Defining Fever.
Ontology highlight
ABSTRACT:
SUBMITTER: Mackowiak PA
PROVIDER: S-EPMC8394829 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AimThe American Academy of Pediatrics and the European Centre for Pediatric and Adolescent Medicine guideline define fever as a temperature >38.0°C for all ages and recommend use of rectal thermometers in children <3 years. Based on new literature, this definition of fever using a fixed threshold of 38.0°C needs to be re-examined.DesignA multi-site diagnostic accuracy study was conducted to compare an "age-based" threshold model with a "fixed" threshold over 38.0°C on a total of 894 patients of which 373 were ill.MethodsThe "age-based" and "fixed" threshold fever determinations were then compared to a clinical categorization ("well" or "ill") conducted by a clinician through a comprehensive examination.ResultsThe sensitivity and accuracy for the age-based thresholds were found to be superior to the fixed thresholds in all ages and current ear thermometers were found equivalent to rectal thermometers in infants <6 months.
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Project description:Pyrin, the familial Mediterranean fever protein, is found in association with the cytoskeleton in myeloid/monocytic cells and modulates IL-1beta processing, NF-kappaB activation, and apoptosis. These effects are mediated in part through cognate interactions with the adaptor protein ASC, which shares an N-terminal motif with pyrin. We sought additional upstream regulators of inflammation by using pyrin as the bait in yeast two-hybrid assays. We now show that proline serine threonine phosphatase-interacting protein [PSTPIP1, or CD2-binding protein 1 (CD2BP1)], a tyrosine-phosphorylated protein involved in cytoskeletal organization, also interacts with pyrin. Recently, PSTPIP1/CD2BP1 mutations were shown to cause the syndrome of pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA), a dominantly inherited autoinflammatory disorder mediated predominantly by granulocytes. Endogenous PSTPIP1/CD2BP1 and pyrin are coexpressed in monocytes and granulocytes and can be coimmunoprecipitated from THP-1 cells. The B box segment of pyrin was necessary and the B box/coiled-coil segment sufficient for this interaction, whereas the SH3 and coiled-coil domains of PSTPIP1/CD2BP1 were both necessary, but neither was sufficient, for pyrin binding. The Y344F PSTPIP1/CD2BP1 mutation, which blocks tyrosine phosphorylation, was associated with a marked reduction in pyrin binding in pervanadate-treated cells. PAPA-associated A230T and E250Q PSTPIP1/CD2BP1 mutations markedly increased pyrin binding as assayed by immunoprecipitation and, relative to WT, these mutants were hyperphosphorylated when coexpressed with c-Abl kinase. Consistent with the hypothesis that these mutations exert a dominant-negative effect on the previously reported activity of pyrin, we found increased IL-1beta production by peripheral blood leukocytes from a clinically active PAPA patient with the A230T PSTPIP1/CD2BP1 mutation and in cell lines transfected with both PAPA-associated mutants.
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Project description:Hereditary periodic fever syndromes are characterized by recurrent episodes of fever and inflammation with no known pathogenic or autoimmune cause. In humans, several genes have been implicated in this group of diseases, but the majority of cases remain unexplained. A similar periodic fever syndrome is relatively frequent in the Chinese Shar-Pei breed of dogs. In the western world, Shar-Pei have been strongly selected for a distinctive thick and heavily folded skin. In this study, a mutation affecting both these traits was identified. Using genome-wide SNP analysis of Shar-Pei and other breeds, the strongest signal of a breed-specific selective sweep was located on chromosome 13. The same region also harbored the strongest genome-wide association (GWA) signal for susceptibility to the periodic fever syndrome (p(raw)?= 2.3 × 10??, p(genome)?= 0.01). Dense targeted resequencing revealed two partially overlapping duplications, 14.3 Kb and 16.1 Kb in size, unique to Shar-Pei and upstream of the Hyaluronic Acid Synthase 2 (HAS2) gene. HAS2 encodes the rate-limiting enzyme synthesizing hyaluronan (HA), a major component of the skin. HA is up-regulated and accumulates in the thickened skin of Shar-Pei. A high copy number of the 16.1 Kb duplication was associated with an increased expression of HAS2 as well as the periodic fever syndrome (p < 0.0001). When fragmented, HA can act as a trigger of the innate immune system and stimulate sterile fever and inflammation. The strong selection for the skin phenotype therefore appears to enrich for a pleiotropic mutation predisposing these dogs to a periodic fever syndrome. The identification of HA as a major risk factor for this canine disease raises the potential of this glycosaminoglycan as a risk factor for human periodic fevers and as an important driver of chronic inflammation.
