Molecular profiling of multiplexed gene markers to assess viability of ex vivo human colon explant cultures

© Janice E. Drew et al. 2015; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. Acknowledgments The authors would like to thank the patients who kindly donated tissue samples, Sally Chalmers of the Tayside Tissue Bank for her help with collecting of the tissue donor samples, Emma Moss for advice on human colon dissection and explant culture, and Claus Dieter Mayer, Biomathematics and Statistics Scotland, for advice on statistical analysis. This work was supported by the Scottish Government (GT403), Scottish Universities Life Science Alliance, and TENOVUS Scotland.Peer reviewedPublisher PD

A search for fast radio burst-like emission from Fermi gamma-ray bursts

We report the results of the rapid follow-up observations of gamma-ray bursts (GRBs) detected by the Fermi satellite to search for associated fast radio bursts. The observations were conducted with the Australian Square Kilometre Array Pathfinder at frequencies from 1.2-1.4 GHz. A set of 20 bursts, of which four were short GRBs, were followed up with a typical latency of about one minute, for a duration of up to 11 hours after the burst. The data was searched using 4096 dispersion measure trials up to a maximum dispersion measure of 3763 pc cm$^{-3}$, and for pulse widths $w$ over a range of duration from 1.256 to 40.48 ms. No associated pulsed radio emission was observed above $26 {\rm Jy ms} (w/1 {\rm ms})^{-1/2}$ for any of the 20 GRBs.Comment: Accepted for publication in Monthly Notices of the Royal Astronomical Society Main Journa

Views and experiences of opioid access amongst palliative care providers and public representatives in a low-resource setting: A qualitative interview study

AbstractOpioids (e.g. morphine) are affordable, effective interventions for cancer-related pain. However, equity of access to this key medication remains a global challenge, particularly in low- and middle-income countries. We aimed to explore views of palliative care providers and public-representatives about opioid analgesia access in two States in India. We conducted a qualitative study using semi-structured interviews. Transcribed audio-recordings were subjected to thematic analysis using a Framework Approach. Palliative care providers and public-representatives were purposively sampled from services reporting consistent opioid availability and prescribing (≥4kg per annum) from Karnataka and Kerala. Twenty participants (doctors (10), nurses (4), pharmacists (2), service managers (2) and public-representatives (2) were interviewed. Three themes were identified: 1) Attitudes and awareness: opioid treatments are perceived as end-of-life (last days/weeks) interventions; fears of addiction and misunderstanding of pain management goals limit access. 2) Expected and unexpected inequities: patients/carers from lower socioeconomic strata accept doctor recommendations if opioids are affordable, more educated patients/families have reservations about opioids, delay access and perceive expensive medicines as better. Non-palliative care specialist doctors have negative entrenched views and require specialist training. 3) Experiential learning–positive experiences can positively alter attitudes (e.g., participants in Kerala report improved attitudes, awareness and understanding influenced by exposure and community awareness, but experience can also reinforce perceptions as end-of-life care. Entrenched negative views are reinforced by poor experiences while positive experiences improve attitudes. To promote access, opioid prescribing must be needs-based rather than prognosis-based. Addressing the lack of training for non-palliative care workforce would help overcome a major barrier

Application of pharmacogenomics and bioinformatics to exemplify the utility of human <i>ex vivo</i> organoculture models in the field of precision medicine

Here we describe a collaboration between industry, the National Health Service (NHS) and academia that sought to demonstrate how early understanding of both pharmacology and genomics can improve strategies for the development of precision medicines. Diseased tissue ethically acquired from patients suffering from chronic obstructive pulmonary disease (COPD), was used to investigate inter-patient variability in drug efficacy using ex vivo organocultures of fresh lung tissue as the test system. The reduction in inflammatory cytokines in the presence of various test drugs was used as the measure of drug efficacy and the individual patient responses were then matched against genotype and microRNA profiles in an attempt to identify unique predictors of drug responsiveness. Our findings suggest that genetic variation in CYP2E1 and SMAD3 genes may partly explain the observed variation in drug response

Combining explainable machine learning, demographic and multi-omic data to inform precision medicine strategies for inflammatory bowel disease.

Inflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn's disease, affect several million individuals worldwide. These diseases are heterogeneous at the clinical, immunological and genetic levels and result from complex host and environmental interactions. Investigating drug efficacy for IBD can improve our understanding of why treatment response can vary between patients. We propose an explainable machine learning (ML) approach that combines bioinformatics and domain insight, to integrate multi-modal data and predict inter-patient variation in drug response. Using explanation of our models, we interpret the ML models' predictions to infer unique combinations of important features associated with pharmacological responses obtained during preclinical testing of drug candidates in ex vivo patient-derived fresh tissues. Our inferred multi-modal features that are predictive of drug efficacy include multi-omic data (genomic and transcriptomic), demographic, medicinal and pharmacological data. Our aim is to understand variation in patient responses before a drug candidate moves forward to clinical trials. As a pharmacological measure of drug efficacy, we measured the reduction in the release of the inflammatory cytokine TNFα from the fresh IBD tissues in the presence/absence of test drugs. We initially explored the effects of a mitogen-activated protein kinase (MAPK) inhibitor; however, we later showed our approach can be applied to other targets, test drugs or mechanisms of interest. Our best model predicted TNFα levels from demographic, medicinal and genomic features with an error of only 4.98% on unseen patients. We incorporated transcriptomic data to validate insights from genomic features. Our results showed variations in drug effectiveness (measured by ex vivo assays) between patients that differed in gender, age or condition and linked new genetic polymorphisms to patient response variation to the anti-inflammatory treatment BIRB796 (Doramapimod). Our approach models IBD drug response while also identifying its most predictive features as part of a transparent ML precision medicine strategy

