The utility of the Theories of Change approach within the evaluation of the Scottish National CHID Health Demonstration Project (Have a Heart Paisley)

The Scottish Executive (SE) commissioned the first phase of a National Coronary Heart Disease (CHD) Demonstration Project, Have a Heart Paisley (HaHP), in 2000. HaHP was a complex community-based partnership intervention. An independent evaluation of HaHP (phase one) was commissioned by the SE in 2001. This thesis presents the learning from the evaluation. The first aim is to identify the key implementation, evaluation and policy lessons to result from the evaluation. The second is to contribute to learning about how best to evaluate complex community-based interventions. The evaluation consisted of four approaches: a theory-based approach (the Theories of Change); the mapping of the context; a quasi-experimental survey; and, a range of integrated case studies. This thesis uses the programme logic (the intervention’s Theories of Change) articulated by the HaHP stakeholders to integrate the results from each of the evaluation approaches. HaHP (phase one) did not achieve significant changes in population level CHD risk factors, behaviours, morbidity or mortality. Like many previous community-based CHD interventions HaHP did not fully implement its intended Theories of Change. HaHP’s activities were not consistently based on best practice. It did not articulate or implement clear strategies for addressing health inequalities. The project delivered mainly individually focussed, ‘downstream’ interventions and struggled to achieve wide-scale local service, policy and agenda changes. It did, however, make progress with regard to improving partnerships and jointly delivering interventions. The findings from HaHP add to existing evidence that large-scale behaviour and cultural change will only be achieved through national action and the increasing use of ‘upstream’, legislative, or policy solutions, or changes in mainstream services and organisations. Activity in localised demonstration projects can add to such change rather than create it. The Theories of Change approach claims to improve planning and implementation, enhance evaluation, and address attribution. The approach (as applied within this evaluation) provided substantial amounts of formative feedback that was of use for improving programme implementation. This learning, however, was not always acted upon

Characterization of Pro-Inflammatory Flagellin Proteins Produced by Lactobacillus ruminis and Related Motile Lactobacilli

peer-reviewedLactobacillus ruminis is one of at least twelve motile but poorly characterized species found in the genus Lactobacillus. Of these, only L. ruminis has been isolated from mammals, and this species may be considered as an autochthonous member of the gastrointestinal microbiota of humans, pigs and cows. Nine L. ruminis strains were investigated here to elucidate the biochemistry and genetics of Lactobacillus motility. Six strains isolated from humans were non-motile while three bovine isolates were motile. A complete set of flagellum biogenesis genes was annotated in the sequenced genomes of two strains, ATCC25644 (human isolate) and ATCC27782 (bovine isolate), but only the latter strain produced flagella. Comparison of the L. ruminis and L. mali DSM20444T motility loci showed that their genetic content and gene-order were broadly similar, although the L. mali motility locus was interrupted by an 11.8 Kb region encoding rhamnose utilization genes that is absent from the L. ruminis motility locus. Phylogenetic analysis of 39 motile bacteria indicated that Lactobacillus motility genes were most closely related to those of motile carnobacteria and enterococci. Transcriptome analysis revealed that motility genes were transcribed at a significantly higher level in motile L. ruminis ATCC27782 than in non-motile ATCC25644. Flagellin proteins were isolated from L. ruminis ATCC27782 and from three other Lactobacillus species, while recombinant flagellin of aflagellate L. ruminis ATCC25644 was expressed and purified from E. coli. These native and recombinant Lactobacillus flagellins, and also flagellate L. ruminis cells, triggered interleukin-8 production in cultured human intestinal epithelial cells in a manner suppressed by short interfering RNA directed against Toll-Like Receptor 5. This study provides genetic, transcriptomic, phylogenetic and immunological insights into the trait of flagellum-mediated motility in the lactobacilli.This work was supported by a Principal Investigator Award (07/IN.1/B1780) from Science Foundation Ireland to PWOT. BAN was the recipient of an Embark studentship from the Irish Research Council for Science Engineering and Technology. TD and KN were supported by the Alimentary Pharmabiotic Centre, funded by Science Foundation Ireland

Estimating the number of people with hepatitis C virus who have ever injected drugs and have yet to be diagnosed: an evidence synthesis approach for Scotland.

AIMS: To estimate the number of people who have ever injected drugs (defined here as PWID) living in Scotland in 2009 who have been infected with the hepatitis C virus (HCV) and to quantify and characterize the population remaining undiagnosed. METHODS: Information from routine surveillance (n=22616) and survey data (n=2511) was combined using a multiparameter evidence synthesis approach to estimate the size of the PWID population, HCV antibody prevalence and the proportion of HCV antibody prevalent cases who have been diagnosed, in subgroups defined by recency of injecting (in the last year or not), age (15-34 and 35-64 years), gender and region of residence (Greater Glasgow and Clyde and the rest of Scotland). RESULTS: HCV antibody-prevalence among PWID in Scotland during 2009 was estimated to be 57% [95% CI=52-61%], corresponding to 46657 [95% credible interval (CI)=33812-66803] prevalent cases. Of these, 27434 (95% CI=14636-47564) were undiagnosed, representing 59% [95% CI=43-71%] of prevalent cases. Among the undiagnosed, 83% (95% CI=75-89%) were PWID who had not injected in the last year and 71% (95% CI=58-85%) were aged 35-64 years. CONCLUSIONS: The number of undiagnosed hepatitis C virus-infected cases in Scotland appears to be particularly high among those who have injected drugs more than 1 year ago and are more than 35 years old

A qualitative study of parental strategies to enable pre-school children’s outdoor and nature experiences during COVID-19 restrictions

Outdoor and nature experiences including play have been shown to be beneficial for children's physical, cognitive, social and emotional development. Parents/carers play an important role in encouraging or impeding their child's access to the outdoor environment and participation in outdoor play. The COVID-19 pandemic and associated restrictions on free movement and social interactions placed an unprecedented pressure on families to manage the drastic change in their daily routines. This paper reports findings from two combined data sets generated in 2020 during the COVID-19 pandemic and provides a deeper understanding of the interconnected nature of how contextual factors influence parenting processes and outcomes relating to young children's outdoor and nature experiences and subsequent child health. Findings have the potential to inform the messaging of existing outdoor play policies and the content of new interventions aiming to promote the exposure of children to the natural outdoor environment

Genome sequences and comparative genomics of two Lactobacillus ruminis strains from the bovine and human intestinal tracts

peer-reviewedBackground: The genus Lactobacillus is characterized by an extraordinary degree of phenotypic and genotypic diversity, which recent genomic analyses have further highlighted. However, the choice of species for sequencing has been non-random and unequal in distribution, with only a single representative genome from the L. salivarius clade available to date. Furthermore, there is no data to facilitate a functional genomic analysis of motility in the lactobacilli, a trait that is restricted to the L. salivarius clade. Results: The 2.06 Mb genome of the bovine isolate Lactobacillus ruminis ATCC 27782 comprises a single circular chromosome, and has a G+C content of 44.4%. In silico analysis identified 1901 coding sequences, including genes for a pediocin-like bacteriocin, a single large exopolysaccharide-related cluster, two sortase enzymes, two CRISPR loci and numerous IS elements and pseudogenes. A cluster of genes related to a putative pilin was identified, and shown to be transcribed in vitro. A high quality draft assembly of the genome of a second L. ruminis strain, ATCC 25644 isolated from humans, suggested a slightly larger genome of 2.138 Mb, that exhibited a high degree of synteny with the ATCC 27782 genome. In contrast, comparative analysis of L. ruminis and L. salivarius identified a lack of long-range synteny between these closely related species. Comparison of the L. salivarius clade core proteins with those of nine other Lactobacillus species distributed across 4 major phylogenetic groups identified the set of shared proteins, and proteins unique to each group. Conclusions: The genome of L. ruminis provides a comparative tool for directing functional analyses of other members of the L. salivarius clade, and it increases understanding of the divergence of this distinct Lactobacillus lineage from other commensal lactobacilli. The genome sequence provides a definitive resource to facilitate investigation of the genetics, biochemistry and host interactions of these motile intestinal lactobacilli

Evaluation of an Extended Stroke Rehabilitation Service (EXTRAS): A Randomized Controlled Trial and Economic Analysis

Background and Purpose— There is limited evidence to guide rehabilitation to meet the longer term needs of stroke survivors. The clinical effectiveness and cost-effectiveness of an extended stroke rehabilitation service (EXTRAS) provided following early supported discharge were determined. Methods— EXTRAS was a pragmatic parallel-group observer-blind randomized controlled trial involving 19 UK centers. Patients with stroke were individually randomized to receive EXTRAS or usual care at discharge from early supported discharge. Five EXTRAS reviews were provided by an early supported discharge team member between one and 18 months, usually by telephone. Reviews consisted of a semi-structured interview assessing progress, rehabilitation needs, and service provision, with goal setting and action planning. The primary outcome was performance in extended activities of daily living (Nottingham EADL Scale) at 24 months post-randomization. The Nottingham EADL Scale is scored 0 to 66, with higher scores indicating better performance in these activities. Cost-effectiveness was estimated using resource utilization costs and Quality Adjusted Life Years. Analyses were intention to treat. Results— Between January 9, 2013 and October 26, 2015, 573 participants were randomized (EXTRAS, n=285; usual care, n=288). Mean 24 month Nottingham EADL Scale scores were EXTRAS (n=219) 40.0 (SD 18.1) and usual care (n=231) 37.2 (SD 18.5) giving an adjusted mean difference of 1.8 (95% CI, –0.7 to 4.2). 1155/1338 (86%) of expected EXTRAS reviews were undertaken. Over 24 months, the mean cost of resource utilization was lower in the intervention group: –£311 (–$450 [95$4764 to $4033]). EXTRAS provided more Quality Adjusted Life Years (0.07 [95$28 940] per Quality Adjusted Life Years), there was a 90% chance that EXTRAS could be considered cost-effective. Conclusions— EXTRAS did not significantly improve stroke survivors’ performance in extended activities of daily living. However, given the impact on costs and Quality Adjusted Life Years, EXTRAS may be an affordable addition to improve stroke care

Gonadotropin administration to mimic mini-puberty in hypogonadotropic males: pump or injections?

Objective: Newborns with congenital hypogonadotropic hypogonadism (CHH) have an impaired postnatal activation of the gonadotropic axis. Substitutive therapy with recombinant gonadotropins can be proposed to mimic physiological male mini-puberty during the first months of life. The aim of this study was to co mpare the clinical and biological efficacy of two treatment modalities of gonadotropins administration during mini-puberty in CHH neonates. Design: Multicenter retrospective analytical epidemiological study comparing two treatments, pump vs injection, between 2004 and 2019. Methods: Clinical (penile size, testis size, testicular descent) and biological parameters (serum concentrations of testosterone, anti-Müllerian hormone (AMH) and Inhibin B) were compared between the two groups by multivariate analyses. Results: Thirty-five patients were included. A significantly higher incre ase in penile length and testosterone level was observed in the injection group compared to the pump group (+0.16 ± 0.02 mm vs +0.10 ± 0.02 mm per day, P = 0.002; and +0.04 ± 0.007 ng/mL vs +0.01 ± 0.008 ng/mL per day, P = 0.001). In both groups, significant increases in penile length and width, testosterone, AMH, and Inhibin B levels were observed, as well as improved testicular descent (odds ratio of not being in a scrotal position at the end of treatment = 0.97 (0.96; 0.99)). Conclusions: Early postnatal administration of recombinant gonadotropins in CHH boys is effective in stimulating penile growth, Sertoli cell proliferati on, and testicular descent, with both treatment modalities

NKG2D/NKG2-Ligand Pathway Offers New Opportunities in Cancer Treatment

The antitumor functions of NK cells are regulated by the integration of positive and negative signals triggered by numerous membrane receptors present on the NK cells themselves. Among the main activating receptors, NKG2D binds several stress-induced molecules on tumor targets. Engagement of NKG2D by its ligands (NKG2D-Ls) induces NK cell activation leading to production of cytokines and target cell lysis. These effects have therapeutic potential as NKG2D-Ls are widely expressed by solid tumors, whereas their expression in healthy cells is limited. Here, we describe the genetic and environmental factors regulating the NKG2D/NKG2D-L pathway in tumors. NKG2D-L expression is linked to cellular stress and cell proliferation, and has been associated with oncogenic mutations. Tumors have been found to alter their to NKG2D-L expression as they progress, which interferes with the antitumor function of the pathway. Nevertheless, this pathway could be advantageously exploited for cancer therapy. Various cancer treatments, including chemotherapy and targeted therapies, indirectly interfere with the cellular and soluble forms of NKG2D-Ls. In addition, NKG2D introduced into chimeric antigen receptors in T- and NK cells is a promising tumor immunotherapy approach

Huntington's Disease assessment using tri axis accelerometers

Huntington’s disease (HD) is a progressive inherited neurodegenerative disorder, causing involuntary movement and cognitive problems, severely affecting the quality of life. Controlling upper limb function is a core feature of daily activity and can prove problematic for people with HD. The Money Box Test (MBT) has been developed with a purpose of quantifying the involuntary movement frequently seen in people with HD. In this research, wearable and highly sensitive accelerometers are used to collect the acceleration of the hands and chest during the performance of the MBT. Using this data, a new approach is proposed to automatically classify the participants into two classes, healthy and HD, on the basis of the time series accelerometer data. A set of 90 time domain features is extracted from the accelerometer data, a feature selection technique is used to analyse the feature significance and to reduce the dimensionality of the dataset, and finally an SVM classifier is used to classify subjects into healthy and HD classes. The data of seven healthy controls and 15 HD patients are used in this study. The highest accuracy with the most significant eight features is 86.36% with the sensitivity and the specificity values being 87.50%, and 83.33% respectively