The Cepheid Period-Luminosity Relation at Mid-Infrared Wavelengths: I. First-Epoch LMC Data

We present the first mid-infrared Period-Luminosity (PL) relations for Large Magellanic Cloud (LMC) Cepheids. Single-epoch observations of 70 Cepheids were extracted from Spitzer IRAC observations at 3.6, 4.5, 5.8 and 8.0 microns, serendipitously obtained during the SAGE (Surveying the Agents of a Galaxy's Evolution) imaging survey of the LMC. All four mid-infrared PL relations have nearly identical slopes over the period range 6 - 88 days, with a small scatter of only +/-0.16 mag independent of period for all four of these wavelengths. We emphasize that differential reddening is not contributing significantly to the observed scatter, given the nearly two orders of magnitude reduced sensitivity of the mid-IR to extinction compared to the optical. Future observations, filling in the light curves for these Cepheids, should noticeably reduce the residual scatter. These attributes alone suggest that mid-infrared PL relations will provide a practical means of significantly improving the accuracy of Cepheid distances to nearby galaxies.Comment: 19 pages, 4 figures, 1 table, Accepted for publication in the Astrophysical Journa

Researchers' experiences of the design and conduct challenges associated with parallel-group cluster-randomised trials and views on a novel open-cohort design

BACKGROUND: Two accepted designs exist for parallel-group cluster-randomised trials (CRTs). Closed-cohort designs follow the same individuals over time with a single recruitment period before randomisation, but face challenges in settings with high attrition. (Repeated) cross-sectional designs recruit at one or more timepoints before and/or after randomisation, collecting data from different individuals present in the cluster at these timepoints, but are unsuitable for assessment of individual change over time. An 'open-cohort' design allows individual follow-up with recruitment before and after cluster-randomisation, but little literature exists on acceptability to inform their use in CRTs. AIM: To document the views and experiences of expert trialists to identify: a) Design and conduct challenges with established parallel-group CRT designs,b) Perceptions of potential benefits and barriers to implementation of open-cohort CRTs,c) Methods for minimising, and investigating the impact of, bias in open-cohort CRTs. METHODS: Qualitative consultation via two expert workshops including triallists (n = 24) who had worked on CRTs over a range of settings. Workshop transcripts were analysed using Descriptive Thematic Analysis utilising inductive and deductive coding. RESULTS: Two central organising concepts were developed. Design and conduct challenges with established CRT designs confirmed that current CRT designs are unable to deal with many of the complex research and intervention circumstances found in some trial settings (e.g. care homes). Perceptions of potential benefits and barriers of open cohort designs included themes on: approaches to recruitment; data collection; analysis; minimising/investigating the impact of bias; and how open-cohort designs might address or present CRT design challenges. Open-cohort designs were felt to provide a solution for some of the challenges current CRT designs present in some settings. CONCLUSIONS: Open-cohort CRT designs hold promise for addressing the challenges associated with standard CRT designs. Research is needed to provide clarity around definition and guidance on application.</p

Resolving debris discs in the far-infrared: early highlights from the DEBRIS survey

We present results from the earliest observations of DEBRIS, a Herschel Key Programme to conduct a volume- and flux-limited survey for debris discs in A-type through M-type stars. PACS images (from chop/nod or scan-mode observations) at 100 and 160 micron are presented toward two A-type stars and one F-type star: beta Leo, beta UMa and eta Corvi. All three stars are known disc hosts. Herschel spatially resolves the dust emission around all three stars (marginally, in the case of beta UMa), providing new information about discs as close as 11 pc with sizes comparable to that of the Solar System. We have combined these data with existing flux density measurements of the discs to refine the SEDs and derive estimates of the fractional luminosities, temperatures and radii of the discs.Comment: to be published in A&A, 5 pages, 2 color figure

Discordant MZ twins With Cleft Lip and Palate: a model for identifying genes in complex traits.

Monozygotic (MZ) twins may be discordant for complex traits due to differential environmental exposure in utero, epigenetic variability in imprinting, X chromosome inactivation, or stochastic effects. Occasionally MZ twins may be discordant for chromosomal and single gene disorders due to somatic mosaicism. For complex traits, which are due to the interactive effects of multiple genes and environmental factors, the affected twin of a discordant MZ pair offers the possibility for identifying somatic mutations in candidate genes. DNA sequencing of candidate genes in discordant MZ twins can identify those rare etiologic mutational events responsible for the different phenotypes since the confounding effects of common single nucleotide polymorphisms are eliminated, as DNA sequences should be identical in MZ pairs. In this report we describe the extensive DNA sequencing of 18 candidate genes in a sample of MZ and dizygotic (DZ) twins with nonsyndromic cleft lip with or without cleft palate. We were unable to identify any somatic differences in approximately 34 Kb of DNA sequenced in 13 MZ pairs, for a total of approximately 900 Kb of sequence comparisons, supporting the hypothesis that nonetiologic posttwinning mutations are rare. While no etiologic variants were identified in this study, sequence comparisons of discordant MZ twins can serve as a tool for identifying etiologic mutations in clefting and other complex traits

