Blurring the boundaries between synthesis and evaluation. A customized realist evaluative synthesis into adolescent risk behavior prevention

Realist methodologies have been increasingly advocated for the investigation of complex social issues. Public health programs, such as those designed to prevent adolescent risk behavior, are typically considered complex. In conducting a realist review of the empirical literature relating to such programs, we encountered several challenges, including (a) an overabundance of empirical evidence, (b) a problematic level of heterogeneity within and between methodological approaches, (c) discrepancies between theoretical underpinnings and program operationalization, (d) homogeneity of program outcomes, with very little variation in program effectiveness, and (d) a paucity of description relating to content and process. To overcome these challenges, we developed a customized approach to realist evidence synthesis, drawing on the VICTORE (Volition, Implementation, Contexts, Time, Outcomes, Rivalry, and Emergence) complexity checklist and incorporating stakeholder engagement as primary data to achieve greater depth of understanding relating to contextual and mechanistic factors, and the complex interactions between them. Here we discuss the benefits of this adapted methodology alongside an overview of the research through which the methodology was developed. A key finding from this research was that combining the complexity checklist with primary data from stakeholder engagement enabled us to systematically interrogate the data across data sources, uncovering and evidencing mechanisms which may otherwise have remained hidden, giving greater ontological depth to our research findings. This paper builds on key methodological developments in realist research, demonstrating how realist methodologies can be customized to overcome challenges in developing and refining program theory from the literature, and contributes to the broader literature of innovative approaches to realist research

Challenges in applying human factors approaches to health service design

A participatory systems approach is a fundamental characteristic of the human factors and ergonomics discipline. However, the appropriate application of relevant methods is challenging in healthcare, since there is very limited time for staff to participate and their knowledge on design methods is usually very limited. An action research was carried out in a health service design project commissioned by a local health service commissioner. The aim of this paper is to examine and discuss challenges in applying the participatory systems approach

A discrete genetic locus confers xyloglucan metabolism in select human gut Bacteroidetes

A well-balanced human diet includes a significant intake of non-starch polysaccharides, collectively termed 'dietary fibre', from the cell walls of diverse fruits and vegetables. Owing to the paucity of alimentary enzymes encoded by the human genome, our ability to derive energy from dietary fibre depends on the saccharification and fermentation of complex carbohydrates by the massive microbial community residing in our distal gut. The xyloglucans (XyGs) are a ubiquitous family of highly branched plant cell wall polysaccharides whose mechanism(s) of degradation in the human gut and consequent importance in nutrition have been unclear. Here we demonstrate that a single, complex gene locus in Bacteroides ovatus confers XyG catabolism in this common colonic symbiont. Through targeted gene disruption, biochemical analysis of all predicted glycoside hydrolases and carbohydrate-binding proteins, and three-dimensional structural determination of the vanguard endo-xyloglucanase, we reveal the molecular mechanisms through which XyGs are hydrolysed to component monosaccharides for further metabolism. We also observe that orthologous XyG utilization loci (XyGULs) serve as genetic markers of XyG catabolism in Bacteroidetes, that XyGULs are restricted to a limited number of phylogenetically diverse strains, and that XyGULs are ubiquitous in surveyed human metagenomes. Our findings reveal that the metabolism of even highly abundant components of dietary fibre may be mediated by niche species, which has immediate fundamental and practical implications for gut symbiont population ecology in the context of human diet, nutrition and health

Epilepsy service provision and re-design with a focus on primary care

This thesis reports four studies which have been designed to promote the greater involvement of primary care in the treatment of epilepsy. The primary aim is to study whether programs of high capacity, low interventional care for people with epilepsy are feasible and effective in primary care, within specific programs. The secondary aims explore the uptake and utility of such programs with preliminary examination on national trends in mortality and hospitalisation for people with epilepsy during the time of the study. 1.) The first study called the Primary Care Clinical Effectiveness program 2 [PRICCE-2] determined the extent to which primary care in East Kent was able to be produce an epilepsy register, ascertain the number of people who were seizure free and identify people at risk from retinal damage from vigabatrin. Also GPs were required to ensure that women were prescribed appropriate contraception and that pregnant women were offered folic acid. The program also studied trends in unplanned visits to hospital which occurred during the program. The PRICCE-2 project demonstrated GPs are willing to participate [89% of eligible practices in 2001] and could identify people who were seizure free [71.25% by the end of the program.] The identification of people on Vigabatrin was also successful identifying 21 people, [20 were expected,] but the ability to support women with epilepsy was less successful. The number of emergency admissions to the local three hospitals for epilepsy was seen to rise steadily, however diagnostic indexing was fairly poor at this stage. 2.) The second study called the Quality and Outcome Framework, determined the extent to which primary care was able to produce an epilepsy register, record seizure frequency, perform a basic epilepsy medication review and 4 determine people who were seizure free. Later on in the study, GPs were required to ensure that women were prescribed appropriate contraceptive medication and offered prenatal advice. The program also studied trends in mortality from epilepsy and trends in unplanned visits to hospital for epilepsy. The study revealed GPs were able to identify people with epilepsy [initially 86.8% rising to 99.8% by 2011], review their medication [95.3% in 2011] and identify people who were seizure free [73.9% in 2011] however they have found it harder to support women with epilepsy with high exception reporting used for this group [36.7% in 2011/12]. The unplanned hospital admissions steadily rose during this time, whilst the mortality for epilepsy began to decline [ R 2 = 0.6118] however whether this was a casual or causal link could not be determined. 3.) The third study determined if primary care could proactively identify social consequences of active epilepsy including the recording of driving status and social factors affected by epilepsy. It also identified and offered women with epilepsy folic acid, pre conception advice and ensured they were prescribed appropriate contraceptive. In addition it required GPs to identify people with epilepsy under hospital care. The study revealed that GPs were able to identify social consequences of epilepsy and identify people under hospital care but once again they found it difficult to support women with epilepsy related issues. The restructuring of PCTs at this time resulted in a loss of data. 4.) The final study determined the extent to which pharmacists can be trained to proactively support people with epilepsy in a Medicines Use Review [MUR] format. Pharmacists grasp of epilepsy before and after training and customer’s knowledge and readiness to approach their pharmacist for support were assessed before and after the consultation. In addition pharmacists were 5 taught how to recognise red flag symptoms and directly refer at risk patients to specialist epilepsy services. The pharmacists readily absorbed the epilepsy training and their customers reported benefit in improved knowledge about epilepsy and also indicated that in future they would seek support for epilepsy from their pharmacist. The direct referral process for epilepsy was not successful however and would need refining in the future. The overall aim to study whether high capacity, low interventional care for epilepsy is both feasible and effective has I believe, been demonstrated in these studies to be possible. Pro-active care for epilepsy is possible in general practice, with GPs being able to provide high capacity epilepsy care. The influence on admission rates and mortality for epilepsy is less clear and requires further study

Logopenic and nonfluent variants of primary progressive aphasia are differentiated by acoustic measures of speech production

Differentiation of logopenic (lvPPA) and nonfluent/agrammatic (nfvPPA) variants of Primary Progressive Aphasia is important yet remains challenging since it hinges on expert based evaluation of speech and language production. In this study acoustic measures of speech in conjunction with voxel-based morphometry were used to determine the success of the measures as an adjunct to diagnosis and to explore the neural basis of apraxia of speech in nfvPPA. Forty-one patients (21 lvPPA, 20 nfvPPA) were recruited from a consecutive sample with suspected frontotemporal dementia. Patients were diagnosed using the current gold-standard of expert perceptual judgment, based on presence/absence of particular speech features during speaking tasks. Seventeen healthy age-matched adults served as controls. MRI scans were available for 11 control and 37 PPA cases; 23 of the PPA cases underwent amyloid ligand PET imaging. Measures, corresponding to perceptual features of apraxia of speech, were periods of silence during reading and relative vowel duration and intensity in polysyllable word repetition. Discriminant function analyses revealed that a measure of relative vowel duration differentiated nfvPPA cases from both control and lvPPA cases (r2 = 0.47) with 88% agreement with expert judgment of presence of apraxia of speech in nfvPPA cases. VBM analysis showed that relative vowel duration covaried with grey matter intensity in areas critical for speech motor planning and programming: precentral gyrus, supplementary motor area and inferior frontal gyrus bilaterally, only affected in the nfvPPA group. This bilateral involvement of frontal speech networks in nfvPPA potentially affects access to compensatory mechanisms involving right hemisphere homologues. Measures of silences during reading also discriminated the PPA and control groups, but did not increase predictive accuracy. Findings suggest that a measure of relative vowel duration from of a polysyllable word repetition task may be sufficient for detecting most cases of apraxia of speech and distinguishing between nfvPPA and lvPPA

