Haplotype-based association analysis of the MAPT locus in Late Onset Alzheimer's disease

BACKGROUND: Late onset Alzheimer's disease (LOAD) is a common sporadic form of the illness, affecting individuals above the age of 65 yrs. A prominent hypothesis for the aetiopathology of Alzheimer's disease is that in the presence of a β-amyloid load, individuals expressing a pathogenic form of tau protein (MAPT) are at increased risk for developing the disease. Genetic studies in this pursuit have, however, yielded conflicting results. A recent study showed a significant haplotype association (H1c) with AD. The current study is an attempt to replicate this association in an independently ascertained cohort. RESULTS: In this report we present the findings of a haplotype analysis at the MAPT locus. We failed to detect evidence of association of the H1c haplotype at the MAPT locus with LOAD. None of the six SNPs forming the H1c haplotype showed evidence of association with disease. In addition, nested clade analysis suggested the presence of independent mutations at multiple points in the haplotype network or homoplasy at the MAPT locus. Such homoplasy can confound single SNP tests for association. We do not detect evidence that the set of SNPs forming the H1c haplotype in general or rs242557 in particular are pathogenic for LOAD. CONCLUSION: In conclusion, we employed two contemporary haplotype analysis tools to perform haplotype association analysis at the MAPT locus. Our data suggest that the tagged SNPs forming the H1c haplotype do not have a causal role in the pathogenesis of LOAD

Methods of classification for women undergoing induction of labour: a systematic review and novel classification system

OBJECTIVE To develop and demonstrate the applicability of a classification system for induction of labour (IOL) that fulfils recognised classification system attributes for clinical, surveillance and research purposes. DESIGN Proof of concept. SETTING, POPULATION Applicability demonstrated in a population cohort of 909,702 maternities in New South Wales, Australia, 2002-2011. METHODS A multidisciplinary collaboration developed a classification system through a systematic literature review, development of a clinically logical model, and presentation to stakeholders for feedback and refinement. Classification factors included parity (nulliparous, parous), previous caesarean section (CS), gestational age (≤36, 37-38, 39-40, ≥41 weeks gestation), number (singleton, multiple) and presentation of the fetus (cephalic, non-cephalic). We determined: the size of each classification group, the contribution each group made to overall IOL rates, and within-group IOL rates (calculated as proportions of all maternities, all maternities excluding prelabour CS and of all continuing maternities). MAIN OUTCOME MEASURES Applicability of IOL classification using routinely collected obstetric data. RESULTS A 10 group classification system was developed. Of all maternities, 25.4% were induced. Nulliparous and parous women without a prior CS at 39-40 weeks gestation with a singleton cephalic-presenting fetus were the largest groups (21.2% and 24.5% respectively) and accounted for the highest proportion of all IOL (20.7% and 21.5% respectively). The highest within group IOL rates were for nullipara (53.8%) and multipara (45.5%) ≥41 weeks gestation. CONCLUSION We propose a classification system for IOL that has the attributes of simplicity and clarity, utilises information that is readily and reliably collected and reported, and enables standard characterisation of populations of women having an IOL.NHMRC 1021025, ARC FT12010006

Population-genomic insights into emergence, crop-adaptation, and dissemination of Pseudomonas syringae pathogens

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.Many bacterial pathogens are well characterized but, in some cases, relatively little is known about the populations from which they emerged. This limits understanding of the molecular mechanisms underlying disease. The crop pathogen Pseudomonas syringae sensu lato has been widely isolated from the environment, including wild plants and components of the water cycle, and causes disease in several economically important crops. Here, we compared genome sequences of 45 P. syringae crop pathogen outbreak strains with 69 closely related environmental isolates. Phylogenetic reconstruction revealed that crop pathogens emerged many times independently from environmental populations. Unexpectedly, differences in gene content between environmental populations and outbreak strains were minimal with most virulence genes present in both. However, a genome-wide association study identified a small number of genes, including the type III effector genes hopQ1 and hopD1, to be associated with crop pathogens, but not with environmental populations, suggesting that this small group of genes may play an important role in crop disease emergence. Intriguingly, genome-wide analysis of homologous recombination revealed that the locus Psyr 0346, predicted to encode a protein that confers antibiotic resistance, has been frequently exchanged among lineages and thus may contribute to pathogen fitness. Finally, we found that isolates from diseased crops and from components of the water cycle, collected during the same crop disease epidemic, form a single population. This provides the strongest evidence yet that precipitation and irrigation water are an overlooked inoculum source for disease epidemics caused by P. syringae.Caroline L. Monteil received support from INRA and the European Union, in the framework of the Marie-Curie FP7 COFUND People Programme, through the award of an AgreenSkills’ fellowship (under grant agreement n° 267196). Research in Boris A. Vinatzer’s laboratory and genome sequencing was funded by the National Science Foundation of the USA (grants IOS-1354215 and DEB-1241068). Funding for work in the Vinatzer laboratory was also provided in part by the Virginia Agricultural Experiment Station and the Hatch Program of the National Institute of Food and Agriculture, U.S. Department of Agriculture. Work carried out in the Sheppard laboratory was supported by the Medical Research Council (MRC) grant MR/L015080/1, and the Wellcome Trust grant 088786/C/09/Z. GM was supported by a NISCHR Health Research Fellowship (HF-14-13)

Perspectives of people living with dementia and their care partners about the impact on social health when participating in a co-designed Dementia café