Researchers’ experiences of the design and conduct challenges associated with parallel-group cluster-randomised trials and views on a novel open-cohort design

Background Two accepted designs exist for parallel-group cluster-randomised trials (CRTs). Closed-cohort designs follow the same individuals over time with a single recruitment period before randomisation, but face challenges in settings with high attrition. (Repeated) cross-sectional designs recruit at one or more timepoints before and/or after randomisation, collecting data from different individuals present in the cluster at these timepoints, but are unsuitable for assessment of individual change over time. An ‘open-cohort’ design allows individual follow-up with recruitment before and after cluster-randomisation, but little literature exists on acceptability to inform their use in CRTs. Aim To document the views and experiences of expert trialists to identify: a) Design and conduct challenges with established parallel-group CRT designs, b) Perceptions of potential benefits and barriers to implementation of open-cohort CRTs, c) Methods for minimising, and investigating the impact of, bias in open-cohort CRTs. Methods Qualitative consultation via two expert workshops including triallists (n = 24) who had worked on CRTs over a range of settings. Workshop transcripts were analysed using Descriptive Thematic Analysis utilising inductive and deductive coding. Results Two central organising concepts were developed. Design and conduct challenges with established CRT designs confirmed that current CRT designs are unable to deal with many of the complex research and intervention circumstances found in some trial settings (e.g. care homes). Perceptions of potential benefits and barriers of open cohort designs included themes on: approaches to recruitment; data collection; analysis; minimising/investigating the impact of bias; and how open-cohort designs might address or present CRT design challenges. Open-cohort designs were felt to provide a solution for some of the challenges current CRT designs present in some settings. Conclusions Open-cohort CRT designs hold promise for addressing the challenges associated with standard CRT designs. Research is needed to provide clarity around definition and guidance on application

Study of the common genetic background for rheumatoid arthritis and systemic lupus erythematosus

BACKGROUND: Evidence is beginning to emerge that there may be susceptibility loci for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) that are common to both diseases. OBJECTIVE: To investigate single nucleotide polymorphisms that have been reported to be associated with SLE in a UK cohort of patients with RA and controls. METHODS: 3962 patients with RA and 9275 controls were included in the study. Eleven SNPs mapping to confirmed SLE loci were investigated. These mapped to the TNFSF4, BANK1, TNIP1, PTTG1, UHRF1BP1, ATG5, JAZF1, BLK, KIAA1542, ITGAM and UBE2L3 loci. Genotype frequencies were compared between patients with RA and controls using the trend test. RESULTS: The SNPs mapping to the BLK and UBE2L3 loci showed significant evidence for association with RA. Two other SNPs, mapping to ATG5 and KIAA1542, showed nominal evidence for association with RA (p=0.02 and p=0.02, respectively) but these were not significant after applying a Bonferroni correction. Additionally, a significant global enrichment in carriage of SLE alleles in patients with RA compared with controls (p=9.1×10(-7)) was found. Meta-analysis of this and previous studies confirmed the association of the BLK and UBE2L3 gene with RA at genome-wide significance levels (p<5×10(-8)). Together, the authors estimate that the SLE and RA overlapping loci, excluding HLA-DRB1 alleles, identified so far explain ∼5.8% of the genetic susceptibility to RA as a whole. CONCLUSION: The findings confirm the association of the BLK and UBE2L3 loci with RA, thus adding to the list of loci showing overlap between RA and SLE

A vision for safer food contact materials: Public health concerns as drivers for improved testing

