Recurrent delirium over 12 months predicts dementia: results of the Delirium and Cognitive Impact in Dementia (DECIDE) study.

BACKGROUND: Delirium is common, distressing and associated with poor outcomes. Previous studies investigating the impact of delirium on cognitive outcomes have been limited by incomplete ascertainment of baseline cognition or lack of prospective delirium assessments. This study quantified the association between delirium and cognitive function over time by prospectively ascertaining delirium in a cohort aged ≥ 65 years in whom baseline cognition had previously been established. METHODS: For 12 months, we assessed participants from the Cognitive Function and Ageing Study II-Newcastle for delirium daily during hospital admissions. At 1-year, we assessed cognitive decline and dementia in those with and without delirium. We evaluated the effect of delirium (including its duration and number of episodes) on cognitive function over time, independently of baseline cognition and illness severity. RESULTS: Eighty two of 205 participants recruited developed delirium in hospital (40%). One-year outcome data were available for 173 participants: 18 had a new dementia diagnosis, 38 had died. Delirium was associated with cognitive decline (-1.8 Mini-Mental State Examination points [95% CI -3.5 to -0.2]) and an increased risk of new dementia diagnosis at follow up (OR 8.8 [95% CI 1.9-41.4]). More than one episode and more days with delirium (>5 days) were associated with worse cognitive outcomes. CONCLUSIONS: Delirium increases risk of future cognitive decline and dementia, independent of illness severity and baseline cognition, with more episodes associated with worse cognitive outcomes. Given that delirium has been shown to be preventable in some cases, we propose that delirium is a potentially modifiable risk factor for dementia.

Hospitalisation without delirium is not associated with cognitive decline in a population-based sample of older people-results from a nested, longitudinal cohort study.

BACKGROUND: Acute hospitalisation and delirium have individually been shown to adversely affect trajectories of cognitive decline but have not previously been considered together. This work aimed to explore the impact on cognition of hospital admission with and without delirium, compared to a control group with no hospital admissions. METHODS: The Delirium and Cognitive Impact in Dementia (DECIDE) study was nested within the Cognitive Function and Ageing Study II (CFAS II)-Newcastle cohort. CFAS II participants completed two baseline interviews, including the Mini-Mental State Examination (MMSE). During 2016, surviving participants from CFAS II-Newcastle were recruited to DECIDE on admission to hospital. Participants were reviewed daily to determine delirium status.During 2017, all DECIDE participants and age, sex and years of education matched controls without hospital admissions during 2016 were invited to repeat the CFAS II interview. Delirium was excluded in the control group using the Informant Assessment of Geriatric Delirium Scale (i-AGeD). Linear mixed effects modelling determined predictors of cognitive decline. RESULTS: During 2016, 82 of 205 (40%) DECIDE participants had at least one episode of delirium. At 1 year, 135 of 205 hospitalised participants completed an interview along with 100 controls. No controls experienced delirium (i-AGeD>4). Delirium was associated with a faster rate of cognitive decline compared to those without delirium (ß = -2.2, P < 0.001), but number of hospital admissions was not (P = 0.447). CONCLUSIONS: These results suggest that delirium during hospitalisation rather than hospitalisation per se is a risk factor for future cognitive decline, emphasising the need for dementia prevention studies that focus on delirium intervention.

Frailty, hospital use and mortality in the older population: findings from the Newcastle 85+ study.

BACKGROUND: Frailty is a significant determinant of health care utilisation and associated costs, both of which also increase with proximity to death. What is not known is how the relationships between frailty, proximity to death, hospital use and costs develop in a population aged 85 years and over. METHODS: This study used data from a prospective observational cohort, the Newcastle 85+ Study, linked with hospital episode statistics and death registrations. Using the Rockwood frailty index (cut off <0.25), we analysed the relationship between frailty and mortality, proximity to death, hospital use and hospital costs over 2, 5 and 7 years using descriptive statistics, Kaplan-Meier survival curves, Cox's proportional hazards and negative binomial regression models. RESULTS: Baseline frailty was associated with a more than two-fold increased risk of mortality after 7 years, compared to people who were non-frail. Participants classified as frail spent more time in hospital over 7 years than the non-frail, but this difference declined over time. Baseline frailty was not associated with increased time spent in hospital during the last 90 days of life. CONCLUSION: Evidence continues to accrue on the impact of frailty on emergency health care use. Hospital and community services need to adapt to meet the challenge of introducing new proactive and preventative approaches, designed to achieve benefits in clinical and/or cost effectiveness of frailty management.

Developing an objective structured clinical examination in comprehensive geriatric assessment - A pilot study.

