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- Griffin, Paul, et al.
(author)
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Safety, acceptability and tolerability of uncoated and excipient-coated high density silicon micro-projection array patches in human subjects
- 2017
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In: Vaccine. - : ELSEVIER SCI LTD. - 0264-410X .- 1873-2518. ; 35:48, s. 6676-6684
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Journal article (peer-reviewed)abstract
- Most vaccinations are performed by intramuscular injection with a needle and syringe. However, this method is not ideal due to limitations, such as the risk of needle-stick injury, the requirement for trained personnel to give injections and the need to reconstitute lyophilized vaccines. Therefore, we tested an alternative delivery technology that overcomes the problems with needle and syringe. The Nanopatch (TM) is an array of 10,000 silicon micro-projections per cm(2) that can be dry-coated with vaccine for skin delivery. The high number and density of micro-projections means that high velocity application is required to achieve consistent skin penetration. Before clinically testing a vaccine Nanopatch, this study tests the safety, tolerability and acceptability/utility of uncoated and excipient-coated Nanopatches in healthy adults. Nanopatches were applied to skin of the upper arm and volar forearm and left in contact with the skin for two minutes before removal. The application sites were assessed for local skin response over 28 days. Acceptability interviews were also performed. No unexpected adverse events directly related to the Nanopatch application were reported, All applications of the Nanopatch resulted in an expected erythema response which faded between days 3 and 7. In some subjects, some skin discolouration was visible for several days or up to 3 weeks after application. The majority (83%) of subjects reported a preference for the Nanopatch compared to the needle and syringe and found the application process to be simple and acceptable. On a pain scale from 0 to 10, 78% of applications were scored "0" (no pain) with the average scores for less than 1. The results from this study demonstrate the feasibility of the Nanopatch to improve vaccination by showing that application of the product without vaccine to human skin is safe, tolerable and preferred to needle and syringe administration. (C) 2017 The Authors. Published by Elsevier Ltd.
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- Kirchhoff, Tomas, et al.
(author)
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Breast cancer risk and 6q22.33 : combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2
- 2012
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In: PLOS ONE. - : Public library of science. - 1932-6203. ; 7:6
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Journal article (peer-reviewed)abstract
- Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.
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- Koelmel, Jeremy P., et al.
(author)
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An actionable annotation scoring framework for gas chromatography-high-resolution mass spectrometry
- 2022
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In: Exposome. - : Oxford University Press. - 2635-2265 .- 2635-2265. ; 2:1
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Journal article (peer-reviewed)abstract
- Omics-based technologies have enabled comprehensive characterization of our exposure to environmental chemicals (chemical exposome) as well as assessment of the corresponding biological responses at the molecular level (eg, metabolome, lipidome, proteome, and genome). By systematically measuring personal exposures and linking these stimuli to biological perturbations, researchers can determine specific chemical exposures of concern, identify mechanisms and biomarkers of toxicity, and design interventions to reduce exposures. However, further advancement of metabolomics and exposomics approaches is limited by a lack of standardization and approaches for assigning confidence to chemical annotations. While a wealth of chemical data is generated by gas chromatography high-resolution mass spectrometry (GC-HRMS), incorporating GC-HRMS data into an annotation framework and communicating confidence in these assignments is challenging. It is essential to be able to compare chemical data for exposomics studies across platforms to build upon prior knowledge and advance the technology. Here, we discuss the major pieces of evidence provided by common GC-HRMS workflows, including retention time and retention index, electron ionization, positive chemical ionization, electron capture negative ionization, and atmospheric pressure chemical ionization spectral matching, molecular ion, accurate mass, isotopic patterns, database occurrence, and occurrence in blanks. We then provide a qualitative framework for incorporating these various lines of evidence for communicating confidence in GC-HRMS data by adapting the Schymanski scoring schema developed for reporting confidence levels by liquid chromatography HRMS (LC-HRMS). Validation of our framework is presented using standards spiked in plasma, and confident annotations in outdoor and indoor air samples, showing a false-positive rate of 12% for suspect screening for chemical identifications assigned as Level 2 (when structurally similar isomers are not considered false positives). This framework is easily adaptable to various workflows and provides a concise means to communicate confidence in annotations. Further validation, refinements, and adoption of this framework will ideally lead to harmonization across the field, helping to improve the quality and interpretability of compound annotations obtained in GC-HRMS.
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