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1.  The Ser82 RAGE Variant Affects Lung Function and Serum RAGE in Smokers and sRAGE Production In Vitro 
PLoS ONE  2016;11(10):e0164041.
Introduction
Genome-Wide Association Studies have identified associations between lung function measures and Chronic Obstructive Pulmonary Disease (COPD) and chromosome region 6p21 containing the gene for the Advanced Glycation End Product Receptor (AGER, encoding RAGE). We aimed to (i) characterise RAGE expression in the lung, (ii) identify AGER transcripts, (iii) ascertain if SNP rs2070600 (Gly82Ser C/T) is associated with lung function and serum sRAGE levels and (iv) identify whether the Gly82Ser variant is functionally important in altering sRAGE levels in an airway epithelial cell model.
Methods
Immunohistochemistry was used to identify RAGE protein expression in 26 human tissues and qPCR was used to quantify AGER mRNA in lung cells. Gene expression array data was used to identify AGER expression during lung development in 38 fetal lung samples. RNA-Seq was used to identify AGER transcripts in lung cells. sRAGE levels were assessed in cells and patient serum by ELISA. BEAS2B-R1 cells were transfected to overexpress RAGE protein with either the Gly82 or Ser82 variant and sRAGE levels identified.
Results
Immunohistochemical assessment of 6 adult lung samples identified high RAGE expression in the alveoli of healthy adults and individuals with COPD. AGER/RAGE expression increased across developmental stages in human fetal lung at both the mRNA (38 samples) and protein levels (20 samples). Extensive AGER splicing was identified. The rs2070600T (Ser82) allele is associated with higher FEV1, FEV1/FVC and lower serum sRAGE levels in UK smokers. Using an airway epithelium model overexpressing the Gly82 or Ser82 variants we found that HMGB1 activation of the RAGE-Ser82 receptor results in lower sRAGE production.
Conclusions
This study provides new information regarding the expression profile and potential role of RAGE in the human lung and shows a functional role of the Gly82Ser variant. These findings advance our understanding of the potential mechanisms underlying COPD particularly for carriers of this AGER polymorphism.
doi:10.1371/journal.pone.0164041
PMCID: PMC5068780  PMID: 27755550
2.  Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12 
Thorax  2016;71(6):501-509.
Background
Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants.
Objective
To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation.
Methods
3226 current or former smokers of European ancestry with lung function measures indicative of Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 COPD or worse were genotyped using an exome array. An analysis of risk of COPD was carried out using ever smoking controls (n=4784). Associations with %predicted FEV1 were tested in cases. We followed-up signals of interest (p<10−5) in independent samples from a subset of the UK Biobank population and also undertook a more powerful discovery study by meta-analysing the exome array data and UK Biobank data for variants represented on both arrays.
Results
Among the associated variants were two in regions previously unreported for COPD; a low frequency non-synonymous SNP in MOCS3 (rs7269297, pdiscovery=3.08×10−6, preplication=0.019) and a rare SNP in IFIT3, which emerged in the meta-analysis (rs140549288, pmeta=8.56×10−6). In the meta-analysis of % predicted FEV1 in cases, the strongest association was shown for a splice variant in a previously unreported region, SERPINA12 (rs140198372, pmeta=5.72×10−6). We also confirmed previously reported associations with COPD risk at MMP12, HHIP, GPR126 and CHRNA5. No associations in novel regions reached a stringent exome-wide significance threshold (p<3.7×10−7).
Conclusions
This study identified several associations with the risk of COPD and severity of airflow limitation, including novel regions MOCS3, IFIT3 and SERPINA12, which warrant further study.
doi:10.1136/thoraxjnl-2015-207876
PMCID: PMC4893124  PMID: 26917578
COPD epidemiology; Tobacco and the lung
3.  Deconstructing Complex Multimorbidity in the Very Old: Findings from the Newcastle 85+ Study 
BioMed Research International  2016;2016:8745670.
Objectives. To examine the extent and complexity of the morbidity burden in 85-year-olds; identify patterns within multimorbidity; and explore associations with medication and healthcare use. Participants. 710 men and women; mean (SD) age 85.5 (0.4) years. Methods. Data on 20 chronic conditions (diseases and geriatric conditions) ascertained from general practice records and participant assessment. Cluster analysis within the multimorbid sample identified subgroups sharing morbidity profiles. Clusters were compared on medication and healthcare use. Results. 92.7% (658/710) of participants had multimorbidity; median number of conditions: 4 (IQR 3–6). Cluster analysis (multimorbid sample) identified five subgroups sharing similar morbidity profiles; 60.0% (395/658) of participants belonged to one of two high morbidity clusters, with only 4.9% (32/658) in the healthiest cluster. Healthcare use was high, with polypharmacy (≥5 medications) in 69.8% (459/658). Between-cluster differences were found in medication count (p = 0.0001); hospital admissions (p = 0.022); and general practitioner (p = 0.034) and practice nurse consultations (p = 0.011). Morbidity load was related to medication burden and use of some, but not all, healthcare services. Conclusions. The majority of 85-year-olds had extensive and complex morbidity. Elaborating participant clusters sharing similar morbidity profiles will help inform future healthcare provision and the identification of common underlying biological mechanisms.
