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- Bonham, LW, et al.
(författare)
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Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 10854-
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Tidskriftsartikel (refereegranskat)abstract
- The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA’s relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration.
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- Hodges, P. W., et al.
(författare)
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Building a Collaborative Model of Sacroiliac Joint Dysfunction and Pelvic Girdle Pain to Understand the Diverse Perspectives of Experts
- 2019
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Ingår i: PM&R. - : Wiley. - 1934-1482 .- 1934-1563. ; 11:Suppl. 1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pelvic girdle pain (PGP) and sacroiliac joint (SIJ) dysfunction/pain are considered frequent contributors to low back pain (LBP). Like other persistent pain conditions, PGP is increasingly recognized as a multifactorial problem involving biological, psychological, and social factors. Perspectives differ between experts and a diversity of treatments (with variable degrees of evidence) have been utilized. Objective: To develop a collaborative model of PGP that represents the collective view of a group of experts. Specific goals were to analyze structure and composition of conceptual models contributed by participants, to aggregate them into a metamodel, to analyze the metamodel's composition, and to consider predicted efficacy of treatments. Design: To develop a collaborative model of PGP, models were generated by invited individuals to represent their understanding of PGP using fuzzy cognitive mapping (FCM). FCMs involved proposal of components related to causes, outcomes, and treatments for pain, disability, and quality of life, and their connections. Components were classified into thematic categories. Weighting of connections was summed for components to judge their relative importance. FCMs were aggregated into a metamodel for analysis of the collective opinion it represented and to evaluate expected efficacy of treatments. Results: From 21 potential contributors, 14 (67%) agreed to participate (representing six disciplines and seven countries). Participants' models included a mean (SD) of 22 (5) components each. FCMs were refined to combine similar terms, leaving 89 components in 10 categories. Biomechanical factors were the most important in individual FCMs. The collective opinion from the metamodel predicted greatest efficacy for injection, exercise therapy, and surgery for pain relief. Conclusions: The collaborative model of PGP showed a bias toward biomechanical factors. Most efficacious treatments predicted by the model have modest to no evidence from clinical trials, suggesting a mismatch between opinion and evidence. The model enables integration and communication of the collection of opinions on PGP.
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