Content validity and clinical meaningfulness of the HFMSE in spinal muscular atrophy

© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise statedBACKGROUND: Reports on the clinical meaningfulness of outcome measures in spinal muscular atrophy (SMA) are rare. In this two-part study, our aim was to explore patients' and caregivers' views on the clinical relevance of the Hammersmith Functional Motor Scale Expanded- (HFMSE). METHODS: First, we used focus groups including SMA patients and caregivers to explore their views on the clinical relevance of the individual activities included in the HFMSE. Then we asked caregivers to comment on the clinical relevance of possible changes of HFMSE scores over time. As functional data of individual patients were available, some of the questions were tailored according to their functional level on the HFMSE. RESULTS: Part 1: Sixty-three individuals participated in the focus groups. This included 30 caregivers, 25 patients and 8 professionals who facilitated the discussion. The caregivers provided a comparison to activities of daily living for each of the HFMSE items. Part 2: One hundred and forty-nine caregivers agreed to complete the questionnaire: in response to a general question, 72% of the caregivers would consider taking part in a clinical trial if the treatment was expected to slow down deterioration, 88% if it would stop deterioration and 97% if the treatment was expected to produce an improvement. Caregivers were informed of the first three items that their child could not achieve on the HFMSE. In response 75% indicated a willingness to take part in a clinical trial if they could achieve at least one of these abilities, 89% if they could achieve two, and 100% if they could achieve more than 2. CONCLUSIONS: Our findings support the use of the HFMSE as a key outcome measure in SMA clinical trials because the individual items and the detected changes have clear content validity and clinical meaningfulness for patients and their caregivers.Peer reviewedFinal Published versio

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Centrality evolution of the charged-particle pseudorapidity density over a broad pseudorapidity range in Pb-Pb collisions at root s(NN)=2.76TeV

Peer reviewe

Infestación natural de Lonchaeidae (Diptera) en variedades de melocotón

Se estudió la ocurrencia de Lonchaeidae en variedades de melocotón, conducidos sobre los patrones ‘Okinawa’ y Umê: Tropical, Ouromel 3, Jóia 4, Régis, Talismã, Aurora 2, Aurora 1, Dourado 2 y Doçura 2. Se colectaron muestras de 30 frutos por planta en el Banco de Germoplasma en Presidente Prudente, Brasil. Se obtuvieron 633 especímenes de Lonchaeidae; 394 de ellos en frutos de variedades sobre ‘Okinawa’ y 239 sobre Umê. Se capturaron especies como Neosilba zadolicha, N. inesperata, N. pendula, N. certa y Neosilba spp. (hembras). N. zadolicha y N. inesperata, se observaron en 77,78% de las muestras de las variedades sobre ‘Okinawa’. Sobre el patrón Umê la mayor incidencia fue de N. zadolicha , N. inesperata y N. pendula (55,6%, 33,3% y 33,3% respectivamente). Las variedades Ouromel 3, Talismã, Doçura 2 y Aurora 2 presentaron mayores infestaciones por Lonchaeidae. N. certa tuvo una menor incidencia y sólo se observó en la variedad Doçura 2 sobre ‘Okinawa’. Plantas con mayor número de frutos presentaron mayor incidencia de moscas por fruto; sin embargo, no hubo correlación entre peso del fruto y número de moscas. No se observó diferencia para peso del fruto y número de moscas por fruto entre los dos patrones, ‘Okinawa’ y Umê. Melocotones crecidos en los patrones ‘Okinawa’ y Umê en Presidente Prudente están infestados por especies de Lonchaeidae que presentan preferencia independientemente del peso de los frutos. El aporte de este trabajo al conocimiento de la comunidad de especies de Lonchaeidae ofrece una base para su control.The occurrence of Lonchaeidae was studied in peach fruit varieties on the rootstocks 'Okinawa' and Ume: Tropical, Ouromel 3, Joia 4, Regis, Talisma, Aurora 2, Aurora 1, Dourado 2 and Docura 2. Samples of 30 fruits were collected from each available plant in the Germplasm Bank located in Presidente Prudente, Brazil. A total of 633 specimens of Lonchaeidae were obtained with 394 from fruit varieties on 'Okinawa' and 239 on Ume. Captured species included Neosilba zadolicha, N. inesperata, N. pendula, N. cella, and Neosilba spp. (females). N. zadolicha and N. inesperata were observed in 77.78% of samples from the varieties on 'Okinawa'. on the lime rootstock, the greatest incidence was of N. zadolicha, N. inesperata and N. penduda (55.6%, 33.3% and 33.3%). The varieties Ouromel 3, Talisma, Docura 2 and Aurora 2 had the highest infestation rates by Lonchaeidae. N. certa had the lowest incidence and was only observed in the variety Docura 2 on 'Okinawa'. Plants with more fruits showed a higher incidence of flies per fruit. Nevertheless, there was no significant correlation between fruit weight and fly number. No significant difference was observed in fruit weight and number of flies per fruit between the two rootstocks, 'Okinawa' and lime. Peaches grown on 'Okinawa' and Ume rootstocks in the city of Presidente Prudente, are infested by Lonchaeidae species that present a preference for the different varieties, independent of fruit weight. This is a contribution to an understanding of the community of Lonchaeidae species, which provides a basis for their control