The disequilibrium of hope: A grounded theory analysis of parents' experiences of receiving a “no primary finding” result from genome sequencing

Genome sequencing (GS) has the potential to reduce the “diagnostic odyssey” that many parents of children with rare undiagnosed conditions experience. While much research has considered the impact of receiving a diagnostic result, research has rarely focused solely on the impact of receiving a “no primary finding” (NPF) result. This study aimed to investigate the experience of parents of children with rare and undiagnosed conditions following an NPF result from GS. Nine parents whose child had an NPF result from GS were recruited through the social media platform of the charity SWAN (Syndromes Without A Name) UK. Semi-structured telephone interviews were conducted, transcribed verbatim, and analyzed using grounded theory. Analysis led to the emergence of two main themes. The first theme “Striving to Solve the Unsolved Puzzle” concerned the experience of striving to end the “diagnostic odyssey.” The second theme “Navigating Hope, Lost then Found” plots the trajectory of hope raised by the promise of a new technology, dashed by the NPF, and the eventual return of small and distant hope for the future. Taken together, these themes allowed for a proposed theory: “The Disequilibrium of Hope,” which highlights the dynamic and modifiable experience of hope participants experience in their GS journey. These results suggest GS can be an emotional rollercoaster for parents. While hope plays an important role in coping with the day-to-day life of living with a rare disease, careful management of expectations from GS is important during pre-test counseling, and continued follow-up and support are needed beyond result disclosure. An understanding of the disappointment and distress caused by an NPF result is valuable for healthcare professionals in this field to ensure counseling can be tailored. Further research should consider how to support parents after an NPF result

Quantifying the burden of rhodesiense sleeping sickness in Urambo district, Tanzania

Sleeping sickness (human African trypanosomiasis - HAT) is a disease transmitted by tsetse flies and is always fatal if left untreated. The disease occurs in foci affecting poor communities with limited access to health service provision and as such the disease is often left undiagnosed, mistaken for more common afflictions. Even if diagnosed, sleeping sickness is costly to treat, both for health services and patients and their families in terms of costs of diagnosis, transport, hospital care, and the prolonged period of convalescence. Here we estimate the health burden of the acute form T. b. rhodesiense sleeping sickness in Urambo District, Tanzania in terms of Disability Adjusted Life Years (DALYs), the yardstick commonly used by policy makers to prioritize disease management practices, representing a year of healthy life lost to disease. In this single district, the burden of the disease over one year was estimated at 979 DALYs and the estimated monetary costs to health services for the 143 treated patients at US$11,841 and to the patients themselves at US$ 3,673 for direct medical costs and US$ 9,781 for indirect non-medical costs. Sleeping sickness thus places a considerable burden on the affected rural communities and health services

A dynamical model reveals gene co-localizations in nucleus

Co-localization of networks of genes in the nucleus is thought to play an important role in determining gene expression patterns. Based upon experimental data, we built a dynamical model to test whether pure diffusion could account for the observed co-localization of genes within a defined subnuclear region. A simple standard Brownian motion model in two and three dimensions shows that preferential co-localization is possible for co-regulated genes without any direct interaction, and suggests the occurrence may be due to a limitation in the number of available transcription factors. Experimental data of chromatin movements demonstrates that fractional rather than standard Brownian motion is more appropriate to model gene mobilizations, and we tested our dynamical model against recent static experimental data, using a sub-diffusion process by which the genes tend to colocalize more easily. Moreover, in order to compare our model with recently obtained experimental data, we studied the association level between genes and factors, and presented data supporting the validation of this dynamic model. As further applications of our model, we applied it to test against more biological observations. We found that increasing transcription factor number, rather than factory number and nucleus size, might be the reason for decreasing gene co-localization. In the scenario of frequency-or amplitude-modulation of transcription factors, our model predicted that frequency-modulation may increase the co-localization between its targeted genes

Area-level deprivation and adiposity in children: is the relationship linear?

OBJECTIVE: It has been suggested that childhood obesity is inversely associated with deprivation, such that the prevalence is higher in more deprived groups. However, comparatively few studies actually use an area-level measure of deprivation, limiting the scope to assess trends in the association with obesity for this indicator. Furthermore, most assume a linear relationship. Therefore, the aim of this study was to investigate associations between area-level deprivation and three measures of adiposity in children: body mass index (BMI), waist circumference (WC) and waist-to-height ratio (WHtR). DESIGN: This is a cross-sectional study in which data were collected on three occasions a year apart (2005-2007). SUBJECTS: Data were available for 13,333 children, typically aged 11-12 years, from 37 schools and 542 lower super-output areas (LSOAs). MEASURES: Stature, mass and WC. Obesity was defined as a BMI and WC exceeding the 95th centile according to British reference data. WHtR exceeding 0.5 defined obesity. The Index of Multiple Deprivation affecting children (IDACI) was used to determine area-level deprivation. RESULTS: Considerable differences in the prevalence of obesity exist between the three different measures. However, for all measures of adiposity the highest probability of being classified as obese is in the middle of the IDACI range. This relationship is more marked in girls, such that the probability of being obese for girls living in areas at the two extremes of deprivation is around half that at the peak, occurring in the middle. CONCLUSION: These data confirm the high prevalence of obesity in children and suggest that the relationship between obesity and residential area-level deprivation is not linear. This is contrary to the 'deprivation theory' and questions the current understanding and interpretation of the relationship between obesity and deprivation in children. These results could help make informed decisions at the local level

A pilot randomised controlled trial of personalised care for depressed patients with symptomatic coronary heart disease in South London general practices: the UPBEAT-UK RCT protocol and recruitment.

