FTIR spectroscopic imaging and mapping with correcting lenses for studies of biological cells and tissues

Histopathology of tissue samples is used to determine the progression of cancer usually by staining and visual analysis. It is recognised that disease progression from healthy tissue to cancerous is accompanied by spectral signature changes in the mid-infrared range. In this work, FTIR spectroscopic imaging in transmission mode using a focal plane array (96 × 96 pixels) has been applied to the characterisation of Barrett's oesophageal adenocarcinoma. To correct optical aberrations, infrared transparent lenses were used of the same material (CaF2) as the slide on which biopsies were fixed. The lenses acted as an immersion objective, reducing scattering and improving spatial resolution. A novel mapping approach using a sliding lens is presented where spectral images obtained with added lenses are stitched together such that the dataset contained a representative section of the oesophageal tissue. Images were also acquired in transmission mode using high-magnification optics for enhanced spatial resolution, as well as with a germanium micro-ATR objective. The reduction of scattering was assessed using k-means clustering. The same tissue section map, which contained a region of high grade dysplasia, was analysed using hierarchical clustering analysis. A reduction of the trough at 1077 cm−1 in the second derivative spectra was identified as an indicator of high grade dysplasia. In addition, the spatial resolution obtained with the lens using high-magnification optics was assessed by measurements of a sharp interface of polymer laminate, which was also compared with that achieved with micro ATR-FTIR imaging. In transmission mode using the lens, it was determined to be 8.5 μm and using micro-ATR imaging, the resolution was 3 μm for the band at a wavelength of ca. 3 μm. The spatial resolution was also assessed with and without the added lens, in normal and high-magnification modes using a USAF target. Spectroscopic images of cells in transmission mode using two lenses are also presented, which are necessary for correcting chromatic aberration and refraction in both the condenser and objective. The use of lenses is shown to be necessary for obtaining high-quality spectroscopic images of cells in transmission mode and proves the applicability of the pseudo hemisphere approach for this and other microfluidic systems

Bias modelling in evidence synthesis

Policy decisions often require synthesis of evidence from multiple sources, and the source studies typically vary in rigour and in relevance to the target question. We present simple methods of allowing for differences in rigour (or lack of internal bias) and relevance (or lack of external bias) in evidence synthesis. The methods are developed in the context of reanalysing a UK National Institute for Clinical Excellence technology appraisal in antenatal care, which includes eight comparative studies. Many were historically controlled, only one was a randomized trial and doses, populations and outcomes varied between studies and differed from the target UK setting. Using elicited opinion, we construct prior distributions to represent the biases in each study and perform a bias‐adjusted meta‐analysis. Adjustment had the effect of shifting the combined estimate away from the null by approximately 10%, and the variance of the combined estimate was almost tripled. Our generic bias modelling approach allows decisions to be based on all available evidence, with less rigorous or less relevant studies downweighted by using computationally simple methods

Predicting the extent of heterogeneity in meta-analysis, using empirical data from the Cochrane Database of Systematic Reviews

Background: Many meta-analyses contain only a small number of studies, which makes it difficult to estimate the extent of between-study heterogeneity. Bayesian meta-analysis allows incorporation of external evidence on heterogeneity, and offers advantages over conventional random-effects meta-analysis. To assist in this, we provide empirical evidence on the likely extent of heterogeneity in particular areas of health care. Methods: Our analyses included 14 886 meta-analyses from the Cochrane Database of Systematic Reviews. We classified each meta-analysis according to the type of outcome, type of intervention comparison and medical specialty. By modelling the study data from all meta-analyses simultaneously, using the log odds ratio scale, we investigated the impact of meta-analysis characteristics on the underlying between-study heterogeneity variance. Predictive distributions were obtained for the heterogeneity expected in future meta-analyses. Results Between-study heterogeneity variances for meta-analyses in which the outcome was all-cause mortality were found to be on average 17% (95% CI 10–26) of variances for other outcomes. In meta-analyses comparing two active pharmacological interventions, heterogeneity was on average 75% (95% CI 58–95) of variances for non-pharmacological interventions. Meta-analysis size was found to have only a small effect on heterogeneity. Predictive distributions are presented for nine different settings, defined by type of outcome and type of intervention comparison. For example, for a planned meta-analysis comparing a pharmacological intervention against placebo or control with a subjectively measured outcome, the predictive distribution for heterogeneity is a log-normal (−2.13, 1.582) distribution, which has a median value of 0.12. In an example of meta-analysis of six studies, incorporating external evidence led to a smaller heterogeneity estimate and a narrower confidence interval for the combined intervention effect. Conclusions: Meta-analysis characteristics were strongly associated with the degree of between-study heterogeneity, and predictive distributions for heterogeneity differed substantially across settings. The informative priors provided will be very beneficial in future meta-analyses including few studies

