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- Ferwerda, Bart, et al.
(författare)
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Functional and genetic evidence that the Mal/TIRAP allele variant 180L has been selected by providing protection against septic shock.
- 2009
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:25, s. 10272-10277
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Tidskriftsartikel (refereegranskat)abstract
- Adequate responses by our innate immune system toward invading pathogens were of vital importance for surviving infections, especially before the antibiotic era. Recently, a polymorphism in Mal (Ser180Leu, TIRAP rs8177374), an important adaptor protein downstream of the Toll-like receptor (TLR) 2 and 4 pathways, has been described to provide protection against a broad range of infectious pathogens. We assessed the functional effects of this polymorphism in human experimental endotoxemia, and we demonstrate that individuals bearing the TIRAP 180L allele display an increased, innate immune response to TLR4 and TLR2 ligands, but not to TLR9 stimulation. This phenotype has been related to an increased resistance to infection. However, an overshoot in the release of proinflammatory cytokines by TIRAP 180L homozygous individuals suggests a scenario of balanced evolution. We have also investigated the worldwide distribution of the Ser180Leu polymorphism in 14 populations around the globe to correlate the genetic makeup of TIRAP with the local infectious pressures. Based on the immunological, clinical, and genetic data, we propose that this mutation might have been selected in West Eurasia during the early settlement of this region after the out-of-Africa migration of modern Homo sapiens. This combination of functional and genetic data provides unique insights to our understanding of the pathogenesis of sepsis.
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- Gulick, Sean, P.S., et al.
(författare)
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The first day of the Cenozoic
- 2019
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : US National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 116, s. 19342-19351
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Tidskriftsartikel (refereegranskat)abstract
- Highly expanded Cretaceous–Paleogene (K-Pg) boundary section from the Chicxulub peak ring, recovered by International Ocean Discovery Program (IODP) –International Continental Scientific Drilling Program (ICDP) Expedition 364, provides an unprecedented window into the immediate aftermath of the impact. Site M0077 includes ∼130 m of impact melt rock and suevite deposited the first day of the Cenozoic covered by <1 m of micrite-rich carbonate deposite over subsequent weeks to years. We present an interpreted series of events based on analyses of these drill cores. Within minutes of the impact, centrally uplifted basement rock collapsed outward to forma peak ring capped in melt rock. Within tens of minutes, the peak ring was covered in ∼40 m of brecciated impact melt rock and coarsegrained suevite, including clasts possibly generated by melt–water interactions during ocean resurge. Within an hour, resurge crested the peak ring, depositing a 10-m-thick layer of suevite with increased particle roundness and sorting. Within hours, the full resurge deposit formed through settling and seiches, resulting in an 80-m-thick fining-upward, sorted suevite in the flooded crater. Within a day, the reflected rim-wave tsunami reached the crater, depositing a cross-bedded sand-to-fine gravel layer enriched in polycyclic aromatic hydrocarbons overlain by charcoal fragments. Generation of a deep crater open to the ocean allowed rapid flooding and sediment accumulation rates among the highest known in the geologic record. The high-resolution section provides insight into the impact environmental effects, including charcoal as evidence for impactinduced wildfires and a paucity of sulfur-rich evaporites from the target supporting rapid global cooling and darkness as extinction mechanisms.
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- Bowman, L. R., et al.
(författare)
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Alarm Variables for Dengue Outbreaks: A Multi-Centre Study in Asia and Latin America
- 2016
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 11:6
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Tidskriftsartikel (refereegranskat)abstract
- Background Worldwide, dengue is an unrelenting economic and health burden. Dengue outbreaks have become increasingly common, which place great strain on health infrastructure and services. Early warning models could allow health systems and vector control programmes to respond more cost-effectively and efficiently. The Shewhart method and Endemic Channel were used to identify alarm variables that may predict dengue outbreaks. Five country datasets were compiled by epidemiological week over the years 2007-2013. These data were split between the years 2007-2011 (historic period) and 2012-2013 (evaluation period). Associations between alarm/outbreak variables were analysed using logistic regression during the historic period while alarm and outbreak signals were captured during the evaluation period. These signals were combined to form alarm/outbreak periods, where 2 signals were equal to 1 period. Alarm periods were quantified and used to predict subsequent outbreak periods. Across Mexico and Dominican Republic, an increase in probable cases predicted outbreaks of hospitalised cases with sensitivities and positive predictive values (PPV) of 93%/83% and 97%/86% respectively, at a lag of 1-12 weeks. An increase in mean temperature ably predicted outbreaks of hospitalised cases in Mexico and Brazil, with sensitivities and PPVs of 79%/73% and 81%/46% respectively, also at a lag of 1-12 weeks. Mean age was predictive of hospitalised cases at sensitivities and PPVs of 72%/74% and 96%/45% in Mexico and Malaysia respectively, at a lag of 4-16 weeks. An increase in probable cases was predictive of outbreaks, while meteorological variables, particularly mean temperature, demonstrated predictive potential in some countries, but not all. While it is difficult to define uniform variables applicable in every country context, the use of probable cases and meteorological variables in tailored early warning systems could be used to highlight the occurrence of dengue outbreaks or indicate increased risk of dengue transmission.