ABSTRACT: Background: Community studies reveal people with coronary heart disease (CHD) are twice as likely to be depressed as the general population and that this co-morbidity negatively affects the course and outcome of both conditions. There is evidence for the efficacy of collaborative care and case management for depression treatment, and whilst NICE guidelines recommend these approaches only where depression has not responded to psychological, pharmacological, or combined treatments, these care approaches may be particularly relevant to the needs of people with CHD and depression in the earlier stages of stepped care in primary care settings. Methods: This pilot randomised controlled trial will evaluate whether a simple intervention involving a personalised care plan, elements of case management and regular telephone review is a feasible and acceptable intervention that leads to better mental and physical health outcomes for these patients. The comparator group will be usual general practitioner (GP) care. 81 participants have been recruited from CHD registers of 15 South London general practices. Eligible participants have probable major depression identified by a score of ≥8 on the Hospital Anxiety and Depression Scale depression subscale (HADS-D) together with symptomatic CHD identified using the Modified Rose Angina Questionnaire. Consenting participants are randomly allocated to usual care or the personalised care intervention which involves a comprehensive assessment of each participant’s physical and mental health needs which are documented in a care plan, followed by regular telephone reviews by the case manager over a 6-month period. At each review, the intervention participant’s mood, function and identified problems are reviewed and the case manager uses evidence based behaviour change techniques to facilitate achievement of goals specified by the patient with the aim of increasing the patient’s self efficacy to solve their problems. Depressive symptoms measured by HADS score will be collected at baseline and 1, 6- and 12 months post randomisation. Other outcomes include CHD symptoms, quality of life, wellbeing and health service utilisation. Discussion: This practical and patient-focused intervention is potentially an effective and accessible approach to the health and social care needs of people with depression and CHD in primary care. Trial registration: ISRCTN21615909

Area deprivation and its association with health in a cross-sectional study: are the results biased by recent migration?

<p>Abstract</p> <p>Background</p> <p>The association between area deprivation and health has mostly been examined in cross-sectional studies or prospective studies with short follow-up. These studies have rarely taken migration into account. This is a possible source of misclassification of exposure, i.e. an unknown number of study participants are attributed an exposure of area deprivation that they may have experienced too short for it to have any influence. The aim of this article was to examine to what extent associations between area deprivation and health outcomes were biased by recent migration.</p> <p>Methods</p> <p>Based on data from the Oslo Health Study, a cross-sectional study conducted in 2000 in Oslo, Norway, we used six health outcomes (self rated health, mental health, coronary heart disease, chronic obstructive pulmonary disease, smoking and exercise) and considered migration nine years prior to the study conduct. Migration into Oslo, between the areas of Oslo, and the changes in area deprivation during the period were taken into account. Associations were investigated by multilevel logistic regression analyses.</p> <p>Results</p> <p>After adjustment for individual socio-demographic variables we found significant associations between area deprivation and all health outcomes. Accounting for migration into Oslo and between areas of Oslo did not change these associations much. However, the people who migrated into Oslo were younger and had lower prevalences of unfavourable health outcomes than those who were already living in Oslo. But since they were evenly distributed across the area deprivation quintiles, they had little influence on the associations between area deprivation and health. Evidence of selective migration within Oslo was weak, as both moving up and down in the deprivation hierarchy was associated with significantly worse health than not moving.</p> <p>Conclusion</p> <p>We have documented significant associations between area deprivation and health outcomes in Oslo after adjustment for socio-demographic variables in a cross-sectional study. These associations were weakly biased by recent migration. From our results it still appears that migration prior to study conduct may be relevant to investigate even within a relatively short period of time, whereas changes in area deprivation during such a period is of limited interest.</p

Responses of marine benthic microalgae to elevated CO<inf>2</inf>

Increasing anthropogenic CO2 emissions to the atmosphere are causing a rise in pCO2 concentrations in the ocean surface and lowering pH. To predict the effects of these changes, we need to improve our understanding of the responses of marine primary producers since these drive biogeochemical cycles and profoundly affect the structure and function of benthic habitats. The effects of increasing CO2 levels on the colonisation of artificial substrata by microalgal assemblages (periphyton) were examined across a CO2 gradient off the volcanic island of Vulcano (NE Sicily). We show that periphyton communities altered significantly as CO2 concentrations increased. CO2 enrichment caused significant increases in chlorophyll a concentrations and in diatom abundance although we did not detect any changes in cyanobacteria. SEM analysis revealed major shifts in diatom assemblage composition as CO2 levels increased. The responses of benthic microalgae to rising anthropogenic CO2 emissions are likely to have significant ecological ramifications for coastal systems. © 2011 Springer-Verlag

