Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs.
We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression.
An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele.
Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors. Neurology® 2012;78:690–695
The EQ-5D is a widely-used, standardised, quality of life measure producing health profiles, indices and states. The aims of this study were to assess the role of various factors in how people with Multiple Sclerosis rate their quality of life, based on responses to the EQ-5D received via the web portal of the UK MS Register.
The 4516 responses to the EQ-5D (between May 2011 and April 2012) were collated with basic demographic and descriptive MS data and the resulting dataset was analysed in SPSS (v.20).
The mean health state for people with MS was 59.73 (SD 22.4, median 61), compared to the UK population mean of 82.48 (which is approximately 1SD above the cohort mean). The characteristics of respondents with high health states (at or above +1SD) were: better health profiles (most predictive dimension: Usual Activities), higher health indices, younger age, shorter durations of MS, female gender, relapsing-remitting MS, higher educational attainment and being in paid employment (all p-values<0.001). Conversely, the characteristics of respondents with low health states (at or below -1SD) were: poorer health profiles (most predictive dimension: Mobility), lower health indices, older age, longer durations of MS, male gender, progressive MS, lower educational attainment and having an employment status of sick/disabled (p = 0.0014 for age, all other p-values<0.001). Particular living arrangements were not associated with either the high or low health status groups.
This large-scale study has enabled in-depth analyses on how people with MS rate their quality of life, and it provides new knowledge on the various factors that contribute to their self-assessed health status. These findings demonstrate the impact of MS on quality of life, and they can be used to inform care provision and further research, to work towards enhancing the quality of life of people with MS.
Fungal pathogens elicit cytokine responses downstream of immunoreceptor tyrosine-based activation motif (ITAM)-coupled or hemiITAM-containing receptors and TLRs. The Linker for Activation of B cells/Non-T cell Activating Linker (LAB/NTAL) encoded by Lat2, is a known regulator of ITAM-coupled receptors and TLR-associated cytokine responses. Here we demonstrate that LAB is involved in anti-fungal immunity. We show that Lat2−/− mice are more susceptible to C. albicans infection than wild type (WT) mice. Dendritic cells (DCs) express LAB and we show that it is basally phosphorylated by the growth factor M-CSF or following engagement of Dectin-2, but not Dectin-1. Our data revealed a unique mechanism whereby LAB controls basal and fungal/pathogen-associated molecular patterns (PAMP)-induced nuclear β-catenin levels. This in turn is important for controlling fungal/PAMP-induced cytokine production in DCs. C. albicans- and LPS-induced IL-12 and IL-23 production was blunted in Lat2−/− DCs. Accordingly, Lat2−/− DCs directed reduced Th1 polarization in vitro and Lat2−/− mice displayed reduced Natural Killer (NK) and T cell-mediated IFN-γ production in vivo/ex vivo. Thus our data define a novel link between LAB and β-catenin nuclear accumulation in DCs that facilitates IFN-γ responses during anti-fungal immunity. In addition, these findings are likely to be relevant to other infectious diseases that require IL-12 family cytokines and an IFN-γ response for pathogen clearance.
Fungal infections are a major healthcare problem and the incidence of fungal infections has increased significantly in recent years. Mortality rates are high even with treatment, highlighting the need for a better understanding of anti-fungal immunity in order to develop improved therapies. Adaptive T-helper 1 and T-helper 17 (Th1 and Th17) responses are important mediators of anti-fungal immunity. Dendritic cells express Dectin-1, Dectin-2 and Toll-like receptors, which interact with fungal pathogens to induce these adaptive immune responses. Here we identify LAB as an important facilitator of IFN-γ production by regulating β-catenin activation. Susceptibility to fungal infections is increased in the absence of LAB, in association with reduced IFN-γ production. β-catenin activation in dendritic cells inhibits the IL-12 production required for IFN-γ production. Thus targeting β-catenin therapeutically could help to promote efficient IFN-γ production in patients suffering from fungal infections. These findings are important for fungal infections and potentially for other diseases where IFN-γ production is important for disease outcome.