Those diagnosed with dementia and those who provide care and support often feel socially isolated with limited opportunities for social engagement, increasing the potential for loneliness and further isolation that is detrimental to social health. This study examined how a co-designed dementia café impacted on the self-reported social health of community dwelling people with dementia and their care partners in the North-West of England. Semi-structured interviews were conducted at two time periods (summer of 2019 and spring of 2020), with five people living with dementia and eight care partners. The key finding was that participating in the cafés led to a sense of belonging and purpose that was beneficial to well-being and social health for all participants. Community-based initiatives that provide opportunities for peer support for the person with the diagnosis and the care partner are essential so that people living with dementia may rebuild their confidence as well as retaining opportunities to socialise

Perspectives of people living with dementia and their care partners about the impact on social health when participating in a co-designed Dementia café

Those diagnosed with dementia and those who provide care and support often feel socially isolated with limited opportunities for social engagement, increasing the potential for loneliness and further isolation that is detrimental to social health. This study examined how a co-designed dementia café impacted on the self-reported social health of community dwelling people with dementia and their care partners in the North-West of England. Semi-structured interviews were conducted at two time periods (summer of 2019 and spring of 2020), with five people living with dementia and eight care partners. The key finding was that participating in the cafés led to a sense of belonging and purpose that was beneficial to well-being and social health for all participants. Community-based initiatives that provide opportunities for peer support for the person with the diagnosis and the care partner are essential so that people living with dementia may rebuild their confidence as well as retaining opportunities to socialise

Temporal trends in mode, site and stage of presentation with the introduction of colorectal cancer screening: a decade of experience from the West of Scotland

background:  Population colorectal cancer screening programmes have been introduced to reduce cancer-specific mortality through the detection of early-stage disease. The present study aimed to examine the impact of screening introduction in the West of Scotland. methods:  Data on all patients with a diagnosis of colorectal cancer between January 2003 and December 2012 were extracted from a prospectively maintained regional audit database. Changes in mode, site and stage of presentation before, during and after screening introduction were examined. results:  In a population of 2.4 million, over a 10-year period, 14 487 incident cases of colorectal cancer were noted. Of these, 7827 (54%) were males and 7727 (53%) were socioeconomically deprived. In the postscreening era, 18% were diagnosed via the screening programme. There was a reduction in both emergency presentation (20% prescreening vs 13% postscreening, P0.001) and the proportion of rectal cancers (34% prescreening vs 31% pos-screening, P0.001) over the timeframe. Within non-metastatic disease, an increase in the proportion of stage I tumours at diagnosis was noted (17% prescreening vs 28% postscreening, P0.001). conclusions:  Within non-metastatic disease, a shift towards earlier stage at diagnosis has accompanied the introduction of a national screening programme. Such a change should lead to improved outcomes in patients with colorectal cancer

Differences in the signaling pathways of α1A- and α1B-adrenoceptors are related to different endosomal targeting

Aims: To compare the constitutive and agonist-dependent endosomal trafficking of α1A- and α1B-adrenoceptors (ARs) and to establish if the internalization pattern determines the signaling pathways of each subtype. Methods: Using CypHer5 technology and VSV-G epitope tagged α1A- and α1B-ARs stably and transiently expressed in HEK 293 cells, we analyzed by confocal microscopy the constitutive and agonist-induced internalization of each subtype, and the temporal relationship between agonist induced internalization and the increase in intracellular calcium (determined by FLUO-3 flouorescence), or the phosphorylation of ERK1/2 and p38 MAP kinases (determined by Western blot). Results and Conclusions: Constitutive as well as agonist-induced trafficking of α1A and α1B ARs maintain two different endosomal pools of receptors: one located close to the plasma membrane and the other deeper into the cytosol. Each subtype exhibited specific characteristics of internalization and distribution between these pools that determines their signaling pathways: α1A-ARs, when located in the plasma membrane, signal through calcium and ERK1/2 pathways but, when translocated to deeper endosomes, through a mechanism sensitive to β-arrestin and concanavalin A, continue signaling through ERK1/2 and also activate the p38 pathway. α1B-ARs signal through calcium and ERK1/2 only when located in the membrane and the signals disappear after endocytosis and by disruption of the membrane lipid rafts by methyl-β-cyclodextrin

A qualitative evaluation of the impact of a Good Life Club on people living with dementia and care partners

Background: Research suggests there is a lack of post diagnostic support to enable people living with dementia to fulfil social and active lives throughout their dementia journey. Gardening has been found to have many benefits for people living with dementia. Although such research is important, most research frames people with dementia as passive recipients of stimulation. The impact of a community-based gardening group where people living with dementia are active in the development of an outdoor space is underdeveloped. Knowledge about the impact of participating in such groups is also sparse. The Good Life Club (GLC) was co-developed and evaluated to respond to these gaps. Objectives: The primary aim of this paper is to present the findings regarding the impact of attending the GLC on the self-reported wellbeing for people living with dementia and care partners. Methods: Qualitative data were collected via 22 semi-structured interviews. Fourteen interviews were conducted before the GLC and eight after the GLC. Thematic Analysis was used to analyse data. Dementia Care Mapping Data was collected to supplement the interview data. Findings: Four key themes were identified. The first was that participants considered having active participation in social life to be a key aspect of living a good life. The second was that the way the GLC was set up and delivered gave the participants ownership of the GLC and within this they felt able to contribute. The third was the importance of social connectedness and peer support to the wellbeing of both people living with dementia and care partners. Fourth, positive mood and wellbeing was directly experienced through gardening. Conclusions: The combination of long-term investment of time and energy to the GLC, on-going friendships and in-session autonomy, act as key ingredients in creating a group that is relaxed, full of humour and highly valued