Vascular disease and vascular risk factors in relation to motor features and cognition in early Parkinson's disease

Funded by Parkinson's UK National Institute for Health Research (NIHR) DeNDRoN network NIHR Newcastle Biomedical Research Unit Newcastle University NIHR funded Biomedical Research Centre in CambridgePeer reviewedPublisher PD

Interventions for prevention of type 2 diabetes in relatives:A systematic review

The relatives and partners of people with type 2 diabetes are at increased risk of developing type 2 diabetes. This systematic review examines randomized controlled trials, written in English that tested an intervention, which aimed to modify behaviors known to delay or prevent type 2 diabetes, among the relatives or partners of people with type 2 diabetes. Study quality was assessed using the Cochrane Collaboration’s tool for assessing risk of bias. Seven studies met the inclusion criteria. The majority of studies were at low risk of bias. Six studies tested an intervention in first-degree relatives of people with type 2 diabetes and one in partners. Intervention components and intervention intensity across studies varied, with those targeting diet and physical activity reporting the most significant changes in primary outcomes. Only one study did not observe significant changes in primary outcomes. There were three main recruitment approaches: advertising in the community, recruiting people through their relatives with diabetes, or identifying people as high risk by screening of their own health care contacts. Some evidence was found for potentially successful interventions to prevent type 2 diabetes among the relatives and partners of people with type 2 diabetes, although finding simple and effective methods to identify and recruit them remains a challenge. Future studies should explore the effect of patients’ perceptions on their family members’ behavior and capitalize on family relationships in order to increase intervention effectiveness

GENETIC COUNSELOR UTILIZATION AND INTERPRETATION OF SOMATIC TUMOR TESTING IN EVALUATION FOR LYNCH SYNDROME

Lynch syndrome (LS) is a hereditary cancer predisposition syndrome characterized by increased risk for colorectal and uterine cancers. Individuals with pathogenic variants in the mismatch repair (MMR) genes (MLH1, MSH2/EPCAM, MSH6, PMS2) are diagnosed with LS and subsequently recommended to proceed with high risk screening protocols to increase prevention and early detection of LS-related cancers. Various tumor studies can help identify those at high risk for LS, but sometimes create uncertainty with discordant screening and germline results, leading to unexplained mismatch repair deficiency (UMMRD). Somatic testing of the MMR genes has created opportunities for resolving UMMRD, thus clarifying LS status and ensuring appropriate cancer surveillance. However, guidelines for such testing are currently limited. The purpose of this study was to examine current and hypothetical ordering practices of cancer genetic counselors for LS evaluation and to investigate participants’ interpretation of somatic MMR testing results. Two-hundred eligible participants were recruited through the National Society of Genetic Counselors listserv and answered questions regarding demographics, ordering practices, barriers to somatic MMR testing, theoretical patient scenarios, and need for further guidelines. Statistical analysis was done using Chi-square, Fisher exact, and Wilcoxon rank-sum tests while themes were identified from free-text responses. Most respondents did not include somatic MMR testing in the work-up for LS and did not routinely order this testing, but indicated interest in ordering this in conjunction with germline testing. The gap between preferred testing strategies and current ordering practices for somatic MMR testing may be due to reported laboratory and insurance-related barriers, particularly cost and coordination of tissue specimens. Nearly all individuals endorsed the need for additional guidelines for somatic MMR testing, which could provide support to reduce barriers, encourage insurance coverage, and allow for appropriate screening recommendations for patients and family members of those with UMMRD

Integrating biomedical research and electronic health records to create knowledge-based biologically meaningful machine-readable embeddings.