FTIR spectroscopic imaging and mapping with correcting lenses for studies of biological cells and tissues

Histopathology of tissue samples is used to determine the progression of cancer usually by staining and visual analysis. It is recognised that disease progression from healthy tissue to cancerous is accompanied by spectral signature changes in the mid-infrared range. In this work, FTIR spectroscopic imaging in transmission mode using a focal plane array (96 × 96 pixels) has been applied to the characterisation of Barrett's oesophageal adenocarcinoma. To correct optical aberrations, infrared transparent lenses were used of the same material (CaF2) as the slide on which biopsies were fixed. The lenses acted as an immersion objective, reducing scattering and improving spatial resolution. A novel mapping approach using a sliding lens is presented where spectral images obtained with added lenses are stitched together such that the dataset contained a representative section of the oesophageal tissue. Images were also acquired in transmission mode using high-magnification optics for enhanced spatial resolution, as well as with a germanium micro-ATR objective. The reduction of scattering was assessed using k-means clustering. The same tissue section map, which contained a region of high grade dysplasia, was analysed using hierarchical clustering analysis. A reduction of the trough at 1077 cm−1 in the second derivative spectra was identified as an indicator of high grade dysplasia. In addition, the spatial resolution obtained with the lens using high-magnification optics was assessed by measurements of a sharp interface of polymer laminate, which was also compared with that achieved with micro ATR-FTIR imaging. In transmission mode using the lens, it was determined to be 8.5 μm and using micro-ATR imaging, the resolution was 3 μm for the band at a wavelength of ca. 3 μm. The spatial resolution was also assessed with and without the added lens, in normal and high-magnification modes using a USAF target. Spectroscopic images of cells in transmission mode using two lenses are also presented, which are necessary for correcting chromatic aberration and refraction in both the condenser and objective. The use of lenses is shown to be necessary for obtaining high-quality spectroscopic images of cells in transmission mode and proves the applicability of the pseudo hemisphere approach for this and other microfluidic systems

"Am iz kwiin" (I'm his queen): Combining interpretative phenomenological analysis with a feminist approach to work with gems in a resource-constrained setting

This article focuses on working with gems using a feminist approach to interpretative phenomenological analysis (IPA) in a resource-constrained setting. The research explores the experiences of maternal disclosure of HIV to children of HIV positive mothers in Kingston, Jamaica. A feminist approach helps recognise power imbalances within research relationships and the women’s lived experiences. We present three “gems” which illuminate women’s lived experiences and explore how popularised representations of women’s sexuality and mothering influence disclosure discourses. We use emotion work as a conceptual resource to structure the women’s narratives and challenge existing policy discourses, which arguably represent disclosure within a binary, rationalist, decision-making framework. This article adds to global literature on maternal HIV disclosure and problematises policy discourses by bringing into relief the emotion work women engage in when deciding if and how to communicate their HIV status to their children. It adds to the body of research using IPA, particularly in resource-constrained settings where IPA has thus far had little application

Using Time-Resolved Fluorescence to Measure Serum Venom-Specific IgE and IgG

We adapted DELFIA™ (dissociation-enhanced lanthanide fluoroimmunoassay), a time resolved fluorescence method, to quantitate whole venom specific and allergenic peptide-specific IgE (sIgE), sIgG1 and sIgG4 in serum from people clinically allergic to Australian native ant venoms, of which the predominant cause of allergy is jack jumper ant venom (JJAV). Intra-assay CV was 6.3% and inter-assay CV was 13.7% for JJAV sIgE. DELFIA and Phadia CAP JJAV sIgE results correlated well and had similar sensitivity and specificity for the detection of JJAV sIgE against intradermal skin testing as the gold standard. DELFIA was easily adapted for detecting sIgE to a panel of other native ant venoms

A feasibility trial to examine the social norms approach for the prevention and reduction of licit and illicit drug use in European University and college students.