doi:10.1155/2016/8745670
PMCID: PMC4738702  PMID: 26885519
4.  Assessing patient preferences for the delivery of different community‐based models of care using a discrete choice experiment 
Abstract
Objectives
To assess patient preferences for different models of care defined by location of care, frequency of care and principal carer within community‐based health‐care services for older people.
Design
Discrete choice experiment administered within a face‐to‐face interview.
Setting
An intermediate care service in a large city within the United Kingdom.
Participants
The projected sample size was calculated to be 200; however, 77 patients were recruited to the study. The subjects had recently been discharged from hospital and were living at home and were receiving short‐term care by a publicly funded intermediate care service.
Interventions
Not applicable.
Main Outcome Measure
The degree of preference, measured using single utility score, for individual service characteristics presented within a series of potential care packages.
Results
Location of care was the dominant service characteristics with care at home being the strongly stated preference when compared with outpatient care (0.003), hospital care (<0.001) and nursing home care (<0.001) relative to home care, although this was less pronounced among less sick patients. Additionally, the respondents indicated a dislike for very frequent care contacts. No particular type of professional carer background was universally preferred but, unsurprisingly, there was evidence that sick patients showed a preference for nurse‐led care.
Conclusions
Patients have clear preferences for the location for their care and were able to state preferences between different care packages when their ideal service was not available. Service providers can use this information to assess which models of care are most preferred within resource constraints.
doi:10.1111/hex.12096
PMCID: PMC5060844  PMID: 23809234
allied health; assistants; community rehabilitation services; conjoint analysis; intermediate care; models of care; outcomes; patient preference; staff; support workers
5.  A pilot randomised controlled trial of a Telehealth intervention in patients with chronic obstructive pulmonary disease: challenges of clinician-led data collection 
Trials  2014;15:313.
Background
The increasing prevalence and associated cost of treating chronic obstructive pulmonary disease (COPD) is unsustainable, and focus is needed on self-management and prevention of hospital admissions. Telehealth monitoring of patients’ vital signs allows clinicians to prioritise their workload and enables patients to take more responsibility for their health. This paper reports the results of a pilot randomised controlled trial (RCT) of Telehealth-supported care within a community-based COPD supported-discharge service.
Methods
A two-arm pragmatic pilot RCT was conducted comparing the standard service with a Telehealth-supported service and assessed the potential for progressing into a full RCT. The co-primary outcome measures were the proportion of COPD patients readmitted to hospital and changes in patients’ self-reported quality of life. The objectives were to assess the suitability of the methodology, produce a sample size calculation for a full RCT, and to give an indication of cost-effectiveness for both pathways.
Results
Sixty three participants were recruited (n = 31 Standard; n = 32 Telehealth); 15 participants were excluded from analysis due to inadequate data completion or withdrawal from the Telehealth arm. Recruitment was slow with significant gaps in data collection, due predominantly to an unanticipated 60% reduction of staff capacity within the clinical team. The sample size calculation was guided by estimates of clinically important effects and COPD readmission rates derived from the literature. Descriptive analyses showed that the standard service group had a lower proportion of patients with hospital readmissions and a greater increase in self-reported quality of life compared to the Telehealth-supported group. Telehealth was cost-effective only if hospital admissions data were excluded.
Conclusions
Slow recruitment rates and service reconfigurations prevented progression to a full RCT. Although there are advantages to conducting an RCT with data collection conducted by a frontline clinical team, in this case, challenges arose when resources within the team were reduced by external events. Gaps in data collection were resolved by recruiting a research nurse. This study reinforces previous findings regarding the difficulty of undertaking evaluation of complex interventions, and provides recommendations for the introduction and evaluation of complex interventions within clinical settings, such as prioritisation of research within the clinical remit.
Trial registration
Current Controlled Trials ISRCTN68856013, registered Nov 2010.
doi:10.1186/1745-6215-15-313
PMCID: PMC4131041  PMID: 25100550
Chronic obstructive pulmonary disease; Implementation; Pilot RCT; Telehealth; Telemonitoring
6.  Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels 
The FASEB Journal  2014;28(2):923-934.
The soluble cleaved urokinase plasminogen activator receptor (scuPAR) is a circulating protein detected in multiple diseases, including various cancers, cardiovascular disease, and kidney disease, where elevated levels of scuPAR have been associated with worsening prognosis and increased disease aggressiveness. We aimed to identify novel genetic and biomolecular mechanisms regulating scuPAR levels. Elevated serum scuPAR levels were identified in asthma (n=514) and chronic obstructive pulmonary disease (COPD; n=219) cohorts when compared to controls (n=96). In these cohorts, a genome-wide association study of serum scuPAR levels identified a human plasma kallikrein gene (KLKB1) promoter polymorphism (rs4253238) associated with serum scuPAR levels in a control/asthma population (P=1.17×10−7), which was also observed in a COPD population (combined P=5.04×10−12). Using a fluorescent assay, we demonstrated that serum KLKB1 enzymatic activity was driven by rs4253238 and is inverse to scuPAR levels. Biochemical analysis identified that KLKB1 cleaves scuPAR and negates scuPAR's effects on primary human bronchial epithelial cells (HBECs) in vitro. Chymotrypsin was used as a proproteolytic control, while basal HBECs were used as a control to define scuPAR-driven effects. In summary, we reveal a novel post-translational regulatory mechanism for scuPAR using a hypothesis-free approach with implications for multiple human diseases.—Portelli, M. A., Siedlinski, M., Stewart, C. E., Postma, D. S., Nieuwenhuis, M. A., Vonk, J. M., Nurnberg, P., Altmuller, J., Moffatt, M. F., Wardlaw, A. J., Parker, S. G., Connolly, M. J., Koppelman, G. H., Sayers, I. Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels.
doi:10.1096/fj.13-240879
PMCID: PMC3898658  PMID: 24249636
GWAS; proteolysis; respiratory disease; HBECs; cellular proliferation and wound repair
7.  Older People’s Quality of Life and Role of Home-Based Technology 
Background: Household devices may have a positive impact on daily lives by reducing the burden of several tasks and enriching social interaction. There are varieties of assistive devices such as alarms, sensors, detectors, and life style monitoring devices, which can help in compensating for the activity limitations caused by impairments. This study aimed to review the contribution that residential technology devices can make to older people’s lives.
Methods: An open-ended literature review following the guidance of the Centre for Review and Dissemination was conducted to establish the current understanding of the topics by using clear and appropriate criteria to select or reject studies. The studies entered into the review were limited by language, topic, and date of publication.
Results: The research literature indicated that residential facilities which appropriately are designed and supplied can have many benefits for older people such as increasing in-dependence, maximising physical and mental health, and improving their quality of life.
Conclusion: Although most of the literature has explored the positive effects of technology devices on older adults’ social networks, independence, psychological well-being, and social status, the possibilities of negative consequences have been neglected. Keywords: Quality of life, Older people, Residential technology, Computer-mediated communication
doi:10.5681/hpp.2012.001
PMCID: PMC3963656  PMID: 24688912
Quality of life; Older people; Residential technology; Computer-mediated; communication
8.  The role of ALOX5AP, LTA4H and LTB4R polymorphisms in determining baseline lung function and COPD susceptibility in UK smokers 
BMC Medical Genetics  2011;12:173.
Background
We have previously shown evidence that polymorphisms within genes controlling leukotriene B4 (LTB4) production (ALOX5AP and LTA4H) are associated with asthma susceptibility in children. Evidence also suggests a potential role of LTB4 in COPD disease mechanisms including recruitment of neutrophils to the lung. The aim of the current study was to see if these SNPs and those spanning the receptor genes for LTB4 (LTB4R1 and LTB4R2) influence baseline lung function and COPD susceptibility/severity in smokers.
Methods
Eight ALOX5AP, six LTA4H and six LTB4R single nucleotide polymorphisms (SNPs) were genotyped in a UK Smoking Cohort (n = 992). Association with baseline lung function (FEV1 and FEV1/FVC ratio) was determined by linear regression. Logistic regression was used to compare smoking controls (n = 176) with spirometry-defined COPD cases (n = 599) and to more severe COPD cases (GOLD stage 3 and 4, n = 389).
Results
No association with ALOX5AP, LTA4H or LTB4R survived correction for multiple testing. However, we showed modest association with LTA4H rs1978331C (intron 11) with increased FEV1 (p = 0.029) and with increased FEV1/FVC ratio (p = 0.020).
Conclusions
These data suggest that polymorphisms spanning ALOX5AP, LTA4H and the LTB4R locus are not major determinants of baseline lung function in smokers, but provide tentative evidence for LTA4H rs1978331C (intron 11) in determining baseline FEV1 and FEV1/FVC ratio in Caucasian Smokers in addition to our previously identified role in asthma susceptibility.
doi:10.1186/1471-2350-12-173
PMCID: PMC3267686  PMID: 22206291
9.  The contribution of home-based technology to older people's quality of life in extra care housing 
BMC Geriatrics  2011;11:68.