Shared decision making for prostate cancer screening: the results of a combined analysis of two practice-based randomized controlled trials

Abstract Background Professional societies recommend shared decision making (SDM) for prostate cancer screening, however, most efforts have promoted informed rather than shared decision making. The objective of this study is to 1) examine the effects of a prostate cancer screening intervention to promote SDM and 2) determine whether framing prostate information in the context of other clearly beneficial men’s health services affects decisions. Methods We conducted two separate randomized controlled trials of the same prostate cancer intervention (with or without additional information on more clearly beneficial men’s health services). For each trial, we enrolled a convenience sample of 2 internal medicine practices, and their interested physicians and male patients with no prior history of prostate cancer (for a total of 4 practices, 28 physicians, and 128 men across trials). Within each practice site, we randomized men to either 1) a video-based decision aid and researcher-led coaching session or 2) a highway safety video. Physicians at each site received a 1-hour educational session on prostate cancer and SDM. To assess intervention effects, we measured key components of SDM, intent to be screened, and actual screening. After finding that results did not vary by trial, we combined data across sites, adjusting for the random effects of both practice and physician. Results Compared to an attention control, our prostate cancer screening intervention increased men’s perceptions that screening is a decision (absolute difference +41%; 95% CI 25 to 57%) and men’s knowledge about prostate cancer screening (absolute difference +34%; 95% CI 19% to 50%), but had no effect on men’s self-reported participation in shared decisions or their participation at their preferred level. Overall, the intervention decreased screening intent (absolute difference −34%; 95% CI −50% to −18%) and actual screening rates (absolute difference −22%; 95% CI −38 to −7%) with no difference in effect by frame. Conclusions SDM interventions can increase men’s knowledge, alter their perceptions of prostate cancer screening, and reduce actual screening. However, they may not guarantee an increase in shared decisions. Trial registration #NCT0063018

The Murchison Widefield Array: Design Overview

The Murchison Widefield Array (MWA) is a dipole-based aperture array synthesis telescope designed to operate in the 80-300 MHz frequency range. It is capable of a wide range of science investigations, but is initially focused on three key science projects. These are detection and characterization of 3-dimensional brightness temperature fluctuations in the 21cm line of neutral hydrogen during the Epoch of Reionization (EoR) at redshifts from 6 to 10, solar imaging and remote sensing of the inner heliosphere via propagation effects on signals from distant background sources,and high-sensitivity exploration of the variable radio sky. The array design features 8192 dual-polarization broad-band active dipoles, arranged into 512 tiles comprising 16 dipoles each. The tiles are quasi-randomly distributed over an aperture 1.5km in diameter, with a small number of outliers extending to 3km. All tile-tile baselines are correlated in custom FPGA-based hardware, yielding a Nyquist-sampled instantaneous monochromatic uv coverage and unprecedented point spread function (PSF) quality. The correlated data are calibrated in real time using novel position-dependent self-calibration algorithms. The array is located in the Murchison region of outback Western Australia. This region is characterized by extremely low population density and a superbly radio-quiet environment,allowing full exploitation of the instrumental capabilities.Comment: 9 pages, 5 figures, 1 table. Accepted for publication in Proceedings of the IEE

The need to promote behaviour change at the cultural level: one factor explaining the limited impact of the MEMA kwa Vijana adolescent sexual health intervention in rural Tanzania. A process evaluation

Background - Few of the many behavioral sexual health interventions in Africa have been rigorously evaluated. Where biological outcomes have been measured, improvements have rarely been found. One of the most rigorous trials was of the multi-component MEMA kwa Vijana adolescent sexual health programme, which showed improvements in knowledge and reported attitudes and behaviour, but none in biological outcomes. This paper attempts to explain these outcomes by reviewing the process evaluation findings, particularly in terms of contextual factors. Methods - A large-scale, primarily qualitative process evaluation based mainly on participant observation identified the principal contextual barriers and facilitators of behavioural change. Results - The contextual barriers involved four interrelated socio-structural factors: culture (i.e. shared practices and systems of belief), economic circumstances, social status, and gender. At an individual level they appeared to operate through the constructs of the theories underlying MEMA kwa Vijana - Social Cognitive Theory and the Theory of Reasoned Action – but the intervention was unable to substantially modify these individual-level constructs, apart from knowledge. Conclusion - The process evaluation suggests that one important reason for this failure is that the intervention did not operate sufficiently at a structural level, particularly in regard to culture. Recently most structural interventions have focused on gender or/and economics. Complementing these with a cultural approach could address the belief systems that justify and perpetuate gender and economic inequalities, as well as other barriers to behaviour change