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- Juszczak, Edmund, et al.
(författare)
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Introducing the CONsolidated Standards of Reporting Trials (CONSORT) statement for randomised controlled trials (RCTs) using cohorts and routinely collected health data
- 2019
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Ingår i: Trials. - : BMC. - 1745-6215. ; 20:Suppl. 1, s. 131-131
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Randomised controlled trials (RCTs) are increasingly being conducted using existing sources of data, such as cohorts, administrative databases, disease registries and electronic health records. RCTs conducted using existing data sources require additional information to be reported. This reporting guideline is an extension of the 2010 version of the Consolidated Standards of Reporting Trials (CONSORT) Statement for RCTs using cohorts and routinely collected health data.Methods: A long-list of potential items for the checklist was identified through two methods: firstly, modifications to the current CONSORT checklist were generated using existing reporting guidelines, including the Reporting of Observational Studies in Epidemiology (STROBE) and REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statements. Secondly, ascoping review of RCTs conducted in the last decade using cohorts and routinely collected health data facilitated the modification and identification of other potential items. Using the long-list, a three-stage Delphi exercise was conducted to assess the importance of each item for inclusion in the final extension checklist, which was finalised at a face-to-face meeting of experts.Results: A long-list of 27 items was created and 125 experts registered for the three-round Delphi exercise (92, 77 and 62 experts participated in each round respectively). Consensus was reached on 21 out of 27 items. The results of the Delphi exercise informed a face-to-face consensus meeting in May 2019; core items to be included in the extension checklist were finalised at this meeting. Corresponding explanations of extensions and new items with examples of good reporting were developed subsequently.Conclusion: The guideline checklist can facilitate transparent reporting of RCTs using cohorts and routinely collected health data, to assist evaluations of rigour and reproducibility, enhance understanding of the methodology, and make the results more useful for clinicians, journal editors, reviewers, guideline authors, and funders.
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- Lloyd-Donald, P, et al.
(författare)
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Assessing TEG6S reliability between devices and across multiple time points: A prospective thromboelastography validation study
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 7045-
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Tidskriftsartikel (refereegranskat)abstract
- The TEG6S is a novel haemostasis analyser utilising resonance technology. It offers potentially greater coagulation information and ease of use, however has not been independently validated in a clinical setting. We aimed to determine if the TEG6S is reliable between devices and across time points. We performed a prospective observational study with ethical approval. For interdevice reliability, we performed simultaneous analysis on two TEG6S devices on 25 adult ICU patients. For time point reliability, we performed repeated sampling across five different time points on 15 adult participants. Blood was collected with informed consent, or as standard care, before four-channel citrated kaolin analysis. We observed almost perfect interdevice reliability across all TEG parameters. The Lin’s concordance correlation coefficients (95% CI, major axis regression slope, intercept) were R-time: 0.96 (0.92–0.99, 0.88, 0.57); K-time: 0.93 (0.87–0.98, 1.07, 0.00); Alpha Angle: 0.87 (0.78–0.96, 1.20, −14.10); Maximum Amplitude: 0.99 (0.98–0.99, 1.02, −1.38); Clot Lysis: 0.89 (0.82–0.97, 1.20, 0.07). Additionally, we observed moderate-to-high reliability across time points. Demonstrating almost perfect agreement across different devices and moderate-to-high reliability across multiple time points, suggests the TEG6S platform can be used with haemostatic accuracy and generalisability. This has potentially significant implications for clinical practice and multi-site research programs.
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