Development of primary human nasal epithelial cell cultures for the study of cystic fibrosis pathophysiology

Cultured primary epithelial cells are used to examine inflammation in cystic fibrosis (CF). We describe a new human model system using cultured nasal brushings. Nasal brushings were obtained from 16 F508del homozygous patients and 11 healthy controls. Cells were resuspended in airway epithelial growth medium and seeded onto collagen-coated flasks and membranes for use in patch-clamp, ion transport, and mediator release assays. Viable cultures were obtained with a 75% success rate from subjects with CF and 100% from control subjects. Amiloride-sensitive epithelial Na channel current of similar size was present in both cell types while forskolin-activated CF transmembrane conductance regulator current was lacking in CF cells. In Ussing chambers, cells from CF patients responded to UTP but not to forskolin. Spontaneous and cytomix-stimulated IL-8 release was similar (stimulated 29,448 ± 9,025 pg/ml; control 16,336 ± 3,308 pg/ml CF; means ± SE). Thus nasal epithelial cells from patients with CF can be grown from nasal brushings and used in electrophysiological and mediator release studies in CF research.

Radiochromic film spectroscopy of laser-accelerated proton beams using the FLUKA code and dosimetry traceable to primary standards

A new approach to spectroscopy of laser induced proton beams using radiochromic film (RCF) is presented. This approach allows primary standards of absorbed dose-to-water as used in radiotherapy to be transferred to the calibration of GafChromic HD-810 and EBT in a 29 MeV proton beam from the Birmingham cyclotron. These films were then irradiated in a common stack configuration using the TARANIS Nd:Glass multi-terawatt laser at Queens University Belfast, which can accelerate protons to 10-12 MeV, and a depth-dose curve was measured from a collimated beam. Previous work characterizing the relative effectiveness (RE) of GafChromic film as a function of energy was implemented into Monte Carlo depth-dose curves using FLUKA. A Bragg peak (BP) "library" for proton energies 0-15 MeV was generated, both with and without the RE function. These depth-response curves were iteratively summed in a FORTRAN routine to solve for the measured RCF depth-dose using a simple direct search algorithm. By comparing resultant spectra with both BP libraries, it was found that the effect of including the RE function accounted for an increase in the total number of protons by about 50%. To account for the energy loss due to a 20 mu m aluminum filter in front of the film stack, FLUKA was used to create a matrix containing the energy loss transformations for each individual energy bin. Multiplication by the pseudo-inverse of this matrix resulted in "up-shifting" protons to higher energies. Applying this correction to two laser shots gave further increases in the total number of protons, N of 31% and 56%. Failure to consider the relative response of RCF to lower proton energies and neglecting energy losses in a stack filter foil can potentially lead to significant underestimates of the total number of protons in RCF spectroscopy of the low energy protons produced by laser ablation of thin targets.

Wellbeing, academic buoyancy and educational achievement in primary school students

The study explored the relationship between student wellbeing and academic achievement among 7–11 years old students and whether the relationship was moderated by gender and deprivation. 1081 students in Northern Ireland participated in a crosssectional survey that captured data on academic achievement and a range of wellbeing indicators. Findings suggested the existence of an underlying wellbeing factor, which was positively related to achievement. The relationship was not moderated by gender and/or deprivation. Findings were explored using a model of ‘academic buoyancy’. There was no evidence that suggested efforts to improve achievement that focus on wellbeing should be targeted speci?cally at students in economically deprived areas or be modi?ed in terms of gender.

Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis

We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P <5 × 10(-8)), increasing the number of known susceptibility loci to 25. The most associated variant at 19p12 is a low-frequency nonsynonymous SNP in TYK2, further implicating JAK-STAT and cytokine signaling in disease pathogenesis. An additional five loci contained nonsynonymous variants in high linkage disequilibrium (LD; r(2) > 0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non-human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r(2) > 0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up.

Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis

In addition to the HLA locus, six genetic risk factors for primary biliary cirrhosis (PBC) have been identified in recent genome-wide association studies (GWAS). To identify additional loci, we carried out a GWAS using 1,840 cases from the UK PBC Consortium and 5,163 UK population controls as part of the Wellcome Trust Case Control Consortium 3 (WTCCC3). We followed up 28 loci in an additional UK cohort of 620 PBC cases and 2,514 population controls. We identified 12 new susceptibility loci (at a genome-wide significance level of P <5 × 10?8) and replicated all previously associated loci. We identified three further new loci in a meta-analysis of data from our study and previously published GWAS results. New candidate genes include STAT4, DENND1B, CD80, IL7R, CXCR5, TNFRSF1A, CLEC16A and NFKB1. This study has considerably expanded our knowledge of the genetic architecture of PBC.

The changing pattern of adult primary glomerular disease

Published biopsy series have shown geographical and temporal variations in the patterns of primary glomerulonephritis (GN). IgA nephropathy is the most common type of GN in most European studies, but there is evidence suggesting that focal segmental glomerulosclerosis (FSGS) is increasingly common in the USA in all ethnic groups. We report the analysis of 30 years of native renal biopsies and the temporal pattern of primary glomerular disease in a single United Kingdom (UK) region.

Improving clinician self-efficacy does not increase asthma guideline use by primary care clinicians

Objective: The purpose of this study was to show the association between changes in clinician self-efficacy and readiness to change and implementation of an asthma management program (Easy Breathing). Methods: A 36 month randomized, controlled trial was conducted involving 24 pediatric practices (88 clinicians). Randomized clinicians received interventions designed to enhance clinician self-efficacy and readiness to change which were measured at baseline and 3 years. Interventions consisted of an educational toolbox, seminars, teleconferences, mini-fellowships, opinion leader visits, clinician-specific feedback, and pay for performance. The primary outcome was program utilization (number of children enrolled in Easy Breathing/year); secondary outcomes included development of a written treatment plan and severity-appropriate therapy. Results: At baseline, clinicians enrolled 149 ± 147 (mean ± SD) children/clinician/year; 84% of children had a written treatment plan and 77% of plans used severity-appropriate therapy. At baseline, higher self-efficacy scores were associated with greater program utilization (relative rate [RR], 1.34; 95% confidence interval [CI], 1.04-1.72; P =.04) but not treatment plan development (RR, 0.63; 95% CI, 0.29-1.35; P =.23) or anti-inflammatory use (RR, 1.76; 95% CI, 0.92-3.35; P =.09). Intervention clinicians participated in 17 interventions over 36 months. At study end, self-efficacy scores increased in intervention clinicians compared to control clinicians (P =.01) and more clinicians were in an action stage of change (P =.001) but these changes were not associated with changes in primary or secondary outcomes. Conclusions: Self-efficacy scores correlated with program use at baseline and increased in the intervention arm, but these increases were not associated with greater program-related activities. Self-efficacy may be necessary but not sufficient for behavior change. Copyright © 2012 by Academic Pediatric Association.

Effect of preventive primary care outreach on health related quality of life among older adults at risk of functional decline: Randomised controlled trial

Objective: To evaluate the impact of a provider initiated primary care outreach intervention compared with usual care among older adults at risk of functional decline. Design: Randomised controlled trial. Setting: Patients enrolled with 35 family physicians in five primary care networks in Hamilton, Ontario, Canada. Participants Patients: were eligible if they were 75 years of age or older and were not receiving home care services. Of 3166 potentially eligible patients, 2662 (84%) completed the validated postal questionnaire used to determine risk of functional decline. Of 1724 patients who met the risk criteria, 769 (45%) agreed to participate and 719 were randomised. Intervention: The 12 month intervention, provided by experienced home care nurses in 2004-6, consisted of a comprehensive initial assessment using the resident assessment instrument for home care; collaborative care planning with patients, their families, and family physicians; health promotion; and referral to community health and social support services. Main outcome measures: Quality adjusted life years (QALYs), use and costs of health and social services, functional status, self rated health, and mortality. Results: The mean difference in QALYs between intervention and control patients during the study period was not statistically significant (0.017, 95% confidence interval -0.022 to 0.056; P=0.388). The mean difference in overall cost of prescription drugs and services between the intervention and control groups was not statistically significant, (-$C165 (£107; €118; $162), 95% confidence interval -$C16 545 to $C16 214; P=0.984). Changes over 12 months in functional status and self rated health were not significantly different between the intervention and control groups. Ten patients died in each group. Conclusions: The results of this study do not support adoption of this preventive primary care intervention for this target population of high risk older adults. Trial registration: Clinical trials NCT00134836.

The impact of antibiotic use on the incidence and resistance pattern of extended-spectrum beta-lactamase-producing bacteria in primary and secondary healthcare settings

Aims: The objective of the present study was to study the relationship between hospital antibiotic use, community antibiotic use and the incidence of extended-spectrum beta-lactamase (ESBL)-producing bacteria in hospitals, while assessing the impact of a fluoroquinolone restriction policy on ESBL-producing bacteria incidence rates. METHODS: The study was retrospective and ecological in design. A multivariate autoregressive integrated moving average (ARIMA) model was built to relate antibiotic use to ESB-producing bacteria incidence rates and resistance patterns over a 5 year period (January 2005-December 2009). Results: Analysis showed that the hospital incidence of ESBLs had a positive relationship with the use of fluoroquinolones in the hospital (coefficient = 0.174, P= 0.02), amoxicillin-clavulanic acid in the community (coefficient = 1.03, P= 0.03) and mean co-morbidity scores for hospitalized patients (coefficient = 2.15, P= 0.03) with various time lags. The fluoroquinolone restriction policy was implemented successfully with the mean use of fluoroquinolones (mainly ciprofloxacin) being reduced from 133 to 17 defined daily doses (DDDs)/1000 bed days (P <0.001) and from 0.65 to 0.54 DDDs/1000 inhabitants/day (P= 0.0007), in both the hospital and its surrounding community, respectively. This was associated with an improved ciprofloxacin susceptibility in both settings [ciprofloxacin susceptibility being improved from 16% to 28% in the community (P <0.001)] and with a statistically significant reduction in ESBL-producing bacteria incidence rates. Discussion: This study supports the value of restricting the use of certain antimicrobial classes to control ESBL, and demonstrates the feasibility of reversing resistance patterns post successful antibiotic restriction. The study also highlights the potential value of the time-series analysis in designing efficient antibiotic stewardship. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Steps to a better Belfast: physical activity assessment and promotion in primary care

BACKGROUND: Low physical activity (PA) levels which increase the risk of chronic disease are reported by two-thirds of the general UK population. Promotion of PA by primary healthcare professionals is advocated but more evidence is needed regarding effective ways of integrating this within everyday practice. This study aims to explore the feasibility of a randomised trial of a pedometer-based intervention, using step-count goals, recruiting patients from primary care. METHOD: Patients, aged 35-75, attending four practices in socioeconomically deprived areas, were invited to complete a General Practice PA Questionnaire during routine consultations. Health professionals invited 'inactive' individuals to a pedometer-based intervention and were randomly allocated to group 1 (prescribed a self-determined goal) or group 2 (prescribed a specific goal of 2500 steps/day above baseline). Both groups kept step-count diaries and received telephone follow-up at 1, 2, 6 and 11 weeks. Step counts were reassessed after 12 weeks. RESULTS: Of the 2154 patients attending, 192 questionnaires were completed (8.9%). Of these, 83 were classified as 'inactive'; 41(10 men; 31 women) completed baseline assessments, with the mean age of participants being 51 years. Mean baseline step counts were similar in group 1 (5685, SD 2945) and group 2 (6513, SD 3350). The mean increase in steps/day was greater in groups 1 than 2 ((2602, SD 1957) vs (748, SD 1997) p=0.005). CONCLUSIONS: A trial of a pedometer-based intervention using self-determined step counts appears feasible in primary care. Pedometers appear acceptable to women, particularly at a perimenopausal age, when it is important to engage in impact loading activities such as walking to maintain bone mineral density. An increase of 2500 steps/day is achievable for inactive patients, but the effectiveness of different approaches to realistic goal-setting warrants further study.