Managing natural resources often depends on influencing people's behaviour, however effectively targeting interventions to discourage environmentally harmful behaviours is challenging because those involved may be unwilling to identify themselves. Non-sensitive indicators of sensitive behaviours are therefore needed. Previous studies have investigated people's attitudes, assuming attitudes reflect behaviour. There has also been interest in using people's estimates of the proportion of their peers involved in sensitive behaviours to identify those involved, since people tend to assume that others behave like themselves. However, there has been little attempt to test the potential of such indicators. We use the randomized response technique (RRT), designed for investigating sensitive behaviours, to estimate the proportion of farmers in north-eastern South Africa killing carnivores, and use a modified logistic regression model to explore relationships between our best estimates of true behaviour (from RRT) and our proposed non-sensitive indicators (including farmers' attitudes, and estimates of peer-behaviour). Farmers' attitudes towards carnivores, question sensitivity and estimates of peers' behaviour, predict the likelihood of farmers killing carnivores. Attitude and estimates of peer-behaviour are useful indicators of involvement in illicit behaviours and may be used to identify groups of people to engage in interventions aimed at changing behaviour.
leopard; randomized response technique; attitude; brown hyaena; illegal; false consensus effect
The MSIS-29 was developed to assess the physical and psychological impact of MS. The aims of this study were to use the responses to the MSIS-29 via the web portal of the UK MS Register to: examine the internal properties of the scale delivered via the internet, profile the cohort, and assess how well the scale measures impact of disability on the potential workforce.
Between May 2011 and April 2012, 4558 people with MS completed the MSIS-29(v.1). The responses were collated with basic demographic and descriptive MS data and the resulting dataset was analysed in SPSS(v.20).
Internal consistency was high (Cronbach's alpha 0.97 MSIS-29-PHYS, 0.92 MSIS-29-PSYCH). The mean MSIS-29-PHYS score was 60.5 (50.6%) with a median of 62 and the mean MSIS-29-PSYCH score was 24.8 (43.8%) with a median of 24. Physical scores increased with age and disease duration (p<0.001, p<0.001), but there was a weak negative relationship between psychological scores and age (p<0.001). The odds of people having an employment status of sick/disabled were 7.2 (CI 5.5, 9.4, p<0.001) for people with a moderate physical score, and 22.3 (CI 17.0, 29.3, p<0.001) for people with a high physical score (relative to having a low physical score).
This largest known study of its kind has demonstrated how the MSIS-29 can be administered via the internet to characterise a cohort, and to predict the likely impact of disability on taking an active part in the workforce, as a reasonable proxy for the effects of MS on general activities. The findings examining MSIS-29-PHYS and MSIS-29-PSYCH scores against age support the use of two sub-scales, not a combined score. These results underline the importance of using a scale such as this to monitor disability levels regularly in guiding MS care to enable people to be as active as possible.
Strains from a collection of Drosophila GFP protein trap lines express GFP in the normal tissues where the endogenous protein is present. This collection can be used to screen for proteins distributed in the nucleus in a non-uniform pattern.
We analyzed four lines that show peripheral or punctate nuclear staining. One of these lines affects an uncharacterized gene named CG11138. The CG11138 protein shows a punctate distribution in the nuclear periphery similar to that of Drosophila insulator proteins but does not co-localize with known insulators. Interestingly, mutations in Lamin proteins result in alterations in CG11138 localization, suggesting that this protein may be a novel component of the nuclear lamina. A second line affects the Decondensation factor 31 (Df31) gene, which encodes a protein with a unique nuclear distribution that appears to segment the nucleus into four different compartments. The X-chromosome of males is confined to one of these compartments. We also find that Drosophila Nucleoplasmin (dNlp) is present in regions of active transcription. Heat shock leads to loss of dNlp from previously transcribed regions of polytene chromosome without redistribution to the heat shock genes. Analysis of Stonewall (Stwl), a protein previously found to be necessary for the maintenance of germline stem cells, shows that Stwl is present in a punctate pattern in the nucleus that partially overlaps with that of known insulator proteins. Finally we show that Stwl, dNlp, and Df31 form part of a highly interactive network. The properties of other components of this network may help understand the role of these proteins in nuclear biology.
These results establish screening of GFP protein trap alleles as a strategy to identify factors with novel cellular functions. Information gained from the analysis of CG11138 Stwl, dNlp, and Df31 sets the stage for future studies of these proteins.