Background: Acquiring medical competencies alone does not necessarily lead to the delivery of quality clinical care. Many UK training programs are soon to be based on the curricula of entrustable professional capabilities (EPCs). These are tasks carried out in practice requiring proficiency in several competencies for quality practice. Assessments to evaluate EPCs for independent practice are needed. Comprehensive geriatric assessment (CGA) is an EPC in geriatric medicine. We describe the development of an assessment of CGA as an example of examining EPCs. Methods: A CGA station was introduced in the Diploma in Geriatric Medicine clinical examination. Candidates rotate through four stations: three single competency-based stations (history, communication/ethics and physical examination) and an EPC-based station in CGA. Results: One hundred and seventy-eight (female: 96 [53.9%]) candidates took it. There was a weak but significantly positive correlation between the score at CGA and the total score in the other stations (r = 0.46; P < 0.001). Most candidates passing the station passed the examination. Correlation with other stations similarly showed weak significant correlations (Station 1: r = 0.38; P < 0.001, Station 3: r = 0.28; P < 0.001, and Station 4: r = 0.37; P < 0.001). There was 61.4% (kappa: 0.61; P = 0.000) agreement between examiners whether a candidate passed or failed. Agreement was higher for the other stations, i.e. Station 1 (kappa: 0.85; P < 0.001), Station 3 (kappa: 0.72; P < 0.001), and Station 4 (kappa: 0.85; P < 0.001). Discussion: Performance on the station correlated positively with overall performance, suggesting that it has discriminatory value in differentiating candidates with varying ability and the more able candidates pass the examination.

Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12.

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.

Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels.

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.

Assessing patient preferences for the delivery of different community-based models of care using a discrete choice experiment.

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.

The role of ALOX5AP, LTA4H and LTB4R polymorphisms in determining baseline lung function and COPD susceptibility in UK smokers.

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.

A systematic review of comprehensive geriatric assessment to improve outcomes for frail older people being rapidly discharged from acute hospital: 'interface geriatrics'.

BACKGROUND: many frail older people who attend acute hospital settings and who are discharged home within short periods (up to 72 h) have poor outcomes. This review assessed the role of comprehensive geriatric assessment (CGA) for such people. METHODS: standard bibliographic databases were searched for high-quality randomised controlled trials (RCTs) of CGA in this setting. When appropriate, intervention effects were presented as rate ratios with 95% confidence intervals. RESULTS: five trials of sufficient quality were included. There was no clear evidence of benefit for CGA interventions in this population in terms of mortality [RR 0.92 (95% CI 0.55-1.52)] or readmissions [RR 0.95 (95% CI 0.83-1.08)] or for subsequent institutionalisation, functional ability, quality-of-life or cognition. CONCLUSIONS: there is no clear evidence of benefit for CGA interventions in frail older people being discharged from emergency departments or acute medical units. However, few such trials have been carried out and their overall quality was poor. Further well designed trials are justified.

Rehabilitation of older patients: day hospital compared with rehabilitation at home. Clinical outcomes.

OBJECTIVES: to test the hypothesis that older people and their informal carers are not disadvantaged by home-based rehabilitation (HBR) relative to day hospital rehabilitation (DHR). DESIGN: pragmatic randomised controlled trial. SETTING: four geriatric day hospitals and four home rehabilitation teams in England. PARTICIPANTS: eighty-nine patients referred for multidisciplinary rehabilitation. The target sample size was 460. INTERVENTION: multidisciplinary rehabilitation either in the home or in the day hospital. MEASUREMENTS: the primary outcome measure was the Nottingham extended activities of daily living scale (NEADL). Secondary outcome measures included EQ-5D, hospital anxiety and depression scale, therapy outcome measures, hospital admissions and the General Health Questionnaire for carers. RESULTS: at the primary end point of 6 months NEADL scores were not significantly in favour of HBR cf. DHR; mean difference -2.139 (95% confidence interval -6.87 to 2.59, P = 0.37). A post hoc analysis suggested non-inferiority for HBR for NEADL but there was considerable statistical uncertainty. CONCLUSION: taken together the statistical analyses and lack of power of the trial outcomes do not provide sufficient evidence to conclude that patients in receipt of HBR are disadvantaged compared with those receiving DHR.

The contribution of home-based technology to older people's quality of life in extra care housing.

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.

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.

PLAUR polymorphisms and lung function in UK smokers.

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 (FEV(1), FEV(1)/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 FEV(1) respectively. rs740587(-22346), rs11668247(-20040) and rs344779(-3666) in the 5'region were associated with increased FEV(1)/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.

A randomized study of a multidisciplinary program to intervene on geriatric syndromes in vulnerable older people who live at home (Dutch EASYcare Study).

BACKGROUND: The effectiveness of community-based geriatric intervention models for vulnerable older adults is controversial. We evaluated a problem-based multidisciplinary intervention targeting vulnerable older adults at home that promised efficacy through better timing and increased commitment of patients and primary care physicians. This study compared the effects of this new model to usual care. METHODS: Primary care physicians referred older people for problems with cognition, nutrition, behavior, mood, or mobility. One hundred fifty-one participants (mean age 82.2 years, 74.8% women) were included in a pseudocluster randomized trial with 6-month follow-up for the primary outcomes. Eighty-five participants received the new intervention, and 66 usual care. In the intervention arm, geriatric nurses visited patients at home for geriatric assessment and management in cooperation with primary care physicians and geriatricians. Modified intention-to-treat analyses focused on differences between treatment arms in functional abilities (Groningen Activity Restriction Scale-3) and mental well-being (subscale mental health Medical Outcomes Study [MOS]-20), using a mixed linear model. RESULTS: After 3 months, treatment arms showed significant differences in favor of the new intervention. Functional abilities improved 2.2 points (95% confidence interval [CI], 0.3-4.2) and well-being 5.8 points (95% CI, 0.1-11.4). After 6 months, the favorable effect increased for well-being (9.1; 95% CI, 2.4-15.9), but the effect on functional abilities was no longer significant (1.6; 95% CI, -0.7 to 3.9). CONCLUSIONS: This problem-based geriatric intervention improved functional abilities and mental well-being of vulnerable older people. Problem-based interventions can increase the effectiveness of primary care for this population.

