| 1. |
- Asselbergs, Folkert W., et al.
(author)
-
Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci
- 2012
-
In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 91:5, s. 823-838
-
Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering similar to 2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.
|
|
| 2. |
- Berglund, Erik, et al.
(author)
-
Clinical Significance of Alloantibodies in Hand Transplantation : A Multicenter Study
- 2019
-
In: Transplantation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0041-1337 .- 1534-6080. ; 103:10, s. 2173-2182
-
Journal article (peer-reviewed)abstract
- Background. Donor-specific antibodies (DSAs) have a strong negative correlation with long-term survival in solid organ transplantation. Although the clinical significance of DSA and antibody-mediated rejection (AMR) in upper extremity transplantation (UET) remains to be established, a growing number of single-center reports indicate their presence and potential clinical impact. Methods. We present a multicenter study assessing the occurrence and significance of alloantibodies in UET in reference to immunological parameters and functional outcome. Results. Our study revealed a high prevalence and early development of de novo DSA and non-DSA (43%, the majority detected within the first 3 postoperative y). HLA class II mismatch correlated with antibody development, which in turn significantly correlated with the incidence of acute cellular rejection. Cellular rejections preceded antibody development in almost all cases. A strong correlation between DSA and graft survival or function cannot be statistically established at this early stage but a correlation with a lesser outcome seems to emerge. Conclusions. While the phenotype and true clinical effect of AMR remain to be better defined, the high prevalence of DSA and the correlation with acute rejection highlight the need for optimizing immunosuppression, close monitoring, and the relevance of an HLA class II match in UET recipients.
|
|
| 3. |
- Holmes, Michael V., et al.
(author)
-
Mendelian randomization of blood lipids for coronary heart disease
- 2015
-
In: European Heart Journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 36:9, s. 539-539
-
Journal article (peer-reviewed)abstract
- Aims To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization. Methods and results We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a priormeta-analysis (threshold P < 2 x 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P <= 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestrictedallele score (48SNPs) was associated with CHD(OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75). Conclusion The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.
|
|
| 4. |
- Huels, David J., et al.
(author)
-
E-cadherin can limit the transforming properties of activating beta-catenin mutations
- 2015
-
In: EMBO Journal. - : EMBO. - 0261-4189 .- 1460-2075. ; 34:18, s. 2321-2333
-
Journal article (peer-reviewed)abstract
- Wnt pathway deregulation is a common characteristic of many cancers. Only colorectal cancer predominantly harbours mutations in APC, whereas other cancer types (hepatocellular carcinoma, solid pseudopapillary tumours of the pancreas) have activating mutations in beta-catenin (CTNNB1). We have compared the dynamics and the potency of beta-catenin mutations in vivo. Within the murine small intestine (SI), an activating mutation of beta-catenin took much longer to achieve Wnt deregulation and acquire a crypt-progenitor cell (CPC) phenotype than Apc or Gsk3 loss. Within the colon, a single activating mutation of beta-catenin was unable to drive Wnt deregulation or induce the CPC phenotype. This ability of beta-catenin mutation to differentially transform the SI versus the colon correlated with higher expression of E-cadherin and a higher number of E-cadherin: beta-catenin complexes at the membrane. Reduction in E-cadherin synergised with an activating mutation of beta-catenin resulting in a rapid CPC phenotype within the SI and colon. Thus, there is a threshold of beta-catenin that is required to drive transformation, and E-cadherin can act as a buffer to sequester mutated beta-catenin.
|
|
| 5. |
- McCormack, Brendan, et al.