Food contact materials (FCMs) and food contact articles are ubiquitous in today's globalized food system. Chemicals migrate from FCMs into foodstuffs, so called food contact chemicals (FCCs), but current regulatory requirements do not sufficiently protect public health from hazardous FCCs because only individual substances used to make FCMs are tested and mostly only for genotoxicity while endocrine disruption and other hazard properties are disregarded. Indeed, FCMs are a known source of a wide range of hazardous chemicals, and they likely contribute to highly prevalent non-communicable diseases. FCMs can also include non-intentionally added substances (NIAS), which often are unknown and therefore not subject to risk assessment. To address these important shortcomings, we outline how the safety of FCMs may be improved by (1) testing the overall migrate, including (unknown) NIAS, of finished food contact articles, and (2) expanding toxicological testing beyond genotoxicity to multiple endpoints associated with non-communicable diseases relevant to human health. To identify mechanistic endpoints for testing, we group chronic health outcomes associated with chemical exposure into Six Clusters of Disease (SCOD) and we propose that finished food contact articles should be tested for their impacts on these SCOD. Research should focus on developing robust, relevant, and sensitive in-vitro assays based on mechanistic information linked to the SCOD, e.g., through Adverse Outcome Pathways (AOPs) or Key Characteristics of Toxicants. Implementing this vision will improve prevention of chronic diseases that are associated with hazardous chemical exposures, including from FCMs

Community Occupational Therapy in Dementia intervention for people with mild to moderate dementia and their family carers in the UK: the VALID research programme including RCT

BackgroundPeople with dementia find it increasingly difficult to carry out daily activities (activities of daily living), and may require increasing support from family carers. Researchers in the Netherlands developed the Community Occupational Therapy in Dementia intervention, which was delivered in 10 1-hour sessions over 5 weeks to people with dementia and their family carers at home. Community Occupational Therapy in Dementia was found to be clinically effective and cost-effective.ObjectivesTranslate and adapt Community Occupational Therapy in Dementia to develop the Community Occupational Therapy in Dementia - the UK version intervention and training programme and to optimise its suitability for use within the UK. To estimate the clinical effectiveness and cost-effectiveness of Community Occupational Therapy in Dementia - the UK version for people with mild to moderate dementia and their family carers compared with treatment as usual.DesignThe development phase used mixed methods to develop Community Occupational Therapy in Dementia - the UK version: translation, expert review, and adaptation of the manual and training materials; training occupational therapists; focus groups and interviews, including occupational therapists, managers, people with dementia and family carers; consensus conference; and an online survey of occupational therapists to scope UK practice. A multicentre, two-arm, parallel-group, single-blind individually randomised pragmatic trial was preceded by an internal pilot. Pairs were randomly allocated between Community Occupational Therapy in Dementia - the UK version and treatment as usual. A cost–utility analysis, fidelity study and qualitative study were also completed.SettingCommunity services for people with dementia across England.ParticipantsPeople with mild to moderate dementia recruited in pairs with a family carer/supporter.InterventionsCommunity Occupational Therapy in Dementia - the UK version is an activity-based, goal-setting approach for people with dementia and family carers, and is delivered at home by an occupational therapist for 10 hours over 10 weeks. Treatment as usual comprised the usual local service provision, which may or may not include standard occupational therapy.Main outcome measuresData were collected through interviews conducted in person with dyads at baseline and at 12 and 26 weeks post randomisation, and then over the telephone with a reduced sample of just carers at 52 and 78 weeks post randomisation. The primary outcome was the Bristol Activities of Daily Living Scale at 26 weeks. The secondary outcomes were as follows: person with dementia – cognition, activities of daily living, quality of life and mood; carer – sense of competence, quality of life and mood; all participants – social contacts, leisure activities and serious adverse events.ResultsThe Community Occupational Therapy in Dementia manual and training materials were translated and reviewed. In total, 44 occupational therapists were trained and delivered Community Occupational Therapy in Dementia to 130 pairs. A total of 197 occupational therapists completed the survey, of whom 138 also provided qualitative data. In total, 31 people attended the consensus conference. Community Occupational Therapy in Dementia - the UK version has more flexibility than Community Occupational Therapy in Dementia in terms of content and delivery; for example, occupational therapists can use the wider range of assessment tools that are already in regular use within UK practice and the time span for delivery is 10 weeks to better meet the needs of pairs and be more feasible for services to deliver. In total, 31 occupational therapists provided Community Occupational Therapy in Dementia - the UK version within the randomised controlled trial. A total of 468 pairs were randomised (249 pairs to Community Occupational Therapy in Dementia - the UK version, 219 pairs to treatment as usual). People with dementia ranged in age from 55 to 97 years (mean 78.6 years), and family carers ranged in age from 29 to 94 years (mean 69.1 years). The majority of those with dementia (74.8%) were married; 19.2% lived alone. Most family carers (72.6%) were spouses but 22.2% were adult children. At 26 weeks, 406 (87%) pairs remained in the trial, and the Bristol Activities of Daily Living Scale total score did not differ at the 5% level when comparing groups (adjusted mean difference estimate 0.35, 95% confidence interval –0.81 to 1.51; p = 0.55). The adjusted (for baseline Bristol Activities of Daily Living Scale total score and randomised group) intracluster correlation coefficient estimate at week 26 was 0.043. There were no significant differences in secondary outcomes. At 52 and 78 weeks, there were no differences between the two groups in Bristol Activities of Daily Living Scale total score and secondary outcomes. The probability that Community Occupational Therapy in Dementia - the UK version is cost-effective at a threshold of willingness to pay per quality-adjusted life-year of £20,000 is 0.02%. In the qualitative interviews, participants reported positive benefits and outcomes. Of the 249 pairs allocated to Community Occupational Therapy in Dementia - the UK version, 227 reached the goal-setting phase, and 838 of the 920 goals set (90.8%) were fully or partially achieved.LimitationsThe development phase took longer than estimated because of translation time and organisational delays in delivering the intervention. Recruitment to the randomised controlled trial took longer than expected. Fidelity overall was moderate, with variation across sites and therapists. It is possible that Community Occupational Therapy in Dementia - the UK version did not work well in the UK service model in which usual care differs from that in the Netherlands.ConclusionsThis programme used a rigorous process to develop Community Occupational Therapy in Dementia - the UK version but found no statistical evidence of clinical effectiveness or cost-effectiveness compared with usual care. Qualitative findings provided positive examples of how Community Occupational Therapy in Dementia - the UK version had enabled people to live well with dementia

