Parents' Active Role and ENgagement in The review of their Stillbirth/perinatal death 2 (PARENTS 2) study: a mixed-methods study of implementation.

OBJECTIVE: When a formal review of care takes places after the death of a baby, parents are largely unaware it takes place and are often not meaningfully involved in the review process. Parent engagement in the process is likely to be essential for a successful review and to improve patient safety. This study aimed to evaluate an intervention process of parental engagement in perinatal mortality review (PNMR) and to identify barriers and facilitators to its implementation. DESIGN: Mixed-methods study of parents' engagement in PNMR. SETTING: Single tertiary maternity unit in the UK. PARTICIPANTS: Bereaved parents and healthcare professionals (HCPs). INTERVENTIONS: Parent engagement in the PNMR (intervention) was based on principles derived through national consensus and qualitative research with parents, HCPs and stakeholders in the UK. OUTCOMES: Recruitment rates, bereaved parents and HCPs' perceptions. RESULTS: Eighty-one per cent of bereaved parents approached (13/16) agreed to participate in the study. Two focus groups with bereaved parents (n=11) and HCP (n=7) were carried out postimplementation to investigate their perceptions of the process.Overarching findings were improved dialogue and continuity of care with parents, and improvements in the PNMR process and patient safety. Bereaved parents agreed that engagement in the PNMR process was invaluable and helped them in their grieving. HCP perceived that parent involvement improved the review process and lessons learnt from the deaths; information to understand the impact of aspects of care on the baby's death were often only found in the parents' recollections. CONCLUSIONS: Parental engagement in the PNMR process is achievable and useful for parents and HCP alike, and critically can improve patient safety and future care for mothers and babies. To learn and prevent perinatal deaths effectively, all hospitals should give parents the option to engage with the review of their baby's death

Increased entropy of signal transduction in the cancer metastasis phenotype

Studies into the statistical properties of biological networks have led to important biological insights, such as the presence of hubs and hierarchical modularity. There is also a growing interest in studying the statistical properties of networks in the context of cancer genomics. However, relatively little is known as to what network features differ between the cancer and normal cell physiologies, or between different cancer cell phenotypes. Based on the observation that frequent genomic alterations underlie a more aggressive cancer phenotype, we asked if such an effect could be detectable as an increase in the randomness of local gene expression patterns. Using a breast cancer gene expression data set and a model network of protein interactions we derive constrained weighted networks defined by a stochastic information flux matrix reflecting expression correlations between interacting proteins. Based on this stochastic matrix we propose and compute an entropy measure that quantifies the degree of randomness in the local pattern of information flux around single genes. By comparing the local entropies in the non-metastatic versus metastatic breast cancer networks, we here show that breast cancers that metastasize are characterised by a small yet significant increase in the degree of randomness of local expression patterns. We validate this result in three additional breast cancer expression data sets and demonstrate that local entropy better characterises the metastatic phenotype than other non-entropy based measures. We show that increases in entropy can be used to identify genes and signalling pathways implicated in breast cancer metastasis. Further exploration of such integrated cancer expression and protein interaction networks will therefore be a fruitful endeavour.Comment: 5 figures, 2 Supplementary Figures and Table

A close examination of double filtering with fold change and t test in microarray analysis

<p>Abstract</p> <p>Background</p> <p>Many researchers use the double filtering procedure with fold change and <it>t </it>test to identify differentially expressed genes, in the hope that the double filtering will provide extra confidence in the results. Due to its simplicity, the double filtering procedure has been popular with applied researchers despite the development of more sophisticated methods.</p> <p>Results</p> <p>This paper, for the first time to our knowledge, provides theoretical insight on the drawback of the double filtering procedure. We show that fold change assumes all genes to have a common variance while <it>t </it>statistic assumes gene-specific variances. The two statistics are based on contradicting assumptions. Under the assumption that gene variances arise from a mixture of a common variance and gene-specific variances, we develop the theoretically most powerful likelihood ratio test statistic. We further demonstrate that the posterior inference based on a Bayesian mixture model and the widely used significance analysis of microarrays (SAM) statistic are better approximations to the likelihood ratio test than the double filtering procedure.</p> <p>Conclusion</p> <p>We demonstrate through hypothesis testing theory, simulation studies and real data examples, that well constructed shrinkage testing methods, which can be united under the mixture gene variance assumption, can considerably outperform the double filtering procedure.</p

PARENTS 2 Study: A qualitative study of the views of healthcare professionals and stakeholders on parental engagement in the perinatal mortality review - From 'bottom of the pile' to joint learning

OBJECTIVE: Engaging bereaved parents in the review process that examines their care before and after a perinatal death might help parents deal with their grief more effectively and drive improvements in patient safety. The objective of this study is to explore whether healthcare professionals would accept or support parent engagement in the perinatal mortality review process. DESIGN: Qualitative focus group interviews. Transcripts were analysed with an inductive thematic approach. SETTING: Two geographically distinct tertiary maternity hospitals in the UK. PARTICIPANTS: Five focus groups were conducted with clinical staff including midwives, obstetricians, neonatologists, nursing staff and chaplaincy services. RESULTS: Twenty-seven healthcare professionals unanimously agreed that parents’ involvement in the perinatal mortality review process is useful and necessary. Six key themes emerged including: parental engagement; need for formal follow-up; critical structure of perinatal mortality review meeting; coordination and streamlining of care; advocacy for parents including role of the bereavement care lead; and requirement for training and support for staff to enable parental engagement. CONCLUSIONS: Healthcare professionals strongly advocated engaging bereaved parents in the perinatal mortality review: empowering parents to ask questions, providing feedback on care, helping generate lessons and providing them with the opportunity to discuss a summary of the review conclusions with their primary healthcare professional contact. The participants agreed it is time to move on from ‘a group of doctors reviewing notes’ to active learning and improvement together with parents, to enable better care and prevention of perinatal death

Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus

BACKGROUND: Diabetic nephropathy is a serious complication of diabetes mellitus and is associated with considerable morbidity and high mortality. There is increasing evidence to suggest that dysregulation of the epigenome is involved in diabetic nephropathy. We assessed whether epigenetic modification of DNA methylation is associated with diabetic nephropathy in a case-control study of 192 Irish patients with type 1 diabetes mellitus (T1D). Cases had T1D and nephropathy whereas controls had T1D but no evidence of renal disease. METHODS: We performed DNA methylation profiling in bisulphite converted DNA from cases and controls using the recently developed Illumina Infinium(R) HumanMethylation27 BeadChip, that enables the direct investigation of 27,578 individual cytosines at CpG loci throughout the genome, which are focused on the promoter regions of 14,495 genes. RESULTS: Singular Value Decomposition (SVD) analysis indicated that significant components of DNA methylation variation correlated with patient age, time to onset of diabetic nephropathy, and sex. Adjusting for confounding factors using multivariate Cox-regression analyses, and with a false discovery rate (FDR) of 0.05, we observed 19 CpG sites that demonstrated correlations with time to development of diabetic nephropathy. Of note, this included one CpG site located 18 bp upstream of the transcription start site of UNC13B, a gene in which the first intronic SNP rs13293564 has recently been reported to be associated with diabetic nephropathy. CONCLUSION: This high throughput platform was able to successfully interrogate the methylation state of individual cytosines and identified 19 prospective CpG sites associated with risk of diabetic nephropathy. These differences in DNA methylation are worthy of further follow-up in replication studies using larger cohorts of diabetic patients with and without nephropathy

Combinatorial CRISPR-Cas9 screens for de novo mapping of genetic interactions.

We developed a systematic approach to map human genetic networks by combinatorial CRISPR-Cas9 perturbations coupled to robust analysis of growth kinetics. We targeted all pairs of 73 cancer genes with dual guide RNAs in three cell lines, comprising 141,912 tests of interaction. Numerous therapeutically relevant interactions were identified, and these patterns replicated with combinatorial drugs at 75% precision. From these results, we anticipate that cellular context will be critical to synthetic-lethal therapies

Consumption patterns of sweet drinks in a population of Australian children and adolescents (2003–2008)

<p>Abstract</p> <p>Background</p> <p>Intake of sweet drinks has previously been associated with the development of overweight and obesity among children and adolescents. The present study aimed to assess the consumption pattern of sweet drinks in a population of children and adolescents in Victoria, Australia.</p> <p>Methods</p> <p>Data on 1,604 children and adolescents (4–18 years) from the comparison groups of two quasi-experimental intervention studies from Victoria, Australia were analysed<it>.</it> Sweet drink consumption (soft drink and fruit juice/cordial) was assessed as one day’s intake and typical intake over the last week or month at two time points between 2003 and 2008 (mean time between measurement: 2.2 years).</p> <p>Results</p> <p>Assessed using dietary recalls, more than 70% of the children and adolescents consumed sweet drinks, with no difference between age groups (p = 0.28). The median intake among consumers was 500 ml and almost a third consumed more than 750 ml per day. More children and adolescents consumed fruit juice/cordial (69%) than soft drink (33%) (p < 0.0001) and in larger volumes (median intake fruit juice/cordial: 500 ml and soft drink: 375 ml). Secular changes in sweet drink consumption were observed with a lower proportion of children and adolescents consuming sweet drinks at time 2 compared to time 1 (significant for age group 8 to <10 years, p = 0.001).</p> <p>Conclusion</p> <p>The proportion of Australian children and adolescents from the state of Victoria consuming sweet drinks has been stable or decreasing, although a high proportion of this sample consumed sweet drinks, especially fruit juice/cordial at both time points.</p

Variability of myocardial perfusion dark rim Gibbs artifacts due to sub-pixel shifts

<p>Abstract</p> <p>Background</p> <p>Gibbs ringing has been shown as a possible source of dark rim artifacts in myocardial perfusion studies. This type of artifact is usually described as transient, lasting a few heart beats, and localised in random segments of the myocardial wall. Dark rim artifacts are known to be unpredictably variable. This article aims to illustrate that a sub-pixel shift, i.e. a small displacement of the pixels with respect to the endocardial border, can result in different Gibbs ringing and hence different artifacts. Therefore a hypothesis for one cause of dark rim artifact variability is given based on the sub-pixel position of the endocardial border. This article also demonstrates the consequences for Gibbs artifacts when two different methods of image interpolation are applied (post-FFT interpolation, and pre-FFT zero-filling).</p> <p>Results</p> <p>Sub-pixel shifting of <it>in vivo </it>perfusion studies was shown to change the appearance of Gibbs artifacts. This effect was visible in the original uninterpolated images, and in the post-FFT interpolated images. The same shifted data interpolated by pre-FFT zero-filling exhibited much less variability in the Gibbs artifact. The <it>in vivo </it>findings were confirmed by phantom imaging and numerical simulations.</p> <p>Conclusion</p> <p>Unless pre-FFT zero-filling interpolation is performed, Gibbs artifacts are very dependent on the position of the subendocardial wall within the pixel. By introducing sub-pixel shifts relative to the endocardial border, some of the variability of the dark rim artifacts in different myocardial segments, in different patients and from frame to frame during first-pass perfusion due to cardiac and respiratory motion can be explained. Image interpolation by zero-filling can be used to minimize this dependency.</p