Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Modelo prolab: Wasicare, una propuesta sostenible para mejorar la calidad de vida de las familias en sus hogares

El presente plan de negocio se basa en un modelo innovador y pionero que busca contribuir a solucionar un problema serio en el sector salud, como es una alta demanda de camas hospitalarias y un déficit de las mismas. Este problema social relevante puede resolverse en una mediana escala con la implementación de la Hospitalización domiciliaria; la cual implica llevar a los hogares el equipamiento médico básico para que los pacientes puedan ser atendidos bajo la calidez de su hogar. Se ha desarrollado una solución basada en el uso de metodologías ágiles para obtener así un servicio viable y sostenible a nivel social, ambiental y económico. La solución que se plantea es Wasicare, un emprendimiento que busca brindar una alternativa logística en cómo gestionar la salud en los hogares o sin salir de casa. El servicio a brindar por Wasicare se considera deseable, debido a la validación que se realizó bajo un proceso de encuestas a posibles usuarios, donde más del 60% ve factible contratar el servicio a pesar de tratarse de un tema de salud. Esto se debe a que la finalidad del servicio tiene un aspecto emocional relevante ya que lo que más valoran los usuarios es poder atenderse en su hogar y contar con el soporte de la familia para una recuperación más temprana. Asimismo, se identificó que el usuario está dispuesto a pagar el rango de precios del servicio a ofrecer, con lo cual el emprendimiento toma mayor fuerza en su viabilidad. En el caso del factor factibilidad, se realizaron simulaciones para determinar la ganancia en relación con el costo de marketing para la adquisición de clientes con una efectividad del 100 %; mientras que la viabilidad financiera se simuló bajo cinco escenarios, entre pesimista y muy optimista, teniendo como resultado todos los escenarios favorables para el negocio con una eficiencia del 88.40%, en donde el VAN simulado supera el VAN esperado. Finalmente, se concluye que Wasicare es un modelo de negocio sostenible y escalable que responde directamente a las ODS 3 y 10, con un índice de relevancia social del 12.7 %, y que genera un VAN de S/1 336 262 y un TIR del 47.36 % mediante una inversión inicial de S/478 255.This business plan is based on an innovative and pioneering model that seeks to help solve a serious problem in the health sector, such as a high demand for hospital beds and a shortage of them. This relevant social problem can be solved on a medium scale with the implementation of Home Hospitalization; which implies bringing basic medical equipment to homes so that patients can be treated in the warmth of their home. A solution based on the use of agile methodologies has been developed to obtain a viable and sustainable service socially, environmentally and economically. The proposed solution is Wasicare , a venture that seeks to provide a logistical alternative in how to manage health at home or without leaving home. The service to be provided by Wasicare is considered desirable, due to the validation that was carried out under a survey process to potential users, where more than 60% consider it feasible to contract the service despite being a health issue. This is due to the fact that the purpose of the service has a relevant emotional aspect, since what users value most is being able to receive care at home and have the support of the family for an earlier recovery. Likewise, it was identified that the user is willing to pay the price range of the service to be offered, with which the undertaking gains greater strength in its viability. In the case of the feasibility factor, simulations were carried out to determine the profit in relation to the cost of marketing for the acquisition of clients with an effectiveness of 100%; while the financial viability was simulated under five scenarios, between pessimistic and very optimistic, resulting in all the favorable scenarios for the business with an efficiency of 88.40%, where the simulated NPV exceeds the expected NPV. Finally, it is concluded that Wasicare is a sustainable and scalable business model that responds directly to SDGs 3 and 10, with a social relevance index of 12.7%, and that generates a NPV of S/1,336,262 and an IRR of 47.36%. through an initial investment of S/478,255

Clinical and genetic characteristics of late-onset Huntington's disease

Background: The frequency of late-onset Huntington's disease (>59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Methods: Participants with late- and common-onset (30–50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P <.001). Overall motor and cognitive performance (P <.001) were worse, however only disease motor progression was slower (coefficient, −0.58; SE 0.16; P <.001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P <.001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P <.001). Conclusions: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients

Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356

non present

Precision measurement of the structure of the CMS inner tracking system using nuclear interactions

The structure of the CMS inner tracking system has been studied using nuclear interactions of hadrons striking its material. Data from proton-proton collisions at a center-of-mass energy of 13 TeV recorded in 2015 at the LHC are used to reconstruct millions of secondary vertices from these nuclear interactions. Precise positions of the beam pipe and the inner tracking system elements, such as the pixel detector support tube, and barrel pixel detector inner shield and support rails, are determined using these vertices. These measurements are important for detector simulations, detector upgrades, and to identify any changes in the positions of inactive elements

Precision measurement of the structure of the CMS inner tracking system using nuclear interactions

The structure of the CMS inner tracking system has been studied using nuclear interactions of hadrons striking its material. Data from proton-proton collisions at a center-of-mass energy of 13 TeV recorded in 2015 at the LHC are used to reconstruct millions of secondary vertices from these nuclear interactions. Precise positions of the beam pipe and the inner tracking system elements, such as the pixel detector support tube, and barrel pixel detector inner shield and support rails, are determined using these vertices. These measurements are important for detector simulations, detector upgrades, and to identify any changes in the positions of inactive elements