Dementia and the population health approach: Promise, pitfalls and progress. An Australian perspective

The increasing prevalence of dementia in Australia (and worldwide) over the next few decades poses enormous social, health and economic challenges. In the absence of a cure, strategies to prevent, delay the onset of, or reduce the impact of dementia are required to contain a growing disease burden, and health and care costs. A population health approach has the potential to substantially reduce the impact of dementia. Internationally, many countries have started to adopt population health strategies that incorporate elements of dementia prevention. The authors examine some of the elements of such an approach and barriers to its implementation. International dementia frameworks and strategies were reviewed to identify options utilized for a population health approach to dementia. Internationally and nationally, dementia frameworks are being developed that include population health approaches. Most of the frameworks identified included early diagnosis and intervention, and increasing community awareness as key objectives, while several included promotion of the links between a healthy lifestyle and reduced risk for dementia. A poor evidence base (especially for illness prevention), diagnostic and technical limitations, and policy and implementation issues are significant barriers in maximizing the promise of population health approaches in this area. The review and analysis of the population health approach to dementia will inform national and jurisdictional policy development.

Interventions targeting the elderly population to reduce emergency department utilisation: A literature review

Objective High utilisation of emergency department (ED) among the elderly is of worldwide concern. This study aims to review the effectiveness of interventions targeting the elderly population in reducing ED utilisation. Methods Major biomedical databases were searched for relevant studies. Qualitative approach was applied to derive common themes in the myriad interventions and to critically assess the variations influencing interventions’ effectiveness. Quality of studies was appraised using the Effective Public Health Practice Project (EPPHP) tool. Results 36 studies were included. Nine of 16 community-based interventions reported significant reductions in ED utilisation. Five of 20 hospital-based interventions proved effective while another four demonstrated failure. Seven key elements were identified. Ten of 14 interventions associated with significant reduction on ED use integrated at least three of the seven elements. All four interventions with significant negative results lacked five or more of the seven elements. Some key elements including multidisciplinary team, integrated primary care and social care often existed in effective interventions, while were absent in all significantly ineffective ones. Conclusions The investigated interventions have mixed effectiveness. Our findings suggest the hospital-based interventions have relatively poorer effects, and should be better connected to the community-based strategies. Interventions seem to achieve the most success with integration of multi-layered elements, especially when incorporating key elements such as a nurse-led multidisciplinary team, integrated social care, and strong linkages to the longer-term primary and community care. Notwithstanding limitations in generalising the findings, this review builds on the growing body of evidence in this particular area.

Investigating the population structure of Queensland invasive Streptococcus pneumoniae isolates in children: Using a modified multi-locus variable number of tandem repeat analysis and a novel minimum SNPs capsular typing method

This research investigated the use of DNA fingerprinting to characterise the bacteria Streptococcus pneumoniae or pneumococcus, and hence gain insight into the development of new vaccines or antibiotics. Different bacterial DNA fingerprinting methods were studied, and a novel method was developed and validated, which characterises different cell coatings that pneumococci produce. This method was used to study the epidemiology of pneumococci in Queensland before and after the introduction of the current pneumococcal vaccine. This study demonstrated that pneumococcal disease is highly prevalent in children under four years, that the bacteria can `switch' its cell coating to evade the vaccine, and that some DNA fingerprinting methods are more discriminatory than others. This has an impact on understanding which strains are more prone to cause invasive disease. Evidence of the excellent research findings have been published in high impact internationally refereed journals.

Genetic structure of the Korean black scraper Thamnaconus modestus inferred from microsatellite marker analysis

The Korean black scraper, Thamnaconus modestus, is one of the most economically important maricultural fish species in Korea. However, the annual catch of this fish has been continuously declining over the past several decades. In this study, the genetic diversity and relationships among four wild populations and two hatchery stocks of Korean black scraper were assessed based on 16 microsatellite (MS) markers. A total of 319 different alleles were detected over all loci with an average of 19.94 alleles per locus. The hatchery stocks [mean number of alleles (N A) = 12, allelic richness (A R) = 12, expected heterozygosity (He) = 0.834] showed a slight reduction (P > 0.05) in genetic variability in comparison with wild populations (mean N A = 13.86, A R = 12.35, He = 0.844), suggesting a sufficient level of genetic variation in the hatchery populations. Similarly low levels of inbreeding and significant Hardy–Weinberg equilibrium deviations were detected in both wild and hatchery populations. The genetic subdivision among all six populations was low but significant (overall F ST = 0.008, P < 0.01). Pairwise F ST, a phylogenetic tree, and multidimensional scaling analysis suggested the existence of three geographically structured populations based on different sea basin origins, although the isolation-by-distance model was rejected. This result was corroborated by an analysis of molecular variance. This genetic differentiation may result from the co-effects of various factors, such as historical dispersal, local environment and ocean currents. These three geographical groups can be considered as independent management units. Our results show that MS markers may be suitable not only for the genetic monitoring of hatchery stocks but also for revealing the population structure of Korean black scraper populations. These results will provide critical information for breeding programs, the management of cultured stocks and the conservation of this species.