Studies have found that people with Multiple Sclerosis experience relatively high rates of anxiety and depression. Although methodologically robust, many of these studies had access to only modest sample sizes (N<200). The aims of this study were to use responses gained via the web portal of the UK MS Register (N>4000) to: describe the depression and anxiety profiles of people with MS; to determine if anxiety and depression are related to age or disease duration; and to assess whether the levels of anxiety and depression differ between genders and types of MS.
From its launch in May 2011 to the end of December 2011, 7786 adults with MS enrolled to take part in the UK MS Register via the web portal. The responses to the Hospital Anxiety and Depression Scale (HADS) were collated with basic demographic and descriptive MS data provided at registration and the resulting dataset was analysed in SPSS (v.16).
The mean HADS score among the 4178 respondents was 15.7 (SE 0.117, SD 7.55) with a median of 15.0 (IQR 11). Anxiety and depression rates were notably high, with over half (54.1%) scoring ≥8 for anxiety and 46.9% scoring ≥8 for depression. Women with relapsing-remitting MS were more anxious than men with this type (p<0.001), and than women with other types of MS (p = 0.017). Within each gender, men and women with secondary progressive MS were more depressed than men or women with other types of MS (p<0.001, p<0.001).
This largest known study of its kind has shown that anxiety and depression are highly prevalent in people with MS, indicating that their mental health needs could be better addressed. These findings support service planning and further research to provide the best care for people with MS to help alleviate these debilitating conditions.
Understanding the evolution of cultivated barley is important for two reasons. First, the evolutionary relationships between different landraces might provide information on the spread and subsequent development of barley cultivation, including the adaptation of the crop to new environments and its response to human selection. Second, evolutionary information would enable landraces with similar traits but different genetic backgrounds to be identified, providing alternative strategies for the introduction of these traits into modern germplasm.
The evolutionary relationships between 651 barley landraces were inferred from the genotypes for 24 microsatellites. The landraces could be divided into nine populations, each with a different geographical distribution. Comparisons with ear row number, caryopsis structure, seasonal growth habit and flowering time revealed a degree of association between population structure and phenotype, and analysis of climate variables indicated that the landraces are adapted, at least to some extent, to their environment. Human selection and/or environmental adaptation may therefore have played a role in the origin and/or maintenance of one or more of the barley landrace populations. There was also evidence that at least some of the population structure derived from geographical partitioning set up during the initial spread of barley cultivation into Europe, or reflected the later introduction of novel varieties. In particular, three closely-related populations were made up almost entirely of plants with the daylength nonresponsive version of the photoperiod response gene PPD-H1, conferring adaptation to the long annual growth season of northern Europe. These three populations probably originated in the eastern Fertile Crescent and entered Europe after the initial spread of agriculture.
The discovery of population structure, combined with knowledge of associated phenotypes and environmental adaptations, enables a rational approach to identification of landraces that might be used as sources of germplasm for breeding programs. The population structure also enables hypotheses concerning the prehistoric spread and development of agriculture to be addressed.
HIV-specific cytotoxic T lymphocytes (CTL) are important in controlling HIV replication, but the magnitude of the CTL response does not predict clinical outcome. In four donors with delayed disease progression we identified Vβ13.2 T cell receptors (TCRs) with very similar and unusually long β-chain complementarity determining region 3 (CDR3) regions in CTL specific for the immunodominant human histocompatibility leukocyte antigens (HLA)-B8–restricted human immunodeficiency virus-1 (HIV-1) nef epitope, FLKEKGGL (FL8). CTL expressing Vβ13.2 TCRs tolerate naturally arising viral variants in the FL8 epitope that escape recognition by other CTL. In addition, they expand efficiently in vitro and are resistant to apoptosis, in contrast to FL8–specific CTL using other TCRs. Selection of Vβ13.2 TCRs by some patients early in the FL8-specific CTL response may be linked with better clinical outcome.
