

BACKGROUND: Healthcare and other front-line workers are at particular risk of infection with Ebola virus (EBOV). Despite the large-scale deployment of international responders, few cases of Ebola virus disease have been diagnosed in this group. Since asymptomatic or pauci-symptomatic infection has been described, it is plausible that infections have occurred in healthcare workers but have escaped being diagnosed. We aimed to assess the prevalence of asymptomatic or pauci-symptomatic infection, and of exposure events, among returned responders to the West African Ebola epidemic 2014-2016. METHODS AND FINDINGS: We used snowball sampling to identify responders who had returned to the UK or Ireland, and used an online consent and questionnaire to determine their exposure to EBOV and their experience of illness. Oral fluid collection devices were sent and returned by post, and samples were tested using an EBOV IgG capture assay that detects IgG to Ebola glycoprotein. Blood was collected from returnees with reactive samples for further testing. Unexposed UK controls were also recruited. In all, 300 individuals consented, of whom 268 (89.3%) returned an oral fluid sample (OFS). The majority had worked in Sierra Leone in clinical, laboratory, research, and other roles. Fifty-three UK controls consented and provided samples using the same method. Of the returnees, 47 (17.5%) reported that they had had a possible EBOV exposure. Based on their free-text descriptions, using a published risk assessment method, we classified 43 (16%) as having had incidents with risk of Ebola transmission, including five intermediate-risk and one high-risk exposure. Of the returnees, 57 (21%) reported a febrile or diarrhoeal illness in West Africa or within 1 mo of return, of whom 40 (70%) were not tested at the time for EBOV infection. Of the 268 OFSs, 266 were unreactive. Two returnees, who did not experience an illness in West Africa or on return, had OFSs that were reactive on the EBOV IgG capture assay, with similar results on plasma. One individual had no further positive test results; the other had a positive result on a double-antigen bridging assay but not on a competitive assay or on an indirect EBOV IgG ELISA. All 53 controls had non-reactive OFSs. While the participants were not a random sample of returnees, the number participating was high. CONCLUSIONS: This is the first study, to our knowledge, of the prevalence of EBOV infection in international responders. More than 99% had clear negative results. Sera from two individuals had discordant results on the different assays; both were negative on the competitive assay, suggesting that prior infection was unlikely. The finding that a significant proportion experienced "near miss" exposure events, and that most of those who experienced symptoms did not get tested for EBOV at the time, suggests a need to review and standardise protocols for the management of possible exposure to EBOV, and for the management of illness, across organisations that deploy staff to outbreaks

Asymptomatic infection and family contact patterns in households of Ebola Virus Disease survivors, Sierra Leone 2015

The data set contains information on 937 people (living and dead) who were resident in the households of people who survived Ebola Virus Disease (EVD) in the Kerry Town Ebola Treatment Centre in Western Area Province, Sierra Leone, during the 2014-2016 epidemic. It includes individual and household characteristics, information on exposure levels, symptoms experienced by individuals during the period when the household was affected by EVD, outcomes, possible routes of transmission, and ELISA results from antibody testing for Ebola IgG in oral fluid. Survivor households were chosen because they were more easily contactable through the Save the Children survivors outreach programme: 123 of 152 survivors and their households were interviewed

Hodge Theory on Metric Spaces

Hodge theory is a beautiful synthesis of geometry, topology, and analysis, which has been developed in the setting of Riemannian manifolds. On the other hand, spaces of images, which are important in the mathematical foundations of vision and pattern recognition, do not fit this framework. This motivates us to develop a version of Hodge theory on metric spaces with a probability measure. We believe that this constitutes a step towards understanding the geometry of vision. The appendix by Anthony Baker provides a separable, compact metric space with infinite dimensional \alpha-scale homology.Comment: appendix by Anthony W. Baker, 48 pages, AMS-LaTeX. v2: final version, to appear in Foundations of Computational Mathematics. Minor changes and addition

Boosting understanding of Lassa Fever virus epidemiology: Field testing a novel assay to identify past Lassa Fever virus infection in blood and oral fluids of survivors and unexposed controls in Sierra Leone.