Why do Queenslanders seek care in emergency departments? A population study

Objective This study aims to identify the main reasons for which first time and multiple users seek medical care through Queensland emergency departments (ED). Methods A cross-sectional survey was conducted at eight public EDs among presenting patients (n = 911). The questions measured the socio-demographic characteristics of patients, their beliefs and attitudes towards EDs services, and perceptions of health status. Bivariate and binary logistic regression analyses were performed to examine the differences between first time and multiple users of EDs. Results First time and multiple users accounted for 55.5% and 44.5%, respectively. Multiple users themselves believed to be sicker, have poorer health status, and additional and/or chronic health conditions. Multiple users more strongly believed that their condition required treatment at an ED and perceived their condition as being very serious. Multiple users reported weekly household incomes below $600, and half of the multiple users were not working as compared to 35% first time users. Multivariate analysis showed that multiple use was significantly associated with the existence of additional health problems, having chronic condition, lower self-efficacy, and need for ED treatment. Conclusions Patients who sought care for multiple times at EDs more often than first time users suffered from additional and chronic conditions. Their opinion of an ED as the most suitable place to address their current health problem was stronger than first time users. Any proposed demand management strategies need to address these beliefs together with the reasoning of patients to provide effective and appropriate care outside or within ED services.

Correction: Genome-wide association studies of asthma in population-based cohorts confirm known and suggested loci and identify an additional association near HLA

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Genome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA

Rationale: Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies. Objectives: To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations. Methods: The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P<5x10-8) and three variants reported as suggestive (P<5×10-7). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever. Main Results: We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4×10-9). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (PStage1+Stage2 = 1.1x10-9), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (PStage1+Stage2 = 1.1x10-8), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status. Conclusions: Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma. © 2012 Ramasamy et al.

Surgical fusion of early onset severe scoliosis increases survival in the child with rett syndrome: A population based study

Introduction. Rett Syndrome is a rare genetic neurodevelopmental disorder usually affecting females. Scoliosis is a common comorbidity and spinal fusion may be recommended if severe. Little is known about long term outcomes. We examined the impact of spinal fusion on survival and risk of severe lower respiratory tract infection (LRTI) in Rett Syndrome. Methods Data were ascertained from hospital medical records, the Australian Rett Syndrome Database, a longitudinal and population-based registry of Rett Syndrome cases established in 1993, and the Australian Institute of Health and Welfare National Death Index database. An extended Cox regression model was used to estimate the effect of spinal surgery on survival in females who developed severe scoliosis (Cobb angle > 45 degrees). Generalized estimating equation modelling was used to estimate the effect of spinal surgery on the odds of developing severe LRTI. Results Severe scoliosis was identified in 140 cases (60.3%) of whom slightly fewer than half (48.6%) developed scoliosis prior to eight years of age. Scoliosis surgery was performed in 98 (69.0%) of those at a median age of 13 years 3 months (IQR 11 years 5 months – 14 years 10 months). After adjusting for mutation type and age of scoliosis onset, the rate of death was lower in the surgery group (HR 0.30, 95% CI 0.12, 0.74, P = 0.009) compared to those without surgery. Rate of death was particularly reduced for those with early onset scoliosis (HR 0.17, 95% CI 0.06, 0.52, P = 0.002). Spinal fusion was not associated with reduction in the occurrence of a severe LRTI overall (OR 0.60, 95%CI 0.27, 1.33, P=0.206) but was associated with a large reduction in odds of severe LRTI among those with early onset scoliosis (OR 0.32, 95%CI 0.11, 0.93, P=0.036). Conclusion With appropriate cautions, spinal fusion confers an advantage to life expectancy in Rett syndrome.

Common polygenic variation contributes to risk of migraine in the Norfolk Island population

Migraine has been defined as a common disabling primary headache disorder. Epidemiology studies have provided with the undeniable evidence of genetic components as active players in the development of the disease under a polygenic model in which multiple risk alleles exert modest individual effects. Our objective was to test the contribution of a polygenic effect to migraine risk in the Norfolk Island population using a panel of SNPs reported to be disease associated in published migraine GWAS. We also investigated whether individual SNPs were associated with gene expression levels measured in whole-blood. Polygenic scores were calculated in a total of 285 related individuals (74 cases, 211 controls) from the Norfolk Island using 51 SNPs previously reported to be associated with migraine in published GWAS. The association between polygenic score and migraine case-control status was tested using logistic regression. Results indicate that a migraine polygenic risk score was associated with migraine case-control status in this population (P=0.016). This supports the hypothesis that multiple SNPs with weak effects collectively contribute to migraine risk in this population. Amongst the SNPs included in the polygenic model, 4 were associated with the expression of the USMG5 gene, including rs171251 (P = 0.012). Results from this study provide evidence for a polygenic contribution to migraine risk in an isolated population and highlight specific SNPs that regulate the expression of USMG5, a gene critical for mitochondrial function.

HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom

Objective - To investigate the HLA class I associations of ankylosing spondylitis (AS) in the white population, with particular reference to HLA-B27 subtypes. Methods - HLA-B27 and -B60 typing was performed in 284 white patients with AS. Allele frequencies of HLA-B27 and HLA-B60 from 5926 white bone marrow donors were used for comparison. HLA-B27 subtyping was performed by single strand conformation polymorphism (SSCP) in all HLA-B27 positive AS patients, and 154 HLA-B27 positive ethnically matched blood donors. Results - The strong association of HLA-B27 and AS was confirmed (odds ratio (OR) 171, 95% confidence interval (CI) 135 to 218; p < 10-99). The association of HLA-B60 with AS was confirmed in HLA-B27 positive cases (OR 3.6, 95% CI 2.1 to 6.3; p < 5 x 10-5), and a similar association was demonstrated in HLA-B27 negative AS (OR 3.5, 95% CI 1.1 to 11.4; p < 0.05). No significant difference was observed in the frequencies of HLA-B27 allelic subtypes in patients and controls (HLA-B*2702, three of 172 patients v five of 154 controls; HLA-B*2705, 169 of 172 patients v 147 of 154 controls; HkA-B*2708, none of 172 patients v two of 154 controls), and no novel HLA-B27 alleles were detected. Conclusion - HLA-B27 and -B60 are associated with susceptibility to AS, but differences in BLA-B27 subtype do not affect susceptibility to AS in this white population.

Corrections: Association of variants in MMEL1 and CTLA4 with rheumatoid arthritis in the Han Chinese population (Annals of the Rheumatic Diseases (2011) 70, (1793-1797))

Patrick Danoy, Meng Wei, Hadler Johanna, et al. Association of variants in MMEL1 and CTLA4 with rheumatoid arthritis in the Han Chinese population. Ann Rheum Dis 2011;70:1793–97. The following authors were listed as contributing equally to the study...

Association of variants in MMEL1 and CTLA4 with rheumatoid arthritis in the Han Chinese population

Background: The genome-wide association study era has made great progress in identifying susceptibility genes and genetic loci for rheumatoid arthritis (RA) in populations of White European ancestry. However, few studies have tried to dissect disease aetiopathogenesis in other ethnic populations. Objective: To investigate these associations in the Han Chinese population. Methods: Haplotypes from the HapMap database Chinese population were used to select tag-single-nucleotide polymorphisms (SNPs) (r2 =0.8) across 19 distinct RA genomic regions. A two phase case-control association study was performed, with 169 SNPs genotyped in phase I (n=571 cases, n=880 controls), and 64 SNPs achieving p<0.2 in the first phase being genotyped in phase II (n=464 cases, n=822 controls). Association statistics were calculated using permutation tests both unadjusted and adjusted for the number of markers studied. Results: Robust association was detected for MMEL1 and CTLA4 , and modest association was identified for another six loci: PADI4 , STAT4 , PRDM1 , CDK6 , TRAF1-C5 and KIF5A-PIP4K2C. All three markers genotyped in MMEL1 demonstrated association, with peak signal for rs3890745 (p=2.6×10 -5unadjusted, p=0.003 adjusted, OR=0.79). For CTLA4 , significance was detected for three of five variants showing association, with peak association for marker rs12992492 (p=4.3×10-5 unadjusted, p=0.0021 adjusted, OR=0.77). Lack of association of common variants in PTPN22 with RA in Han Chinese was confirmed. Conclusion: This study identifies MMEL1 and CTLA4 as RA susceptibility genes, provides suggestive evidence of association for a further six loci in the Han Chinese population and confirms lack of PTPN22 association in Asian populations. It also confirms the value of multiethnic population studies to help dissect disease aetiopathogenesis.

