Opportunistic detection of atrial fibrillation using blood pressure monitors: a systematic review

Background: Atrial Fibrillation (AF) affects around 2% of the population and early detection is beneficial, allowing patients to begin potentially life-saving anticoagulant therapies. Blood pressure (BP) monitors may offer an opportunity to screen for AF. Aim: To identify and appraise studies which report the diagnostic accuracy of automated BP monitors used for opportunistic AF detection. Methods: A systematic search was performed of the Medline, Medline-in-process and Embase literature databases. Papers were eligible if they described primary studies of the evaluation of a BP device for AF detection, were published in a peer reviewed journal and reported values for the sensitivity and specificity. Included studies were appraised using the QUADAS-2 tool to assess their risk of bias and applicability to opportunistic AF detection. Values for the sensitivity and specificity of AF detection were extracted from each paper and compared. Results and Conclusion: We identified seven papers evaluating six devices from two manufacturers. Only one study scored low risk in all of the QUADAS-2 domains. All studies reported specificity greater than 85% and six reported sensitivity greater than 90%. The studies showed that blood pressure devices with embedded algorithms for detecting arrhythmias show promise as screening tools for AF, comparing favourably with manual pulse palpation. But the studies used different methodologies and many were subject to potential bias. More studies are needed to more precisely define the sensitivity and specificity of opportunistic screening for AF during blood pressure measurement before its clinical utility in the population of interest can be assessed fully

Accuracy of pulse interval timing in ambulatory blood pressure measurement

Blood pressure (BP) monitors rely on pulse detection. Some blood pressure monitors use pulse timings to analyse pulse interval variability for arrhythmia screening, but this assumes that the pulse interval timings detected from BP cuffs are accurate compared with RR intervals derived from ECG. In this study we compared the accuracy of pulse intervals detected using an ambulatory blood pressure monitor (ABPM) with single lead ECG. Twenty participants wore an ABPM for three hours and a data logger which synchronously measured cuff pressure and ECG. RR intervals were compared with corresponding intervals derived from the cuff pressure tracings using three different pulse landmarks. Linear mixed effects models were used to assess differences between ECG and cuff pressure timings and to investigate the effect of potential covariates. In addition, the maximum number of successive oscillometric beats detectable in a measurement was assessed. From 243 BP measurements, the foot landmark of the oscillometric pulse was found to be associated with fewest covariates and had a random error of 9.5 ms. 99% of the cuff pressure recordings had more than 10 successive detectable oscillometric beats. RR intervals can be accurately estimated using an ABPM

Evaluating the robustness of connectivity methods to noise for in silico drug repurposing studies

Drug repurposing is an approach to identify new therapeutic applications for existing drugs and small molecules. It is a field of growing research interest due to its time and cost effectiveness as compared with de novo drug discovery. One method for drug repurposing is to adopt a systems biology approach to associate molecular ‘signatures’ of drug and disease. Drugs which have an inverse relationship with the disease signature may be able to reverse the molecular effects of the disease and thus be candidates for repurposing. Conversely, drugs which mimic the disease signatures can inform on potential molecular mechanisms of disease. The relationship between these disease and drug signatures are quantified through connectivity scores. Identifying a suitable drug-disease scoring method is key for in silico drug repurposing, so as to obtain an accurate representation of the true drug-disease relationship. There are several methods to calculate these connectivity scores, notably the Kolmogorov-Smirnov (KS), Zhang and eXtreme Sum (XSum). However, these methods can provide discordant estimations of the drug-disease relationship, and this discordance can affect the drug-disease indication. Using the gene expression profiles from the Library of Integrated Network-Based Cellular Signatures (LINCS) database, we evaluated the methods based on their drug-disease connectivity scoring performance. In this first-of-its-kind analysis, we varied the quality of disease signatures by using only highly differential genes or by the inclusion of non-differential genes. Further, we simulated noisy disease signatures by introducing varying levels of noise into the gene expression signatures. Overall, we found that there was not one method that outperformed the others in all instances, but the Zhang method performs well in a majority of our analyses. Our results provide a framework to evaluate connectivity scoring methods, and considerations for deciding which scoring method to apply in future systems biology studies for drug repurposing

Rare and common epilepsies converge on a shared gene regulatory network providing opportunities for novel antiepileptic drug discovery