BACKGROUND: Despite identification 50 years ago, the true burden of Lassa Fever (LF) across Africa remains undefined for reasons including research focus on hospitalised patients, lack of validated field-feasible tools which reliably identify past infection, and the fact that all assays require blood samples making large-scale surveys difficult. Designated a priority pathogen of epidemic potential requiring urgent research by the World Health Organisation, a better understanding of LF sero-epidemiology is essential to developing and evaluating new interventions including vaccines. We describe the first field testing of a novel species-neutral Double Antigen Binding Assay (DABA) designed to detect antibodies to LF in plasma and oral fluid. METHODOLOGY/PRINCIPAL FINDINGS: Paired plasma and oral fluid were collected in Sierra Leone from survivors discharged from Kenema Government Hospital Lassa Fever Unit between 1980 and 2018, and from controls recruited in Freetown in 2019. Epidemiological sensitivity and specificity of the DABA measured against historical diagnosis in survivors and self-declared non-exposed controls was 81.7% (95% CI 70.7%- 89.9%) and 83.3% (72.7%- 91.1%) respectively in plasma, and 71.8% (60.0%- 81.9%) and 83.3% (72.7%- 91.1%) respectively in oral fluid. Antibodies were identified in people infected up to 15 years and, in one case, 40 years previously. Participants found oral fluid collection easy and painless with 80% happy to give an oral fluid sample regularly. CONCLUSIONS/SIGNIFICANCE: Given the difficulties of assay validation in a resource-limited setting, including unexpected exposures and diagnostics of varying accuracy, the new assay performed well in both plasma and oral fluid. Sensitivity and specificity are expected to be higher when case/control ascertainment is more definitive and further work is planned to investigate this. Even at the performance levels achieved, the species-neutral DABA has the potential to facilitate the large-scale seroprevalence surveys needed to underpin essential developments in LF control, as well as support zoonotic investigations

New 4-aryl-1,3,2-oxathiazolylium-5-olates: chemical synthesis and photochemical stability of a novel series of S-nitrosothiols

S-nitrosothiols (RSNOs) remain one of the most popular classes of NO-donating compounds due to their ability to release nitric oxide (NO) under non-enzymatic means whilst producing an inert disulphide byproduct. However, alligning these compounds to the different biological fields of NO research has proved to be problematic due to the inherent instability of such compounds under a variety of conditions including heat, light and the presence of copper ions. 1,3,2-Oxathiazolylium-5-olates (OZOs) represent an interesting subclass of S-nitrosothiols that lock the –SNO moiety into a five membered heterocyclic ring in an attempt to improve the compound’s overall stability. The synthesis of a novel series of halogen-containing OZOs was comprehensively studied resulting in a seven-step route and overall yields ranging between 21 and 37%. The photochemical stability of these compounds was assessed to determine if Snitrosothiols locked within these mesoionic ring systems can offer greater stability and thereby release NO in a more controllable fashion than their non-cyclic counterparts

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer

MR fluoroscopy in vascular and cardiac interventions (review)

Vascular and cardiac disease remains a leading cause of morbidity and mortality in developed and emerging countries. Vascular and cardiac interventions require extensive fluoroscopic guidance to navigate endovascular catheters. X-ray fluoroscopy is considered the current modality for real time imaging. It provides excellent spatial and temporal resolution, but is limited by exposure of patients and staff to ionizing radiation, poor soft tissue characterization and lack of quantitative physiologic information. MR fluoroscopy has been introduced with substantial progress during the last decade. Clinical and experimental studies performed under MR fluoroscopy have indicated the suitability of this modality for: delivery of ASD closure, aortic valves, and endovascular stents (aortic, carotid, iliac, renal arteries, inferior vena cava). It aids in performing ablation, creation of hepatic shunts and local delivery of therapies. Development of more MR compatible equipment and devices will widen the applications of MR-guided procedures. At post-intervention, MR imaging aids in assessing the efficacy of therapies, success of interventions. It also provides information on vascular flow and cardiac morphology, function, perfusion and viability. MR fluoroscopy has the potential to form the basis for minimally invasive image–guided surgeries that offer improved patient management and cost effectiveness

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.352

Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 ] HEALTH ]F2 ]2009 ]223175). The CIMBA data management and data analysis were supported by Cancer Research.UK grants 12292/A11174 and C1287/A10118. The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME ]ON Post ]GWAS Initiative (U19 ]CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute (dbGap accession number phs000178.v8.p7). The cBio portal is developed and maintained by the Computational Biology Center at Memorial Sloan ] Kettering Cancer Center. SH is supported by an NHMRC Program Grant to GCT. Details of the funding of individual investigators and studies are provided in the Supplementary Note. This study made use of data generated by the Wellcome Trust Case Control consortium, funding for which was provided by the Wellcome Trust under award 076113. The results published here are, in part, based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancerhttp://dx.doi.org/10.1038/ng.3185This is the Author Accepted Manuscript of 'Identification of six new susceptibility loci for invasive epithelial ovarian cancer' which was published in Nature Genetics 47, 164–171 (2015) © Nature Publishing Group - content may only be used for academic research

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat