The Role of Penning Collisions in Hollow Cathode Helium Cadmium Lasers

The excitation mechanisms leading to the formation of the 5s² ²D5/2 level, the upper level of the 4416 Å transition of Cd+, have been investigated. Experiments were carried out in both a helium cadmium discharge and corresponding afterglow. A self absorption technique was used to measure the variation, with current, pressure and oven temperature, of the densities of selected excited helium levels and the cadmium ion ground state. A comparison of the parametric behaviour of the Penning collision rate with the 4416 Å spontaneous emission provided good evidence that Penning ionization was the dominant mechanism leading to laser oscillation at 4416 Å. Gas temperature effects were found to have a significant influence on the interpretation of the experimental results. Signal averaging techniques were employed to record the pressure, current and oven temperature dependence of the 4416 Å spontaneous decay in the hollow cathode helium cadmium afterglow. The decay was more complex than anticipated but was eventually attributed to the temporal evolution of the helium triplet metastable species in the afterglow. A simplified model of the afterglow was developed and, using the available excited state densities and estimates of the electron and helium ion densities and electron collision rates, the system of coupled differential rate equations was solved and found to be in reasonable agreement with the experimentally observed trends of the 4416 Å decay. Taken as a whole, the results of the study of the helium cadmium d.c. discharge and afterglow show beyond doubt that Penning ionization is the dominant excitation mechanism of the 5s² ²D5/2 level of Cd II

Set up and assessment of progression criteria for internal pilots:the Brushing RemInder 4 Good oral HealTh (BRIGHT) trial example

Background Dental caries is common in young people and has wide-ranging ramifications for health and quality of life. Text messaging interventions show promise as a means to promote oral health behaviour change among young people. This paper reports the internal pilot of the Brushing RemInder 4 Good oral HealTh (BRIGHT) trial, which is evaluating an intervention comprising an oral health classroom lesson and text messages about toothbrushing, on caries in young people. Pilot trial objectives were to evaluate the feasibility and appropriateness of recruitment and data collection methods, the randomisation strategy, and intervention delivery against progression criteria for the main trial. Methods This is an internal pilot trial embedded within an assessor-blinded, two-arm, cluster randomised controlled trial. Participants were pupils aged 11–13 years (in year 7/S1 or year 8/S2) in secondary schools in England, Scotland, and Wales with above average pupil eligibility for free school meals. Following completion of pupil baseline questionnaires and dental assessments, year groups within schools were randomised to the intervention or control arm. Approximately 12 weeks later, participants completed a follow-up questionnaire, which included questions about sources of oral health advice to assess intervention contamination between year groups. At the end of the pilot phase, trial conduct was reviewed against pre-specified progression criteria. Results Ten schools were recruited for the pilot, with 20 year groups and 1073 pupils randomised (average of 54 pupils per year group). Data collection methods and intervention delivery were considered feasible, the response rate to the follow-up questionnaire was over 80%, there was an indication of a positive effect on self-reported toothbrushing, and interest was obtained from 80% of the schools required for the main trial. Despite partial intervention contamination between year groups, within-school randomisation at the level of the year-group was considered appropriate for the main trial, and the sample size was revised to account for partial contamination. Facilitators and barriers to recruitment and data collection were identified and strategies refined for the main trial. Conclusions Progression to the main trial of BRIGHT, with some design refinements, was concluded. The internal pilot was an efficient way to determine trial feasibility and optimise trial processes

The oral health of secondary school pupils:baseline data from the Brushing RemInder 4 Good oral HealTh (BRIGHT) trial

Background This paper describes the sociodemographics and oral health of UK secondary school pupils. They were participants of the BRIGHT trial, which was designed to evaluate the effectiveness of a toothbrushing intervention to reduce dental caries. Methods Overall, 4,680 pupils aged 11-13 years attending 42 secondary schools in England, Scotland and Wales with above average proportion of pupils eligible for free school meals, were recruited to the trial. Sociodemographic data were collected. Participants had a clinical assessment for caries, plaque and bleeding and completed measures of oral and general health-related quality of life and oral health behaviours (frequency of toothbrushing, dental attendance and cariogenic food/drinks consumed). Regression analyses were performed. Results Over one-third (34.7%) of participants had caries experience, with 44.5% reporting their oral health had an impact on their daily lives. Factors associated with a statistically significant increased likelihood of caries experience were older age, being female, eligibility for free school meals, worse oral health-related quality of life, higher cariogenic diet, less than twice-daily toothbrushing, living in a more deprived area and lower school attendance. Conclusions The prevalence and impact of dental caries on the lives of pupils remains high, with further oral health promotion activities needed in targeted secondary schools.</p

The oral health of secondary school pupils:baseline data from the Brushing RemInder 4 Good oral HealTh (BRIGHT) trial