Does the Design of Settings Where Acute Care Is Delivered Meet the Needs of Older People? Perspectives of Patients, Family Carers, and Staff.

BACKGROUND: Older people with an acute illness, many of whom are also frail, form a significant proportion of the acute hospital inpatient population. Attention is focusing on ways of improving the physical environment to optimize health outcomes and staff efficiency. PURPOSE: This article explores the effects of the physical environment in three acute care settings: acute hospital site, in-patient rehabilitation hospital, and intermediate care provision (a nursing home with some beds dedicated to intermediate care) chosen to represent different steps on the acute care pathway for older people and gain the perspectives of patients, family carers, and staff. METHODS: Semi structured interviews were undertaken with 40 patient/carer dyads (where available) and three staff focus groups were conducted in each care setting with a range of staff. RESULTS: Multiple aspects of the physical environment were reported as important by patients, family carers, and staff. For example, visitors stressed the importance of access and parking, patients valued environments where privacy and dignity were protected, storage space was poor across all sites, and security was important to patients but visitors want easy access to wards. CONCLUSIONS: The physical environment is a significant component of acute care for older people, many of whom are also frail, but often comes second to organization of care, or relationships between actors in an episode of care.

Tumour necrosis factor gene complex polymorphisms in chronic obstructive pulmonary disease.

We aimed to examine the role of tumour necrosis factor gene complex polymorphisms in subjects with chronic obstructive pulmonary disease (COPD). We hypothesized that individuals possessing polymorphic variants associated with higher tumour necrosis factor (TNF) secretion would be more susceptible to and/or have more severe disease. Patients with COPD and population controls underwent detailed clinical phenotyping. Genotyping for the tumour necrosis factor-308 and the lymphotoxin alpha NcoI (LTalpha polymorphisms was carried out by 'blinded' laboratory staff. Three hundred and sixty one individuals (220 cases and 141 controls) were recruited. We showed an association between the LTalphaNcol polymorphism and forced vital capacity (FVC) in a population of older adults with and without COPD. The LTalphaNcol*2 allele was associated with poorer lung function, under a codominant model, with a fall in FVC (expressed as a percentage of its predicted value) of 3.7% for each copy of the LTalphaNcol*2 allele possessed (for FVC, regression coefficient (95% CI)=-3.73(-7.01 to -0.44), P=0.026; for FEV(1) regression coefficient=-3.56(-7.80 to 0.70), P=0.101. However, there was no difference in genotype distribution between the case and control populations. This study adds weight to the suggestion that the TNF gene complex is involved in physiological alterations (FVC) that may affect the development and severity of COPD. The absence of a significant association between the TNF gene-complex polymorphisms in this study does not rule out a modest effect of these polymorphisms on the risk of COPD, as much larger studies are needed to detect modest gene effects on binary disease endpoints.

Understanding help-seeking in older people with urinary incontinence: an interview study.

The prevalence of urinary incontinence (UI) increases with age and can negatively affect quality of life. However, relatively few older people with UI seek treatment. The aim of this study was to explore the views of older people with UI on the process of seeking help. Older people with UI were recruited to the study from three continence services in the north of England: a geriatrician-led hospital outpatient clinic (n = 18), a community-based nurse-led service (n = 22) and a consultant gynaecologist-led service specialising in surgical treatment (n = 10). Participants took part in semi-structured interviews, which were transcribed and underwent thematic content analysis. Three main themes emerged: Being brushed aside, in which participants expressed the feeling that general practitioners did not prioritise or recognise their concerns; Putting up with it, in which participants delayed seeking help for their UI due to various reasons including embarrassment, the development of coping mechanisms, perceiving UI as a normal part of the ageing process, or being unaware that help was available; and Something has to be done, in which help-seeking was prompted by the recognition that their UI was a serious problem, whether as a result of experiencing UI in public, the remark of a relative, the belief that they had a serious illness or the detection of UI during comprehensive geriatric assessment. Greater awareness that UI is a treatable condition and not a normal part of ageing is needed in the population and among health professionals. Comprehensive geriatric assessment appeared an important trigger for referral and treatment in our participants. Screening questions by healthcare professionals could be a means to identify, assess and treat older people with UI.

Deconstructing Complex Multimorbidity in the Very Old: Findings from the Newcastle 85+ Study.

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.

The Ser82 RAGE Variant Affects Lung Function and Serum RAGE in Smokers and sRAGE Production In Vitro.

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.