Hardy's inequality for functions vanishing on a part of the boundary

We develop a geometric framework for Hardy's inequality on a bounded domain when the functions do vanish only on a closed portion of the boundary.Comment: 26 pages, 2 figures, includes several improvements in Sections 6-8 allowing to relax the assumptions in the main results. Final version published at http://link.springer.com/article/10.1007%2Fs11118-015-9463-

Prime movers : mechanochemistry of mitotic kinesins

Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation. Kinesins are key members of these force-generating teams. Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips. The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation

Using molecular data for epidemiological inference: assessing the prevalence of Trypanosoma brucei rhodesiense in Tsetse in Serengeti, Tanzania

Background: Measuring the prevalence of transmissible Trypanosoma brucei rhodesiense in tsetse populations is essential for understanding transmission dynamics, assessing human disease risk and monitoring spatio-temporal trends and the impact of control interventions. Although an important epidemiological variable, identifying flies which carry transmissible infections is difficult, with challenges including low prevalence, presence of other trypanosome species in the same fly, and concurrent detection of immature non-transmissible infections. Diagnostic tests to measure the prevalence of T. b. rhodesiense in tsetse are applied and interpreted inconsistently, and discrepancies between studies suggest this value is not consistently estimated even to within an order of magnitude. Methodology/Principal Findings: Three approaches were used to estimate the prevalence of transmissible Trypanosoma brucei s.l. and T. b. rhodesiense in Glossina swynnertoni and G. pallidipes in Serengeti National Park, Tanzania: (i) dissection/microscopy; (ii) PCR on infected tsetse midguts; and (iii) inference from a mathematical model. Using dissection/microscopy the prevalence of transmissible T. brucei s.l. was 0% (95% CI 0–0.085) for G. swynnertoni and 0% (0–0.18) G. pallidipes; using PCR the prevalence of transmissible T. b. rhodesiense was 0.010% (0–0.054) and 0.0089% (0–0.059) respectively, and by model inference 0.0064% and 0.00085% respectively. Conclusions/Significance: The zero prevalence result by dissection/microscopy (likely really greater than zero given the results of other approaches) is not unusual by this technique, often ascribed to poor sensitivity. The application of additional techniques confirmed the very low prevalence of T. brucei suggesting the zero prevalence result was attributable to insufficient sample size (despite examination of 6000 tsetse). Given the prohibitively high sample sizes required to obtain meaningful results by dissection/microscopy, PCR-based approaches offer the current best option for assessing trypanosome prevalence in tsetse but inconsistencies in relating PCR results to transmissibility highlight the need for a consensus approach to generate meaningful and comparable data

Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself

The Contribution of Social Networks to the Health and Self-Management of Patients with Long-Term Conditions: A Longitudinal Study

Evidence for the effectiveness of patient education programmes in changing individual self-management behaviour is equivocal. More distal elements of personal social relationships and the availability of social capital at the community level may be key to the mobilisation of resources needed for long-term condition self-management to be effective. Aim: To determine how the social networks of people with long-term conditions (diabetes and heart disease) are associated with health-related outcomes and changes in outcomes over time. Methods: Patients with chronic heart disease (CHD) or diabetes (n = 300) randomly selected from the disease registers of 19 GP practices in the North West of England. Data on personal social networks collected using a postal questionnaire, alongside face-to-face interviewing. Follow-up at 12 months via postal questionnaire using a self-report grid for network members identified at baseline. Analysis: Multiple regression analysis of relationships between health status, self-management and health economics outcomes, and characteristics of patients’ social networks. Results: Findings indicated that: (1) social involvement with a wider variety of people and groups supports personal self-management and physical and mental well-being; (2) support work undertaken by personal networks expands in accordance with health needs helping people to cope with their condition; (3) network support substitutes for formal care and can produce substantial saving in traditional health service utilisation costs. Health service costs were significantly (p0.01) reduced for patients receiving greater levels of illness work through their networks. Conclusions: Support for self-management which achieves desirable policy outcomes should be construed less as an individualised set of actions and behaviour and more as a social network phenomenon. This study shows the need for a greater focus on harnessing and sustaining the capacity of networks and the importance of social involvement with community groups and resources for producing a more desirable and cost-effective way of supporting long term illness management