In order to advance precision medicine, detailed clinical features ought to be described in a way that leverages current knowledge. Although data collected from biomedical research is expanding at an almost exponential rate, our ability to transform that information into patient care has not kept at pace. A major barrier preventing this transformation is that multi-dimensional data collection and analysis is usually carried out without much understanding of the underlying knowledge structure. Here, in an effort to bridge this gap, Electronic Health Records (EHRs) of individual patients are connected to a heterogeneous knowledge network called Scalable Precision Medicine Oriented Knowledge Engine (SPOKE). Then an unsupervised machine-learning algorithm creates Propagated SPOKE Entry Vectors (PSEVs) that encode the importance of each SPOKE node for any code in the EHRs. We argue that these results, alongside the natural integration of PSEVs into any EHR machine-learning platform, provide a key step toward precision medicine

The Central role of KNG1 gene as a genetic determinant of coagulation pathway-related traits: Exploring metaphenotypes

Traditional genetic studies of single traits may be unable to detect the pleiotropic effects involved in complex diseases. To detect the correlation that exists between several phenotypes involved in the same biological process, we introduce an original methodology to analyze sets of correlated phenotypes involved in the coagulation cascade in genome-wide association studies. The methodology consists of a two-stage process. First, we define new phenotypic meta-variables (linear combinations of the original phenotypes), named metaphenotypes, by applying Independent Component Analysis for the multivariate analysis of correlated phenotypes (i.e. the levels of coagulation pathway–related proteins). The resulting metaphenotypes integrate the information regarding the underlying biological process (i.e. thrombus/clot formation). Secondly, we take advantage of a family based Genome Wide Association Study to identify genetic elements influencing these metaphenotypes and consequently thrombosis risk. Our study utilized data from the GAIT Project (Genetic Analysis of Idiopathic Thrombophilia). We obtained 15 metaphenotypes, which showed significant heritabilities, ranging from 0.2 to 0.7. These results indicate the importance of genetic factors in the variability of these traits. We found 4 metaphenotypes that showed significant associations with SNPs. The most relevant were those mapped in a region near the HRG, FETUB and KNG1 genes. Our results are provocative since they show that the KNG1 locus plays a central role as a genetic determinant of the entire coagulation pathway and thrombus/clot formation. Integrating data from multiple correlated measurements through metaphenotypes is a promising approach to elucidate the hidden genetic mechanisms underlying complex diseases.Postprint (published version

Vascular changes in diabetic retinopathy-a longitudinal study in the Nile rat.

Diabetic retinopathy is the most common microvascular complication of diabetes and is a major cause of blindness, but an understanding of the pathogenesis of the disease has been hampered by a lack of accurate animal models. Here, we explore the dynamics of retinal cellular changes in the Nile rat (Arvicanthis niloticus), a carbohydrate-sensitive model for type 2 diabetes. The early retinal changes in diabetic Nile rats included increased acellular capillaries and loss of pericytes that correlated linearly with the duration of diabetes. These vascular changes occurred in the presence of microglial infiltration but in the absence of retinal ganglion cell loss. After a prolonged duration of diabetes, the Nile rat also exhibits a spectrum of retinal lesions commonly seen in the human condition including vascular leakage, capillary non-perfusion, and neovascularization. Our longitudinal study documents a range and progression of retinal lesions in the diabetic Nile rat remarkably similar to those observed in human diabetic retinopathy, and suggests that this model will be valuable in identifying new therapeutic strategies

Integrative Bioinformatics Analysis of Proteins Associated with the Cardiorenal Syndrome

The cardiorenal syndrome refers to the coexistence of kidney and cardiovascular disease, where cardiovascular events are the most common cause of death in patients with chronic kidney disease. Both, cardiovascular as well as kidney diseases have been extensively analyzed on a molecular level, resulting in molecular features and associated processes indicating a cross-talk of the two disease etiologies on a pathophysiological level. In order to gain a comprehensive picture of molecular factors contributing to the bidirectional interplay between kidney and cardiovascular system, we mined the scientific literature for molecular features reported as associated with the cardiorenal syndrome, resulting in 280 unique genes/proteins. These features were then analyzed on the level of molecular processes and pathways utilizing various types of protein interaction networks. Next to well established molecular features associated with the renin-angiotensin system numerous proteins involved in signal transduction and cell communication were found, involving specific molecular functions covering receptor binding with natriuretic peptide receptor and ligands as well known example. An integrated analysis of identified features pinpointed a protein interaction network involving mediators of hemodynamic change and an accumulation of features associated with the endothelin and VEGF signaling pathway. Some of these features may function as novel therapeutic targets