Background This paper describes the sociodemographics and oral health of UK secondary school pupils. They were participants of the BRIGHT trial, which was designed to evaluate the effectiveness of a toothbrushing intervention to reduce dental caries. Methods Overall, 4,680 pupils aged 11-13 years attending 42 secondary schools in England, Scotland and Wales with above average proportion of pupils eligible for free school meals, were recruited to the trial. Sociodemographic data were collected. Participants had a clinical assessment for caries, plaque and bleeding and completed measures of oral and general health-related quality of life and oral health behaviours (frequency of toothbrushing, dental attendance and cariogenic food/drinks consumed). Regression analyses were performed. Results Over one-third (34.7%) of participants had caries experience, with 44.5% reporting their oral health had an impact on their daily lives. Factors associated with a statistically significant increased likelihood of caries experience were older age, being female, eligibility for free school meals, worse oral health-related quality of life, higher cariogenic diet, less than twice-daily toothbrushing, living in a more deprived area and lower school attendance. Conclusions The prevalence and impact of dental caries on the lives of pupils remains high, with further oral health promotion activities needed in targeted secondary schools.</p

Data integration in eHealth: a domain/disease specific roadmap

The paper documents a series of data integration workshops held in 2006 at the UK National e-Science Centre, summarizing a range of the problem/solution scenarios in multi-site and multi-scale data integration with six HealthGrid projects using schizophrenia as a domain-specific test case. It outlines emerging strategies, recommendations and objectives for collaboration on shared ontology-building and harmonization of data for multi-site trials in this domain

BAFopathies\u27 DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin-Siris and Nicolaides-Baraitser syndromes.

Coffin-Siris and Nicolaides-Baraitser syndromes (CSS and NCBRS) are Mendelian disorders caused by mutations in subunits of the BAF chromatin remodeling complex. We report overlapping peripheral blood DNA methylation epi-signatures in individuals with various subtypes of CSS (ARID1B, SMARCB1, and SMARCA4) and NCBRS (SMARCA2). We demonstrate that the degree of similarity in the epi-signatures of some CSS subtypes and NCBRS can be greater than that within CSS, indicating a link in the functional basis of the two syndromes. We show that chromosome 6q25 microdeletion syndrome, harboring ARID1B deletions, exhibits a similar CSS/NCBRS methylation profile. Specificity of this epi-signature was confirmed across a wide range of neurodevelopmental conditions including other chromatin remodeling and epigenetic machinery disorders. We demonstrate that a machine-learning model trained on this DNA methylation profile can resolve ambiguous clinical cases, reclassify those with variants of unknown significance, and identify previously undiagnosed subjects through targeted population screening

Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions.

Conventional genetic testing of individuals with neurodevelopmental presentations and congenital anomalies (ND/CAs), i.e., the analysis of sequence and copy number variants, leaves a substantial proportion of them unexplained. Some of these cases have been shown to result from DNA methylation defects at a single locus (epi-variants), while others can exhibit syndrome-specific DNA methylation changes across multiple loci (epi-signatures). Here, we investigate the clinical diagnostic utility of genome-wide DNA methylation analysis of peripheral blood in unresolved ND/CAs. We generate a computational model enabling concurrent detection of 14 syndromes using DNA methylation data with full accuracy. We demonstrate the ability of this model in resolving 67 individuals with uncertain clinical diagnoses, some of whom had variants of unknown clinical significance (VUS) in the related genes. We show that the provisional diagnoses can be ruled out in many of the case subjects, some of whom are shown by our model to have other diseases initially not considered. By applying this model to a cohort of 965 ND/CA-affected subjects without a previous diagnostic assumption and a separate assessment of rare epi-variants in this cohort, we identify 15 case subjects with syndromic Mendelian disorders, 12 case subjects with imprinting and trinucleotide repeat expansion disorders, as well as 106 case subjects with rare epi-variants, a portion of which involved genes clinically or functionally linked to the subjects\u27 phenotypes. This study demonstrates that genomic DNA methylation analysis can facilitate the molecular diagnosis of unresolved clinical cases and highlights the potential value of epigenomic testing in the routine clinical assessment of ND/CAs

Molecular techniques and their limitations shape our view of the holobiont

It is now recognised that the biology of almost any organism cannot be fully understood without recognising the existence and potential functional importance of associated microbes. Arguably, the emergence of this holistic viewpoint may never have occurred without the development of a crucial molecular technique, 16S rDNA amplicon sequencing, which allowed microbial communities to be easily profiled across a broad range of contexts. A diverse array of molecular techniques are now used to profile microbial communities, infer their evolutionary histories, visualise them in host tissues, and measure their molecular activity. In this review, we examine each of these categories of measurement and inference with a focus on the questions they make tractable, and the degree to which their capabilities and limitations shape our view of the holobiont

Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Fibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP. Here we extend that work to imputed genome-wide genotypes and conduct new RNA sequencing studies of lung tissue to identify and characterize new fIIP risk loci.We performed genome-wide genotype imputation association analyses in 1616 non-Hispanic white (NHW) cases and 4683 NHW controls followed by validation and replication (878 cases, 2017 controls) genotyping and targeted gene expression in lung tissue. Following meta-analysis of the discovery and replication populations, we identified a novel fIIP locus in the HLA region of chromosome 6 (rs7887 P meta  = 3.7 × 10(-09)). Imputation of classic HLA alleles identified two in high linkage disequilibrium that are associated with fIIP (DRB1*15:01 P = 1.3 × 10(-7) and DQB1*06:02 P = 6.1 × 10(-8)). Targeted RNA-sequencing of the HLA locus identified 21 genes differentially expressed between fibrotic and control lung tissue (Q < 0.001), many of which are involved in immune and inflammatory response regulation. In addition, the putative risk alleles, DRB1*15:01 and DQB1*06:02, are associated with expression of the DQB1 gene among fIIP cases (Q < 1 × 10(-16)).We have identified a genome-wide significant association between the HLA region and fIIP. Two HLA alleles are associated with fIIP and affect expression of HLA genes in lung tissue, indicating that the potential genetic risk due to HLA alleles may involve gene regulation in addition to altered protein structure. These studies reveal the importance of the HLA region for risk of fIIP and a basis for the potential etiologic role of auto-immunity in fIIP.National Heart, Lung and Blood Institute R01-HL095393 R01-HL097163 P01-HL092870 RC2-HL101715 U01-HL089897 U01-HL089856 U01-HL108642 P50-HL089493

Improving care for older people with long-term conditions and social care needs in Salford : the CLASSIC mixed-methods study, including RCT

BackgroundThe Salford Integrated Care Programme (SICP) was a large-scale transformation project to improve care for older people with long-term conditions and social care needs. We report an evaluation of the ability of the SICP to deliver an enhanced experience of care, improved quality of life, reduced costs of care and improved cost-effectiveness.ObjectivesTo explore the process of implementation of the SICP and the impact on patient outcomes and costs.DesignQualitative methods (interviews and observations) to explore implementation, a cohort multiple randomised controlled trial to assess patient outcomes through quasi-experiments and a formal trial, and an analysis of routine data sets and appropriate comparators using non-randomised methodologies.SettingSalford in the north-west of England.ParticipantsOlder people aged ≥ 65 years, carers, and health and social care professionals.InterventionsA large-scale integrated care project with three core mechanisms of integration (community assets, multidisciplinary groups and an ‘integrated contact centre’).Main outcome measuresPatient self-management, care experience and quality of life, and health-care utilisation and costs.Data sourcesProfessional and patient interviews, patient self-report measures, and routine quantitative data on service utilisation.ResultsThe SICP and subsequent developments have been sustained by strong partnerships between organisations. The SICP achieved ‘functional integration’ through the pooling of health and social care budgets, the development of the Alliance Agreement between four organisations and the development of the shared care record. ‘Service-level’ integration was slow and engagement with general practice was a challenge. We saw only minor changes in patient experience measures over the period of the evaluation (both improvements and reductions), with some increase in the use of community assets and care plans. Compared with other sites, the difference in the rates of admissions showed an increase in emergency admissions. Patient experience of health coaching was largely positive, although the effects of health coaching on activation and depression were not statistically significant. Economic analyses suggested that coaching was likely to be cost-effective, generating improvements in quality of life [mean incremental quality-adjusted life-year gain of 0.019, 95% confidence interval (CI) –0.006 to 0.043] at increased cost (mean incremental total cost increase of £150.58, 95% CI –£470.611 to £711.776).LimitationsThe Comprehensive Longitudinal Assessment of Salford Integrated Care study represents a single site evaluation, with consequent limits on external validity. Patient response rates to the cohort survey were ConclusionsThe SICP has been implemented in a way that is consistent with the original vision. However, there has been more rapid success in establishing new integrated structures (such as a formal integrated care organisation), rather than in delivering mechanisms of integration at sufficient scale to have a large impact on patient outcomes.Future workFurther research could focus on each of the mechanisms of integration. The multidisciplinary groups may require improved targeting of patients or disease subgroups to demonstrate effectiveness. Development of a proven model of health coaching that can be implemented at scale is required, especially one that would provide cost savings for commissioners or providers. Similarly, further exploration is required to assess the longer-term benefits of community assets and whether or not health impacts translate to reductions in care use.Trial registrationCurrent Controlled Trials ISRCTN12286422.FundingThis project was funded by the NIHR Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 6, No. 31. See the NIHR Journals Library website for further project information