Background
British government policy for older people focuses on a vision of active ageing and independent living. In the face of diminishing personal capacities, the use of appropriate home-based technology (HBT) devices could potentially meet a wide range of needs and consequently improve many aspects of older people's quality of life such as physical health, psychosocial well-being, social relationships, and their physical or living environment. This study aimed to examine the use of HBT devices and the correlation between use of such devices and quality of life among older people living in extra-care housing (ECH).
Methods
A structured questionnaire was administered for this study. Using purposive sampling 160 older people living in extra-care housing schemes were selected from 23 schemes in England. A face-to-face interview was conducted in each participant's living unit. In order to measure quality of life, the SEIQoL-Adapted and CASP-19 were used.
Results
Although most basic appliances and emergency call systems were used in the living units, communally provided facilities such as personal computers, washing machines, and assisted bathing equipment in the schemes were not well utilised. Multiple regression analysis adjusted for confounders including age, sex, marital status, living arrangement and mobility use indicated a coefficient of 1.17 with 95% CI (0.05, 2.29) and p = 0.04 [SEIQoL-Adapted] and 2.83 with 95% CI (1.17, 4.50) and p = 0.001 [CASP-19].
Conclusions
The findings of the present study will be value to those who are developing new form of specialised housing for older people with functional limitations and, in particular, guiding investments in technological aids. The results of the present study also indicate that the home is an essential site for developing residential technologies.
doi:10.1186/1471-2318-11-68
PMCID: PMC3215176  PMID: 22040111
Home-Based Technology; Older People; Assistive Technology; Quality of Life; Well-Being; Extra Care Housing
10.  Recruiting older people to a randomised controlled dietary intervention trial - how hard can it be? 
Background
The success of a human intervention trial depends upon the ability to recruit eligible volunteers. Many trials fail because of unrealistic recruitment targets and flawed recruitment strategies. In order to predict recruitment rates accurately, researchers need information on the relative success of various recruitment strategies. Few published trials include such information and the number of participants screened or approached is not always cited.
Methods
This paper will describe in detail the recruitment strategies employed to identify older adults for recruitment to a 6-month randomised controlled dietary intervention trial which aimed to explore the relationship between diet and immune function (The FIT study). The number of people approached and recruited, and the reasons for exclusion, will be discussed.
Results
Two hundred and seventeen participants were recruited to the trial. A total of 7,482 letters were sent to potential recruits using names and addresses that had been supplied by local Family (General) Practices. Eight hundred and forty three potential recruits replied to all methods of recruitment (528 from GP letters and 315 from other methods). The eligibility of those who replied was determined using a screening telephone interview, 217 of whom were found to be suitable and agreed to take part in the study.
Conclusion
The study demonstrates the application of multiple recruitment methods to successfully recruit older people to a randomised controlled trial. The most successful recruitment method was by contacting potential recruits by letter on NHS headed note paper using contacts provided from General Practices. Ninety percent of recruitment was achieved using this method. Adequate recruitment is fundamental to the success of a research project, and appropriate strategies must therefore be adopted in order to identify eligible individuals and achieve recruitment targets.
Trial registration number
ISRCTN45031464.
doi:10.1186/1471-2288-10-17
PMCID: PMC2843618  PMID: 20175903
11.  PLAUR polymorphisms and lung function in UK smokers 
BMC Medical Genetics  2009;10:112.
Background
We have previously identified Urokinase Plasminogen Activator Receptor (PLAUR) as an asthma susceptibility gene. In the current study we tested the hypothesis that PLAUR single nucleotide polymorphisms (SNPs) determine baseline lung function and contribute to the development of Chronic Obstructive Pulmonary Disease (COPD) in smokers.
Methods
25 PLAUR SNPs were genotyped in COPD subjects and individuals with smoking history (n = 992). Linear regression was used to determine the effects of polymorphism on baseline lung function (FEV1, FEV1/FVC) in all smokers. Genotype frequencies were compared in spirometry defined smoking controls (n = 176) versus COPD cases (n = 599) and COPD severity (GOLD stratification) using logistic regression.
Results
Five SNPs showed a significant association (p < 0.01) with baseline lung function; rs2302524(Lys220Arg) and rs2283628(intron 3) were associated with lower and higher FEV1 respectively. rs740587(-22346), rs11668247(-20040) and rs344779(-3666) in the 5'region were associated with increased FEV1/FVC ratio. rs740587 was also protective for COPD susceptibility and rs11668247 was protective for COPD severity although no allele dose relationship was apparent. Interestingly, several of these associations were driven by male smokers not females.
Conclusion
This study provides tentative evidence that the asthma associated gene PLAUR also influences baseline lung function in smokers. However the case-control analyses do not support the conclusion that PLAUR is a major COPD susceptibility gene in smokers. PLAUR is a key serine protease receptor involved in the generation of plasmin and has been implicated in airway remodelling.
doi:10.1186/1471-2350-10-112
PMCID: PMC2784766  PMID: 19878584

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