Background: Incorrect perceptions of high rates of peer alcohol and tobacco use are predictive of increased personal use in student populations. Correcting misperceptions by providing feedback has been shown to be an effective intervention for reducing licit drug use. It is currently unknown if social norms interventions are effective in preventing and reducing illicit drug use in European students. The purpose of this paper is to describe the design of a multi-site cluster controlled trial of a web-based social norms intervention aimed at reducing licit and preventing illicit drug use in European university students. Methods/Design: An online questionnaire to assess rates of drug use will be developed and translated based on existing social norms surveys. Students from sixteen universities in seven participating European countries will be invited to complete the questionnaire. Both intervention and control sites will be chosen by convenience. In each country, the intervention site will be the university that the local principal investigator is affiliated with. We aim to recruit 1000 students per site (baseline assessment). All participants will complete the online questionnaire at baseline. Baseline data will be used to develop social norms messages that will be included in a web-based intervention. The intervention group will receive individualized social norms feedback. The website will remain online during the following 5 months. After five months, a second survey will be conducted and effects of the intervention on social norms and drug use will be measured in comparison to the control site. Discussion: This project is the first cross-national European collaboration to investigate the feasibility of a social norms intervention to reduce licit and prevent illicit drug use among European university students. Final trial registration number DRKS00004375 on the ‘German Clinical Trials Register’.This study is funded by the European Commission, Directorate General Justice, Freedom and Security (JLS/2009-2010/DPIP/AG

Does voice amplification increase intelligibility in people with Parkinson's disease

Background/Aims: Patients with speech intelligibility difficulties associated with a quiet voice are often prescribed a voice amplifier. This study examined whether artificial voice amplification improved intelligibility in people with Parkinson's disease and whether there was an optimum increase that brought about best improvement. Methods: Twelve people diagnosed with Parkinson's disease (mild=4, moderate intelligibility difficulties=8) and five age-matched controls read low predictability sentences in their habitual voice. Audio recordings were digitally manipulated to create samples at +2.3 dB, +5 dB and +10 dB amplification. Listeners transcribed the recorded sentences. The percentage of words correctly identified was compared across levels of amplification and groups. Results: Participants with moderate Parkinson's disease were significantly less intelligible than controls in all conditions. Moderately, but not mildly affected participants with Parkinson's disease showed higher intelligibility in the amplified conditions, though statistically significantly only at +2.3 dB. No other significant effects of intensity or interactions with groups were found. At an individual level, some participants showed clear advantages of amplification. Conclusion: Based on results from the current participants, potential benefits of amplification cannot be promised to all people with Parkinson's disease. Nevertheless, several provisos regarding methods employed suggest the question can gainfully be pursued using broader measures to assess effects of amplification with more varied groups of people with Parkinson's disease and with other aetiologies where voice production can be an issue

Impact of Reporting Bias in Network Meta-Analysis of Antidepressant Placebo-Controlled Trials

BACKGROUND: Indirect comparisons of competing treatments by network meta-analysis (NMA) are increasingly in use. Reporting bias has received little attention in this context. We aimed to assess the impact of such bias in NMAs. METHODS: We used data from 74 FDA-registered placebo-controlled trials of 12 antidepressants and their 51 matching publications. For each dataset, NMA was used to estimate the effect sizes for 66 possible pair-wise comparisons of these drugs, the probabilities of being the best drug and ranking the drugs. To assess the impact of reporting bias, we compared the NMA results for the 51 published trials and those for the 74 FDA-registered trials. To assess how reporting bias affecting only one drug may affect the ranking of all drugs, we performed 12 different NMAs for hypothetical analysis. For each of these NMAs, we used published data for one drug and FDA data for the 11 other drugs. FINDINGS: Pair-wise effect sizes for drugs derived from the NMA of published data and those from the NMA of FDA data differed in absolute value by at least 100% in 30 of 66 pair-wise comparisons (45%). Depending on the dataset used, the top 3 agents differed, in composition and order. When reporting bias hypothetically affected only one drug, the affected drug ranked first in 5 of the 12 NMAs but second (n = 2), fourth (n = 1) or eighth (n = 2) in the NMA of the complete FDA network. CONCLUSIONS: In this particular network, reporting bias biased NMA-based estimates of treatments efficacy and modified ranking. The reporting bias effect in NMAs may differ from that in classical meta-analyses in that reporting bias affecting only one drug may affect the ranking of all drugs