High-throughput sequencing of IL23R reveals a low-frequency, nonsynonymous single-nucleotide polymorphism that is associated with ankylosing spondylitis in a Han Chinese population

Objective Ankylosing spondylitis (AS) is a highly heritable common inflammatory arthritis that targets the spine and sacroiliac joints of the pelvis, causing pain and stiffness and leading eventually to joint fusion. Although previous studies have shown a strong association of IL23R with AS in white Europeans, similar studies in East Asian populations have shown no association with common variants of IL23R, suggesting either that IL23R variants have no role or that rare genetic variants contribute. The present study was undertaken to screen IL23R to identify rare variants associated with AS in Han Chinese. Methods A 170-kb region containing IL23R and its flanking regions was sequenced in 50 patients with AS and 50 ethnically matched healthy control subjects from a Han Chinese population. In addition, the 30-kb region of peak association in white Europeans was sequenced in 650 patients with AS and 1,300 healthy controls. Validation genotyping was undertaken in 846 patients with AS and 1,308 healthy controls. Results We identified 1,047 variants, of which 729 were not found in the dbSNP genomic build 130. Several potentially functional rare variants in IL23R were identified, including one nonsynonomous single-nucleotide polymorphism (nsSNP), Gly149Arg (position 67421184 GA on chromosome 1). Validation genotyping showed that the Gly149Arg variant was associated with AS (odds ratio 0.61, P = 0.0054). Conclusion This is the first study to implicate rare IL23R variants in the pathogenesis of AS. The results identified a low-frequency nsSNP with predicted loss-of-function effects that was protectively associated with AS in Han Chinese, suggesting that decreased function of the interleukin-23 (IL-23) receptor protects against AS. These findings further support the notion that IL-23 signaling has an important role in the pathogenesis of AS.

Association of ERAP1, but not IL23R, with ankylosing spondylitis in a Han Chinese population

Objective The results of a recent genome-wide association study have shown that ERAP1 and IL23R are associated with ankylosing spondylitis (AS) in Caucasian populations from North America and the UK. Based on these findings, we undertook the current study to investigate whether single-nucleotide polymorphisms (SNPs) covering the genes ERAP1 and IL23R are associated with AS in a Han Chinese population. Methods A case-control study was performed in Han Chinese patients with AS (n = 527) and controls (n = 945) from Shanghai and Nanjing. All patients met the modified New York criteria for AS. The Sequenom iPlex platform was used to genotype cases and controls for 21 tag SNPs covering IL23R and 38 tag SNPs covering ERAP1. Statistical analysis was performed using the Cochran-Armitage test for trend. Results Multiple SNPs in ERAP1 were significantly associated with AS (for rs27980, P = 0.0048; for rs7711564, P = 0.0081). However, no association was observed between IL23R and AS (for all SNPs, P > 0.1). The nonsynonymous SNP in IL23R, rs11209026, widely thought to be the primary AS-associated SNP in IL23R in Europeans, was found not to be polymorphic in Chinese. Conclusion Our results demonstrate that genetic polymorphisms in ERAP1 are associated with AS in Han Chinese, suggesting a common pathogenic mechanism for the disease in Chinese and Caucasian populations, and that IL23R is not associated with AS in Chinese, indicating a difference in the mechanism of disease pathogenesis between Chinese and Caucasian populations. This may result from the fact that rs11209026, the nonsynonymous SNP in IL23R, is not polymorphic in Chinese patients, providing further evidence that rs11209026 is the key polymorphism associated with AS (and likely inflammatory bowel disease and psoriasis) in this gene.

Cardiovascular disease is increased prior to onset of rheumatoid arthritis but not osteoarthritis: The population-based Nord-Trøndelag health study (HUNT)

Introduction: Patients with rheumatoid arthritis (RA) have increased risk of cardiovascular (CV) events. We sought to test the hypothesis that due to increased inflammation, CV disease and risk factors are associated with increased risk of future RA development. Methods: The population-based Nord-Trøndelag health surveys (HUNT) were conducted among the entire adult population of Nord-Trøndelag, Norway. All inhabitants 20 years or older were invited, and information was collected through comprehensive questionnaires, a clinical examination, and blood samples. In a cohort design, data from HUNT2 (1995-1997, baseline) and HUNT3 (2006-2008, follow-up) were obtained to study participants with RA (n = 786) or osteoarthritis (n = 3,586) at HUNT3 alone, in comparison with individuals without RA or osteoarthritis at both times (n = 33,567). Results: Female gender, age, smoking, body mass index, and history of previous CV disease were associated with self-reported incident RA (previous CV disease: odds ratio 1.52 (95% confidence interval 1.11-2.07). The findings regarding previous CV disease were confirmed in sensitivity analyses excluding participants with psoriasis (odds ratio (OR) 1.70 (1.23-2.36)) or restricting the analysis to cases with a hospital diagnosis of RA (OR 1.90 (1.10-3.27)) or carriers of the shared epitope (OR 1.76 (1.13-2.74)). History of previous CV disease was not associated with increased risk of osteoarthritis (OR 1.04 (0.86-1.27)). Conclusion: A history of previous CV disease was associated with increased risk of incident RA but not osteoarthritis.