(author)
-
A realist review of interventions and strategies to promote evidence-informed healthcare : a focus on change agency
- 2013
-
In: Implementation Science. - : BioMed Central (BMC). - 1748-5908. ; 8:1, s. 107-
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Change agency in its various forms is one intervention aimed at improving the effectiveness of the uptake of evidence. Facilitators, knowledge brokers and opinion leaders are examples of change agency strategies used to promote knowledge utilization. This review adopts a realist approach and addresses the following question: What change agency characteristics work, for whom do they work, in what circumstances and why?METHODS: The literature reviewed spanned the period 1997-2007. Change agency was operationalized as roles that are aimed at effecting successful change in individuals and organizations. A theoretical framework, developed through stakeholder consultation formed the basis for a search for relevant literature. Team members, working in sub groups, independently themed the data and developed chains of inference to form a series of hypotheses regarding change agency and the role of change agency in knowledge use.RESULTS: 24, 478 electronic references were initially returned from search strategies. Preliminary screening of the article titles reduced the list of potentially relevant papers to 196. A review of full document versions of potentially relevant papers resulted in a final list of 52 papers. The findings add to the knowledge of change agency as they raise issues pertaining to how change agents' function, how individual change agent characteristics effect evidence-informed health care, the influence of interaction between the change agent and the setting and the overall effect of change agency on knowledge utilization. Particular issues are raised such as how accessibility of the change agent, their cultural compatibility and their attitude mediate overall effectiveness. Findings also indicate the importance of promoting reflection on practice and role modeling. The findings of this study are limited by the complexity and diversity of the change agency literature, poor indexing of literature and a lack of theory-driven approaches.CONCLUSION: This is the first realist review of change agency. Though effectiveness evidence is weak, change agent roles are evolving, as is the literature, which requires more detailed description of interventions, outcomes measures, the context, intensity, and levels at which interventions are implemented in order to understand how change agent interventions effect evidence-informed health care.
|
|
| 6. |
- Mulligan, Vanessa, et al.
(author)
-
Prevalence, Macrolide Resistance, and Fluoroquinolone Resistance in Mycoplasma genitalium in Men Who Have Sex With Men Attending an Sexually Transmitted Disease Clinic in Dublin, Ireland in 2017-2018
- 2019
-
In: Sexually Transmitted Diseases. - : Lippincott Williams & Wilkins. - 0148-5717 .- 1537-4521. ; 46:4, s. E35-E37
-
Journal article (peer-reviewed)abstract
- This is the first prevalence study of Mycoplasma genitalium and antimicrobial resistance study in Ireland. In urine samples from men who have sex with men (n = 400) attending a sexually transmitted disease clinic in Dublin, the prevalence of M. genitalium was 3%(12 of 400 specimens; 95% confidence interval, 1.3-4.7%), and the prevalences of macrolide resistance (75%), fluoroquinolone resistance (33.3%), and multidrug resistance (33.3%) were very high.
|
|
| 7. |
- Rycroft-Malone, Jo, et al.
(author)
-
Realist synthesis : illustrating the method for implementation research
- 2012
-
In: Implementation Science. - : BioMed Central (BMC). - 1748-5908. ; 7:33
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Realist synthesis is an increasingly popular approach to the review and synthesis of evidence, which focuses on understanding the mechanisms by which an intervention works (or not). There are few published examples of realist synthesis. This paper therefore fills a gap by describing, in detail, the process used for a realist review and synthesis to answer the question 'what interventions and strategies are effective in enabling evidence-informed healthcare?' The strengths and challenges of conducting realist review are also considered.METHODS: The realist approach involves identifying underlying causal mechanisms and exploring how they work under what conditions. The stages of this review included: defining the scope of the review (concept mining and framework formulation); searching for and scrutinising the evidence; extracting and synthesising the evidence; and developing the narrative, including hypotheses.RESULTS: Based on key terms and concepts related to various interventions to promote evidence-informed healthcare, we developed an outcome-focused theoretical framework. Questions were tailored for each of four theory/intervention areas within the theoretical framework and were used to guide development of a review and data extraction process. The search for literature within our first theory area, change agency, was executed and the screening procedure resulted in inclusion of 52 papers. Using the questions relevant to this theory area, data were extracted by one reviewer and validated by a second reviewer. Synthesis involved organisation of extracted data into evidence tables, theming and formulation of chains of inference, linking between the chains of inference, and hypothesis formulation. The narrative was developed around the hypotheses generated within the change agency theory area.CONCLUSIONS: Realist synthesis lends itself to the review of complex interventions because it accounts for context as well as outcomes in the process of systematically and transparently synthesising relevant literature. While realist synthesis demands flexible thinking and the ability to deal with complexity, the rewards include the potential for more pragmatic conclusions than alternative approaches to systematic reviewing. A separate publication will report the findings of the review.
|
|