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Project description:BackgroundInsights, when acted upon, can result in positive changes to the business, for HCPs, and ultimately for patients. Medical Information, as a customer facing function, is one of the groups that generate insights. Data and insights across different functions of an organization need to be compiled to provide a comprehensive view. The purpose of this paper is to develop a shared definition of insights and to provide a working guidance for the insight process.MethodsTwo surveys were conducted of the phactMI membership first to establish a shared definition of insights and then to benchmark current insight process. From this data and the shared experience of the working group a proposed guidance was developed.ResultsThe developed definition of an insight is "An insight is the deeper understanding of the why behind trends of information that lead us to determine if an action is warranted". For the most robust outcomes, insight identification needs to be a cross functional activity. The proposed structured approach can be leveraged and customized for any organization and include the following five steps: INvestigate, Scrutinize, Identify, Take Action, and Enlighten (INSITE).ConclusionThe INSITE process provides a simple framework that should become routine for all Medical Information colleagues who are leading the work around insights. The process should be shared across all functions that participate in the insight generation process. This is another area where Medical Information can demonstrate leadership and highlight their value to the organization.
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Project description:The traditional definition of natural antibodies (NAbs) states that these antibodies are present prior to the body encountering cognate antigen, providing a first line of defense against infection thereby, allowing time for a specific antibody response to be mounted. The literature has a seemingly common definition of NAbs; however, as our knowledge of antibodies and B cells is refined, re-evaluation of the common definition of Nabs may be required. Defining Nabs becomes important as the function of NAb production is used to define B cell subsets (1) and as these important molecules are shown to play numerous roles in the immune system (Figure 1). Herein, we aim to briefly summarize our current knowledge of NAbs in the context of initiating a discussion within the field of how such an important and multifaceted group of molecules should be defined.
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Project description:Sometimes mutations in two genes produce a phenotype that is surprising in light of each mutation's individual effects. This phenomenon, which defines genetic interaction, can reveal functional relationships between genes and pathways. For example, double mutants with surprisingly slow growth define synergistic interactions that can identify compensatory pathways or protein complexes. Recent studies have used four mathematically distinct definitions of genetic interaction (here termed Product, Additive, Log, and Min). Whether this choice holds practical consequences has not been clear, because the definitions yield identical results under some conditions. Here, we show that the choice among alternative definitions can have profound consequences. Although 52% of known synergistic genetic interactions in Saccharomyces cerevisiae were inferred according to the Min definition, we find that both Product and Log definitions (shown here to be practically equivalent) are better than Min for identifying functional relationships. Additionally, we show that the Additive and Log definitions, each commonly used in population genetics, lead to differing conclusions related to the selective advantages of sexual reproduction.
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Project description:Epichromatin is identified by immunostaining fixed and permeabilized cells with particular bivalent anti-nucleosome antibodies (mAbs PL2-6 and 1H6). During interphase, epichromatin resides adjacent to the inner nuclear membrane; during mitosis, at the outer surface of mitotic chromosomes. By STED (stimulated emission depletion) microscopy, PL2-6 stained interphase epichromatin is ?76 nm thick and quite uniform; mitotic epichromatin is more variable in thickness, exhibiting a "wrinkled" surface with an average thickness of ?78 nm. Co-immunostaining with anti-Ki-67 demonstrates Ki-67 deposition between the PL2-6 "ridges" of mitotic epichromatin. Monovalent papain-derived Fab fragments of PL2-6 yield a strikingly different punctate "chromomeric" immunostaining pattern throughout interphase nuclei and along mitotic chromosome arms. Evidence from electrophoretic mobility shift assay (EMSA) and from analytical ultracentrifugation characterize the Fab/mononucleosome complex, supporting the concept that there are two binding sites per nucleosome. The peptide sequence of the Hv3 region (heavy chain variable region 3) of the PL2-6 antibody binding site strongly resembles other nucleosome acidic patch binding proteins (especially, LANA and CENPC), supporting that the nucleosome acidic patch is included within the epichromatin epitope. It is speculated that the interphase epichromatin epitope is "exposed" with favorable geometric arrangements for binding bivalent PL2-6 at the surface chromatin; whereas, the epitope is "hidden" within internal chromatin. Furthermore, it is suggested that the "exposed" nucleosome surface of mitotic epichromatin may play a role in post-mitotic nuclear envelope reformation.
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Project description:"Environmental Health Literacy" (EHL) is embraced as important for improving public health by preventing disability and disease from our environment. This study aimed to determine knowledge and skill items identified by Environmental Health (EH) professionals as being associated with EHL and to understand how these items rank by importance. Such a coordinated effort to tease out skills and knowledge needed for EHL had not previously been made. We utilized a mixed-methods approach of semi-structured interviews of 24 EH professionals and a quantitative survey with 275 EH professionals across the United States. Interviews identified 37 skill and 69 knowledge items, which were used to create the survey questions. Survey results indicate 32 knowledge items and six skill items considered essential by >50% of respondents where consensus was reached between professional groups (chi square test: p > 0.05). We further identified six knowledge items, which >70% of EH professionals agreed were essential for EHL. The identification of these knowledge and skill items sets the stage for further research that includes exploring agreement with more diverse stakeholders, developing comprehensive measures of EHL and evaluation of methods and materials designed to improve EHL.
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