HIV; cytotoxic T lymphocytes (CTL); T cell receptor; cross-reactivity; apoptosis
Facioscapulohumeral muscular dystrophy (FSHD), the most prevalent myopathy afflicting both children and adults, is predominantly associated with contractions in the 4q35-localized macrosatellite D4Z4 repeat array. Recent studies have proposed that FSHD pathology is caused by the misexpression of the DUX4 (double homeobox 4) gene resulting in production of a pathogenic protein, DUX4-FL, which has been detected in FSHD, but not in unaffected control myogenic cells and muscle tissue. Here, we report the analysis of DUX4 mRNA and protein expression in a much larger collection of myogenic cells and muscle biopsies derived from biceps and deltoid muscles of FSHD affected subjects and their unaffected first-degree relatives. We confirmed that stable DUX4-fl mRNA and protein were expressed in myogenic cells and muscle tissues derived from FSHD affected subjects, including several genetically diagnosed adult FSHD subjects yet to show clinical manifestations of the disease in the assayed muscles. In addition, we report DUX4-fl mRNA and protein expression in muscle biopsies and myogenic cells from genetically unaffected relatives of the FSHD subjects, although at a significantly lower frequency. These results establish that DUX4-fl expression per se is not sufficient for FSHD muscle pathology and indicate that quantitative modifiers of DUX4-fl expression and/or function and family genetic background are determinants of FSHD muscle disease progression.
The temperature dependence of the binding constants for human serum albumin and sulfonated metal-phthalocyanines were estimated by fluorescence spectroscopy. Stern-Volmer’s analysis and Chipman’s fits provided binding data for van’t Hoff calculations of the thermodynamic parameters governing these interactions. Results show that the formations of the HSA- phthalocyanine complexes are favorable processes by both the ΔH° and ΔS°. However, the formation of HSA-AIPcS4 has a stronger dependence than HSA-ZnPcS 4on ΔS°.
Thermodynamics; Phthalocyanines; Stern-Volmer’s analysis; Fluorescence; van’t Hoff analysis; Dissociation constant; Photodynamic therapy
Schistosomiasis is an important neglected tropical disease caused by digenean helminth parasites of the genus Schistosoma. Schistosomes are unusual in that they are dioecious and the adult worms live in the blood system. MicroRNAs play crucial roles during gene regulation and are likely to be important in sex differentiation in dioecious species. Here we characterize 112 microRNAs from adult Schistosoma mansoni individuals, including 84 novel microRNA families, and investigate the expression pattern in different sexes. By deep sequencing, we measured the relative expression levels of conserved and newly identified microRNAs between male and female samples. We observed that 13 microRNAs exhibited sex-biased expression, 10 of which are more abundant in females than in males. Sex chromosomes showed a paucity of female-biased genes, as predicted by theoretical evolutionary models. We propose that the recent emergence of separate sexes in Schistosoma had an effect on the chromosomal distribution and evolution of microRNAs, and that microRNAs are likely to participate in the sex differentiation/maintenance process.
Schistosomiasis is the second most common disease caused by a parasite, affecting over 200 million people. The parasites involved are flatworms of the genus Schistosoma. Unlike most non-parasitic flatworms, Schistosoma species have separate sexes, and the emergence of sex has been associated with the development of a parasitic lifestyle. The identification of gene products that are expressed in a sex-biased fashion permits the study of the origin of sexual dimorphism and, in the case of the schistosomes, the evolution of a human parasite. Here we investigated the differential expression of microRNAs in male and female individuals of the species Schistosoma mansoni. MicroRNAs are crucial gene regulators. We observed that many new microRNAs emerged in the evolutionary lineage leading to the schistosomes. However, many sex-biased microRNAs were present in the hermaphrodite ancestor of the flatworms, and therefore acquired sex-biased expression later on. Our results suggest that changes in microRNA expression patterns were associated with the emergence of separate sexes in the schistosomes.