The Patient Feedback Response Framework – understanding why UK hospital staff find it difficult to make improvements based on patient feedback: A qualitative study

Patients are increasingly being asked for feedback about their healthcare experiences. However, healthcare staff often find it difficult to act on this feedback in order to make improvements to services. This paper draws upon notions of legitimacy and readiness to develop a conceptual framework (Patient Feedback Response Framework – PFRF) which outlines why staff may find it problematic to respond to patient feedback. A large qualitative study was conducted with 17 ward based teams between 2013 and 2014, across three hospital Trusts in the North of England. This was a process evaluation of a wider study where ward staff were encouraged to make action plans based on patient feedback. We focus on three methods here: i) examination of taped discussion between ward staff during action planning meetings ii) facilitators notes of these meetings iii) telephone interviews with staff focusing on whether action plans had been achieved six months later. Analysis employed an abductive approach. Through the development of the PFRF, we found that making changes based on patient feedback is a complex multi-tiered process and not something that ward staff can simply ‘do’. First, staff must exhibit normative legitimacy – the belief that listening to patients is a worthwhile exercise. Second, structural legitimacy has to be in place – ward teams need adequate autonomy, ownership and resource to enact change. Some ward teams are able to make improvements within their immediate control and environment. Third, for those staff who require interdepartmental co-operation or high level assistance to achieve change, organisational readiness must exist at the level of the hospital otherwise improvement will rarely be enacted. Case studies drawn from our empirical data demonstrate the above. It is only when appropriate levels of individual and organisational capacity to change exist, that patient feedback is likely to be acted upon to improve services

Feasibility study for supporting medication adherence for adults with cystic fibrosis: mixed-methods process evaluation

Objectives: To undertake a process evaluation of an adherence support intervention for people with cystic fibrosis (PWCF), to assess its feasibility and acceptability. Setting: Two UK cystic fibrosis (CF) units. Participants: Fourteen adult PWCF; three professionals delivering adherence support (‘interventionists’); five multi-disciplinary CF team members. Interventions: Nebuliser with data recording and transfer capability, linked to a software platform, and strategies to support adherence to nebulised treatments facilitated by interventionists over 5 months (± 1 month). Primary and secondary measures: Feasibility and acceptability of the intervention, assessed through semistructured interviews, questionnaires, fidelity assessments and click analytics. Results: Interventionists were complimentary about the intervention and training. Key barriers to intervention feasibility and acceptability were identified. Interventionists had difficulty finding clinic space and time in normal working hours to conduct review visits. As a result, fewer than expected intervention visits were conducted and interviews indicated this may explain low adherence in some intervention arm participants. Adherence levels appeared to be >100% for some patients, due to inaccurate prescription data, particularly in patients with complex treatment regimens. Flatlines in adherence data at the start of the study were linked to device connectivity problems. Content and delivery quality fidelity were 100% and 60%–92%, respectively, indicating that interventionists needed to focus more on intervention ‘active ingredients’ during sessions. Conclusions: The process evaluation led to 14 key changes to intervention procedures to overcome barriers to intervention success. With the identified changes, it is feasible and acceptable to support medication adherence with this intervention. Trial registration number: ISRCTN13076797; Results