Background The relationship between monogenic and polygenic forms of epilepsy is poorly understood, and the extent to which the genetic and acquired epilepsies share common pathways is unclear. Here, we use an integrated systems-level analysis of brain gene expression data to identify molecular networks disrupted in epilepsy. Results We identify a co-expression network of 320 genes (M30), which is significantly enriched for non-synonymous de novo mutations ascertained from patients with monogenic epilepsy, and for common variants associated with polygenic epilepsy. The genes in M30 network are expressed widely in the human brain under tight developmental control, and encode physically interacting proteins involved in synaptic processes. The most highly connected proteins within M30 network are preferentially disrupted by deleterious de novo mutations for monogenic epilepsy, in line with the centrality-lethality hypothesis. Analysis of M30 expression revealed consistent down-regulation in the epileptic brain in heterogeneous forms of epilepsy including human temporal lobe epilepsy, a mouse model of acquired temporal lobe epilepsy, and a mouse model of monogenic Dravet (SCN1A) disease. These results suggest functional disruption of M30 via gene mutation or altered expression as a convergent mechanism regulating susceptibility to epilepsy broadly. Using the large collection of drug-induced gene expression data from Connectivity Map, several drugs were predicted to preferentially restore the down-regulation of M30 in epilepsy toward health, most notably valproic acid, whose effect on M30 expression was replicated in neurons. Conclusions Taken together, our results suggest targeting the expression of M30 as a potential new therapeutic strategy in epilepsy

MicroRNA profiles in hippocampal granule cells and plasma of rats with pilocarpine-induced epilepsy - Comparison with human epileptic samples

The identification of biomarkers of the transformation of normal to epileptic tissue would help to stratify patients at risk of epilepsy following brain injury, and inform new treatment strategies. MicroRNAs (miRNAs) are an attractive option in this direction. In this study, miRNA microarrays were performed on laser-microdissected hippocampal granule cell layer (GCL) and on plasma, at different time points in the development of pilocarpine-induced epilepsy in the rat: latency, first spontaneous seizure and chronic epileptic phase. Sixty-three miRNAs were differentially expressed in the GCL when considering all time points. Three main clusters were identified that separated the control and chronic phase groups from the latency group and from the first spontaneous seizure group. MiRNAs from rats in the chronic phase were compared to those obtained from the laser-microdissected GCL of epileptic patients, identifying several miRNAs (miR-21-5p, miR-23a-5p, miR-146a-5p and miR- 181c-5p) that were up-regulated in both human and rat epileptic tissue. Analysis of plasma samples revealed different levels between control and pilocarpine-treated animals for 27 miRNAs. Two main clusters were identified that segregated controls from all other groups. Those miRNAs that are altered in plasma before the first spontaneous seizure, like miR-9a-3p, may be proposed as putative biomarkers of epileptogenesis

The Collective Submitted Works from Honors 2030

Students in the Honors 2030, Inquiries in the Social and Behavioral Sciences course each participated in the URS 2020 as their final project for the course. Dr. Wilson worked with each student as a faculty mentor to create, draft, edit, approve and publish each of the final posters and papers submitted to the 2020 URS for the course

The impact of televised tobacco control advertising content on campaign recall: evidence from the International Tobacco Control (ITC) United Kingdom Survey

BACKGROUND: Although there is some evidence to support an association between exposure to televised tobacco control campaigns and recall among youth, little research has been conducted among adults. In addition, no previous work has directly compared the impact of different types of emotive campaign content. The present study examined the impact of increased exposure to tobacco control advertising with different types of emotive content on rates and durations of self-reported recall. METHODS: Data on recall of televised campaigns from 1,968 adult smokers residing in England through four waves of the International Tobacco Control (ITC) United Kingdom Survey from 2005 to 2009 were merged with estimates of per capita exposure to government-run televised tobacco control advertising (measured in GRPs, or Gross Rating Points), which were categorised as either “positive” or “negative” according to their emotional content. RESULTS: Increased overall campaign exposure was found to significantly increase probability of recall. For every additional 1,000 GRPs of per capita exposure to negative emotive campaigns in the six months prior to survey, there was a 41% increase in likelihood of recall (OR = 1.41, 95% CI: 1.24–1.61), while positive campaigns had no significant effect. Increased exposure to negative campaigns in both the 1–3 months and 4–6 month periods before survey was positively associated with recall. CONCLUSIONS: Increased per capita exposure to negative emotive campaigns had a greater effect on campaign recall than positive campaigns, and was positively associated with increased recall even when the exposure had occurred more than three months previously