Next-generation sequencing is making sequence-based molecular pathology and personalized oncology viable. We selected an individual initially diagnosed with conventional but aggressive prostate adenocarcinoma and sequenced the genome and transcriptome from primary and metastatic tissues collected prior to hormone therapy. The histology-pathology and copy number profiles were remarkably homogeneous, yet it was possible to propose the quadrant of the prostate tumour that likely seeded the metastatic diaspora. Despite a homogeneous cell type, our transcriptome analysis revealed signatures of both luminal and neuroendocrine cell types. Remarkably, the repertoire of expressed but apparently private gene fusions, including C15orf21:MYC, recapitulated this biology. We hypothesize that the amplification and over-expression of the stem cell gene MSI2 may have contributed to the stable hybrid cellular identity. This hybrid luminal-neuroendocrine tumour appears to represent a novel and highly aggressive case of prostate cancer with unique biological features and, conceivably, a propensity for rapid progression to castrate-resistance. Overall, this work highlights the importance of integrated analyses of genome, exome and transcriptome sequences for basic tumour biology, sequence-based molecular pathology and personalized oncology.
RNA sequencing; DNA sequencing; prostate cancer; fusion genes; neuroendocrine; personalized medicine; cancer genetics
Childhood sexual abuse (CSA) has been associated with HIV/AIDS risk behavior; however, much of this work is retrospective and focuses on women. The current study used semiparametric mixture modeling with youth (n = 844; 48.8% boys) from the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN) to examine the link between trajectories of CSA (2 to 12 y.o.) and HIV/AIDS risk behavior at age 14 (i.e., sexual intercourse & alcohol use). Trajectory analyses revealed a link between a history of CSA and the development of risky behavior. In addition, trajectories for physical and emotional abuse, but not neglect or witnessed violence, contributed to risky behavior over and above the role of CSA. Child gender did not moderate the findings. Findings highlight the signficance of CSA histories, as well as the broader context of maltreatment, for better understanding the development of risk behaviors in both girls and boys.
Supergenes are tight clusters of loci that facilitate the co-segregation of adaptive variation, providing integrated control of complex adaptive phenotypes1. Polymorphic supergenes, in which specific combinations of traits are maintained within a single population, were first described for ‘pin’ and ‘thrum’ floral types in Primula1 and Fagopyrum2, but classic examples are also found in insect mimicry3–5 and snail morphology6. Understanding the evolutionary mechanisms that generate these co-adapted gene sets, as well as the mode of limiting the production of unfit recombinant forms, remains a substantial challenge7–10. Here we show that individual wing-pattern morphs in the polymorphic mimetic butterfly Heliconius numata are associated with different genomic rearrangements at the supergene locus P. These rearrangements tighten the genetic linkage between at least two colour-pattern loci that are known to recombine in closely related species9–11, with complete suppression of recombination being observed in experimental crosses across a 400-kilobase interval containing at least 18 genes. In natural populations, notable patterns of linkage disequilibrium (LD) are observed across the entire P region. The resulting divergent haplotype clades and inversion breakpoints are found in complete association with wing-pattern morphs. Our results indicate that allelic combinations at known wing-patterning loci have become locked together in a polymorphic rearrangement at the Plocus, forming a supergene that acts as a simple switch between complex adaptive phenotypes found in sympatry. These findings highlight how genomic rearrangements can have a central role in the coexistence of adaptive phenotypes involving several genes acting in concert, by locally limiting recombination and gene flow.
Objective. To compare knowledge and attitudes of human papillomavirus (HPV) and the vaccine between different cultures of African descent. Methods. A cross-sectional survey of 555 African-Americans and Afro-Caribbeans residing in the US and the Bahamas (BHM) was conducted. Results. General knowledge about HPV and the HPV vaccine differed between the two countries significantly. Bahamian respondents were less likely to have higher numbers of correct knowledge answers when compared to Americans (Adjusted Odds Ratio [Adj. OR] 0.47, 95% Confidence Interval [CI] 0.30–0.75). Older age, regardless of location, was also associated with answering fewer questions correctly (Adj. OR 0.61, 95% CI 0.40–0.92). Attitudes related to HPV vaccination were similar between the US and BHM, but nearly 80% of BHM respondents felt that children should not be able to receive the vaccine without parental consent compared to 57% of American respondents. Conclusions. Grave lack of knowledge, safety and cost concerns, and influence of parental restrictions may negatively impact vaccine uptake among African-American and Afro-Caribbean persons. Interventions to increase the vaccine uptake in the Caribbean must include medical provider and parental involvement. Effective strategies for education and increasing vaccine uptake in BHM are crucial for decreasing cervical cancer burden in the Caribbean.