Brisk walking, fitness, and cardiovascular risk:a randomized controlled trial in primary care

To examine the effects of 30 min of self-paced, non-supervised, brisk walking, 5 days per week on the health and fitness of people aged 50-65 years.

Aldo goes to Primary School: Experiencing school through the lens of the autistic spectrum.

The document draws largely on the results of research carried out by Hugh McNally and Dominic Morris of McNally Morris Architects and Keith McAllister of Queen’s University Belfast between 2012 and 2013. The objective of the study was to obtain a greater understanding of the impact that architecture and the built environment can have on people with autism spectrum disorder (ASD). The investigation into the subject centred on parents of young children with ASD in the belief that they are most likely to have an intimate knowledge of the issues that affect their children and are relatively well positioned to communicate those issues.

The study comprised a number of components.

- Focus Group Discussions with parents of children with ASD
- A Postal Questionnaire completed by parents of children with ASD
- A Comprehensive Desktop study of contemporary research into the relationship between ASD and aspects of the built environment.

Social stories are then used to help illustrate the world of a child with ASD to the reader and identify a series of potential difficulties for the pupil with ASD in a primary school setting. Design considerations and mitigating measures are then proposed for each difficulty.

The intention is that the document will raise awareness of some of the issues affecting primary school children with ASD and generate discourse among those whose task it is to provide an appropriate learning environment for all children. This includes teachers, health professionals, architects, parents, carers, school boards, government bodies and those with ASD themselves.

While this document uses the primary school as a lens through which to view some of the issues associated with ASD, it is the authors’ contention that the school can be seen as a “microcosm” for the wider world and that lessons taken from the learning environment can be applied elsewhere. The authors therefore hope that the document will help raise awareness of the myriad of issues for those with ASD that are embedded in the vast landscape of urban configurations and building types making up the spatial framework of our society.

Organizational culture predicts job satisfaction and perceived clinical effectiveness in pediatric primary care practices

Background: In recent years, there has been a growing understanding that organizational culture is related to an organization's performance. However, fewstudies have examined organizational culture in medical group practices. Objectives: The purpose of this study was to examine the relationship of organizational culture on provider job satisfaction and perceived clinical effectiveness in primary care pediatric practices. Research Design: This cross-sectional study included 36 primary care pediatric practices located in Connecticut. Participants: There were 374 participants in this study, which included 127 clinicians and 247 nonclinicians. Measures: Office managers completed a questionnaire that recorded staff and practice characteristics; all participants completed the Organizational Culture Scale, a questionnaire that assessed the practice on four cultural domains (i.e., group, developmental, rational, and hierarchical), and the Primary Care Organizational Questionnaire that evaluated perceived effectiveness and job satisfaction. Results: Hierarchical linear models using a restricted maximum likelihood estimation method were used to evaluate whether the practice culture types predicted job satisfaction and perceived effectiveness. Group culture was positively associated with both satisfaction and perceived effectiveness. In contrast, hierarchical and rational culture were negatively associated with both job satisfaction and perceived effectiveness. These relationships were true for clinicians, nonclinicians, and the practice as a whole. Conclusions: Our study demonstrates that practice culture is associated with job satisfaction and perceived clinical effectiveness and that a group culture was associated with high job satisfaction and perceived effectiveness. Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.