Context and the evidence based paradigm: The potential for participatory research and systems thinking in oral health

The implementation of research evidence to promote oral health is critical, given the intransigent and emerging challenges for policy-makers at a population level. Despite this, little attention has been paid to implementation research within the evidence-based paradigm. This is important as getting research evidence into clinical practice is not a linear path that consists of simple sequential steps. In this article, we argue that we need to consider a broader range of conceptual and methodological approaches to increase the value of information generated. This should be undertaken either in parallel with empirical and experimental designs, or in some cases, instead of. This is important if we are going to understand the complexity and contextual knowledge of the ‘system’, within which interventions are implemented. Involving key stakeholders alongside empirical and experimental designs is one helpful approach. Examples of these approaches include Patient and Public Involvement and the development of Core Outcome Sets, where the views of those that will be potentially affected by the research, are included. The use of theoretical frameworks and process evaluations alongside trials are also important, if they are fully integrated into the approach taken to address the research question. A more radical approach is using participatory designs and ‘systems thinking’. Participatory approaches include subject matter 'experts by experience’. These include patients, their families, carers, healthcare professionals, services managers, policy-makers, commissioners and researchers. Participatory approaches raise important questions about who facilitates the process, when it should happen and how the diverse actors become meaningfully engaged so that their involvement is active, democratic and on-going. We argue that the issues of control, power and language are central to this and represent a paradigmatic shift to conventional approaches. Systems thinking captures the idea that public health problems commonly involve multiple interdependent and interconnected factors, which interact with each other dynamically. This approach challenges the simplicity of the hierarchy of evidence and linear sequential logic, when it doesn’t account for context. In contrast, systems thinking accepts complexity de novo and emphasises the need to understand the whole system rather than its individual component parts. We conclude with the idea that participatory and systems thinking helps to unpack the diverse agents that are often involved in the generation and translation of evidence into clinical dental practice. It moves our conception of research away from a simple exchange between ‘knowledge producers’ and ‘knowledge users’ and raises both methodological and epistemological challenges

Developing the Diagnostic Adherence to Medication Scale (the DAMS) for use in clinical practice

There is a need for an adherence measure, to monitor adherence services in clinical practice, which can distinguish between different types of non-adherence and measure changes over time. In order to be inclusive of all patients it needs to be able to be administered to both patients and carers and to be suitable for patients taking multiple medications for a range of clinical conditions. A systematic review found that no adherence measure met all these criteria. We therefore wished to develop a theory based adherence scale (the DAMS) and establish its content, face and preliminary construct validity in a primary care population

Widespread dysregulation of mRNA splicing implicates RNA processing in the development and progression of Huntington's disease

Background In Huntington's disease (HD), a CAG repeat expansion mutation in the Huntingtin (HTT) gene drives a gain-of-function toxicity that disrupts mRNA processing. Although dysregulation of gene splicing has been shown in human HD post-mortem brain tissue, post-mortem analyses are likely confounded by cell type composition changes in late-stage HD, limiting the ability to identify dysregulation related to early pathogenesis. Methods To investigate gene splicing changes in early HD, we performed alternative splicing analyses coupled with a proteogenomics approach to identify early CAG length-associated splicing changes in an established isogenic HD cell model. Findings We report widespread neuronal differentiation stage- and CAG length-dependent splicing changes, and find an enrichment of RNA processing, neuronal function, and epigenetic modification-related genes with mutant HTT-associated splicing. When integrated with a proteomics dataset, we identified several of these differential splicing events at the protein level. By comparing with human post-mortem and mouse model data, we identified common patterns of altered splicing from embryonic stem cells through to post-mortem striatal tissue. Interpretation We show that widespread splicing dysregulation in HD occurs in an early cell model of neuronal development. Importantly, we observe HD-associated splicing changes in our HD cell model that were also identified in human HD striatum and mouse model HD striatum, suggesting that splicing-associated pathogenesis possibly occurs early in neuronal development and persists to later stages of disease. Together, our results highlight splicing dysregulation in HD which may lead to disrupted neuronal function and neuropathology. Funding This research is supported by the Lee Kong Chian School of Medicine, Nanyang Technological University Singapore Nanyang Assistant Professorship Start-Up Grant, the Singapore Ministry of Education under its Singapore Ministry of Education Academic Research Fund Tier 1 (RG23/22), the BC Children's Hospital Research Institute Investigator Grant Award (IGAP), and a Scholar Award from the Michael Smith Health Research BC