Just as scientific articles are used as a way of sharing knowledge in scientific communities, stories are used as a way of transferring knowledge within African American communities. This article uses the story and metaphor of Stone Soup to illustrate the Healthy African American Families' (HAAF) Community Partnered Participatory Research (CPPR) method of engaging diverse partners to address health issues, such as preterm birth, depression, diabetes, and kidney disease, and to create community-wide change through education, capacity building, resource sharing, and intervention development.
African American; Family; Community Partnered Participatory Research
This study investigated the effects of long-term-enhanced UV-B, and combined UV-B with elevated CO2 on dwarf shrub berry characteristics in a sub-arctic heath community. Germination of Vaccinium myrtillus was enhanced in seeds produced at elevated UV-B, but seed numbers and berry size were unaffected. Elevated UV-B and CO2 stimulated the abundance of V. myrtillus berries, whilst UV-B alone stimulated the berry abundance of V. vitis-idaea and Empetrum hermaphroditum. Enhanced UV-B reduced concentrations of several polyphenolics in V. myrtillus berries, whilst elevated CO2 increased quercetin glycosides in V. myrtillus, and syringetin glycosides and anthocyanins in E. hermaphroditum berries. UV-B × CO2 interactions were found for total anthocyanins, delphinidin-3-hexoside and peonidin-3-pentosidein in V. myrtillus berries but not E. hermaphroditum. Results suggest positive impacts of UV-B on the germination of V. myrtillus and species-specific impacts of UV-B × elevated CO2 on berry abundance and quality. The findings have relevance and implications for human and animal consumers plus seed dispersal and seedling establishment.
Electronic supplementary material
The online version of this article (doi:10.1007/s13280-012-0311-4) contains supplementary material, which is available to authorized users.
CO2; Elevated; UV-B; Enhanced; Arctic; Reproduction; Berry; Abundance; Secondary metabolites
Medulloblastoma, the most common malignant pediatric brain tumour, is currently treated with non-specific cytotoxic therapies including surgery, whole brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, prior attempts to identify targets for therapy have been underpowered due to small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup enriched. The most common region of focal copy number gain is a tandem duplication of the Parkinson’s disease gene SNCAIP, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1 that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGFβ signaling in Group 3, and NF-κB signaling in Group 4 suggest future avenues for rational, targeted therapy.
Psychotic symptoms occur in approximately 40% of subjects with Alzheimer’s disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWAS) to identify loci that a) increase susceptibility to an AD and subsequent psychotic symptoms; or b) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD-P) and 5659 controls were drawn from GERAD1, the NIA-LOAD family study and the University of Pittsburgh ADRC GWAS. Unobserved genotypes were imputed to provide data on > 1.8 million SNPs. Analyses in each dataset were completed comparing a) AD+P to AD-P cases, and b) AD+P cases with controls (GERAD1, ADRC only). Aside from the APOE locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; ‘AD+PvAD-P’ P=2.85 × 10−7; ‘AD+PvControls’ P=1.11 × 10−4). SNPs upstream of SLC2A9 (rs6834555, P=3.0×10−7) and within VSNL1 (rs4038131, P=5.9×10−7) showed strongest evidence for association with AD+P when compared to controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterised.
Alzheimer’s disease; psychosis; behavioural symptoms; genome-wide association study; genetic
Active participation of community partners in research aspects of community-academic partnered projects is often assumed to have a positive impact on the outcomes of such projects. The value of community engagement in research, however, cannot be empirically determined without good measures of the level of community participation in research activities. Based on our recent evaluation of community-academic partnered projects centered around behavioral health issues, this article uses semi-structured interview and survey data to outline two complementary approaches to measuring the level of community participation in research - a “three-model” approach that differentiates between the levels of community participation and a Community Engagement in Research Index (CERI) that offers a multidimensional view of community engagement in the research process. The primary goal of this article is to present and compare these approaches, discuss their strengths and limitations, summarize the lessons learned, and offer directions for future research. We find that while the three-model approach is a simple measure of the perception of community participation in research activities, CERI allows for a more nuanced understanding by capturing multiple aspects of such participation. Although additional research is needed to validate these measures, our study makes a significant contribution by illustrating the complexity of measuring community participation in research and the lack of reliability in simple scores offered by the three-model approach.