Thrombotic gene polymorphisms and postoperative outcome after coronary artery bypass graft surgery

<p>Abstract</p> <p>Background</p> <p>Emerging perioperative genomics may influence the direction of risk assessment and surgical strategies in cardiac surgery. The aim of this study was to investigate whether single nucleotide polymorphisms (SNP) affect the clinical presentation and predispose to increased risk for postoperative adverse events in patients undergoing coronary artery bypass grafting surgery (CABG).</p> <p>Methods</p> <p>A total of 220 patients undergoing first-time CABG between January 2005 and May 2008 were screened for factor V gene G1691A (FVL), prothrombin/factor II G20210A (PT G20210A), angiotensin I-converting enzyme insertion/deletion (ACE-ins/del) polymorphisms by PCR and Real Time PCR. End points were defined as death, myocardial infarction, stroke, postoperative bleeding, respiratory and renal insufficiency and event-free survival. Patients were compared to assess for any independent association between genotypes for thrombosis and postoperative phenotypes.</p> <p>Results</p> <p>Among 220 patients, the prevalence of the heterozygous FVL mutation was 10.9% (n = 24), and 3.6% (n = 8) were heterozygous carriers of the PT G20210A mutation. Genotype distribution of ACE-ins/del was 16.6%, 51.9%, and 31.5% in genotypes I/I, I/D, and D/D, respectively. FVL and PT G20210A mutations were associated with higher prevalence of totally occluded coronary arteries (p < 0.001). Furthermore the risk of left ventricular aneurysm formation was significantly higher in FVL heterozygote group compared to FVL G1691G (<it>p </it>= 0.002). ACE D/D genotype was associated with hypertension (<it>p </it>= 0.004), peripheral vascular disease (p = 0.006), and previous myocardial infarction (<it>p </it>= 0.007).</p> <p>Conclusions</p> <p>FVL and PT G20210A genotypes had a higher prevalence of totally occluded vessels potentially as a result of atherothrombotic events. However, none of the genotypes investigated were independently associated with mortality.</p

‘Fish out of water’: a cross-sectional study on the interaction between social and neighbourhood effects on weight management behaviours

Objective: To analyse whether an individual’s neighbourhood influences the uptake of weight management strategies and whether there is an interaction between individual socio-economic status and neighbourhood deprivation. Methodology: Data were collected from the Yorkshire Health Study (2010–2012) for 27 806 individuals on the use of the following weight management strategies: ‘slimming clubs’, ‘healthy eating’, ‘increasing exercise’ and ‘controlling portion size’. A multi-level logistic regression was fit to analyse the use of these strategies, controlling for age, sex, body mass index, education, neighbourhood deprivation and neighbourhood population turnover (a proxy for neighbourhood social capital). A cross-level interaction term was included for education and neighbourhood deprivation. Lower Super Output Area was used as the geographical scale for the areal unit of analysis. Results: Significant neighbourhood effects were observed for use of ‘slimming clubs’, ‘healthy eating’ and ‘increasing exercise’ as weight management strategies, independent of individual- and area-level covariates. A significant interaction between education and neighbourhood deprivation was observed across all strategies, suggesting that as an area becomes more deprived, individuals of the lowest education are more likely not to use any strategy compared with those of the highest education. Conclusions: Neighbourhoods modify/amplify individual disadvantage and social inequalities, with individuals of low education disproportionally affected by deprivation. It is important to include neighbourhood-based explanations in the development of community-based policy interventions to help tackle obesit

On the analysis of sedimentation velocity in the study of protein complexes

Sedimentation velocity analytical ultracentrifugation has experienced a significant transformation, precipitated by the possibility of efficiently fitting Lamm equation solutions to the experimental data. The precision of this approach depends on the ability to account for the imperfections of the experiment, both regarding the sample and the instrument. In the present work, we explore in more detail the relationship between the sedimentation process, its detection, and the model used in the mathematical data analysis. We focus on configurations that produce steep and fast-moving sedimentation boundaries, such as frequently encountered when studying large multi-protein complexes. First, as a computational tool facilitating the analysis of heterogeneous samples, we introduce the strategy of partial boundary modeling. It can simplify the modeling by restricting the direct boundary analysis to species with sedimentation coefficients in a predefined range. Next, we examine factors related to the experimental detection, including the magnitude of optical aberrations generated by out-of-focus solution columns at high protein concentrations, the relationship between the experimentally recorded signature of the meniscus and the meniscus parameter in the data analysis, and the consequences of the limited radial and temporal resolution of the absorbance optical scanning system. Surprisingly, we find that large errors can be caused by the finite scanning speed of the commercial absorbance optics, exceeding the statistical errors in the measured sedimentation coefficients by more than an order of magnitude. We describe how these effects can be computationally accounted for in SEDFIT and SEDPHAT