Community Based Participatory Research; Community Participation in Research; Mixed-Methods; Community-Academic Partnerships; Evaluation
AIM: To further reduce the risk of bleeding or bile leakage.
METHODS: We performed endoscopic ultrasound guided biliary drainage in 6 patients in whom endoscopic retrograde cholangiopancreatography (ERCP) had failed. Biliary access of a dilated segment 2 or 3 duct was achieved from the stomach using a 19G needle. After radiologically confirming access a guide wire was placed, a transhepatic tract created using a 6 Fr cystotome followed by balloon dilation of the stricture and antegrade metallic stent placement across the malignant obstruction. This was followed by placement of an endocoil in the transhepatic tract.
RESULTS: Dilated segmental ducts were observed in all patients with the linear endoscopic ultrasound scope from the proximal stomach. Transgastric biliary access was obtained using a 19G needle in all patients. Biliary drainage was achieved in all patients. Placement of an endocoil was possible in 5/6 patients. All patients responded to biliary drainage and no complications occurred.
CONCLUSION: We show that placing endocoils at the time of endoscopic ultrasound guided biliary stenting is feasible and may reduce the risk of bleeding or bile leakage.
Endoscopic ultrasound; Biliary drainage; Transhepatic; Endocoil
The quality of a consultation provided by a physician can have a profound impact on the quality of care and patient engagement in treatment decisions. When the COPD Assessment Test (CAT) was developed, one of its aims was to aid the communication between physician and patient about the impact of COPD. We developed a novel study design to assess this in a primary care consultation.
Primary care physicians across five countries in Europe conducted videoed consultations with six standardised COPD patients (played by trained actors) which had patient-specific issues that the physician needed to identify through questioning. Half the physicians saw the patients with the completed CAT, and half without. Independent assessors scored the physicians on their ability to identify and address the patient-specific issues, review standard COPD aspects, their understanding of the case and their overall performance. This novel study design presented many challenges which needed to be addressed to achieve an acceptable level of robustness to assess the utility of the CAT. This paper discusses these challenges and the measures adopted to eliminate or minimise their impact on the study results.
COPD; CAT; Primary care consultation; Videoed assessment
Proteomic research can benefit from simultaneous access to multiple cutting-edge mass spectrometers. 18 core facilities responded to our investigators seeking service through the ABRF Discussion Forum. Five of the facilities selected completed four plasma proteomics experiments as routine fee-for-service. Each biological experiment entailed an iTRAQ 4-plex proteome comparison of immunodepleted plasma provided as 30 labeled-peptide fractions. Identical samples were analyzed by two AB SCIEX TripleTOF 5600 and three Thermo Orbitrap (Elite/Velos Pro/Q Exactive) instruments. 480 LC-MS/MS runs delivered >250 GB of data over two months.
We compare herein routine service analyses of three peptide fractions of different peptide abundance. Data files from each instrument were studied to develop optimal analysis parameters to compare with default parameters in Mascot Distiller 2.4, ProteinPilot 4.5 beta, AB Sciex MS Data Converter 1.3 beta, and Proteome Discover 1.3. Peak-picking for TripleTOFs was best by ProteinPilot 4.5 beta while Mascot Distiller and Proteome Discoverer were comparable for the Orbitraps.
We compared protein identification and quantitation in SwissProt 2012_07 database by Mascot Server 2.4.01 versus ProteinPilot. By all search methods, more proteins, up to two fold, were identified using the Q Exactive than others. Q Exactive excelled also at the number of unique significant peptide ion sequences. However, software-dependent impact on subsequent interpretation, due to peptide modifications, can be critical. These findings may have special implications for iTRAQ plasma proteomics. For the low abundance peptide ions, the slope of the dynamic range drop-off in the plasma proteome is uniquely sharp compared with cell lysates. Our study provides data for testable improvements in the operation of these mass spectrometers. More importantly, we have demonstrated a new affordable expedient workflow for investigators to perform proteomic experiments through the ABRF infrastructure. (We acknowledge John Cottrell for optimizing the peak-picking parameters for Mascot Distiller).