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.

• MeSH
• Alzheimerova nemoc * genetika   MeSH
• histokompatibilní antigeny MeSH
• HLA antigeny MeSH
• HLA-DRB1 řetězec * genetika   MeSH
• lidé MeSH
• Parkinsonova nemoc * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

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.

• MeSH
• Alzheimerova nemoc * genetika   patologie   MeSH
• celogenomová asociační studie MeSH
• kognitivní dysfunkce * psychologie   MeSH
• lidé MeSH
• proteiny tau genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer's Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10-8) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10-6). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq25 loci, and rare for the WNK3, PJA1, and DACH2 loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.

• MeSH
• Alzheimerova nemoc * genetika   MeSH
• celogenomová asociační studie metody   MeSH
• genetická predispozice k nemoci genetika   MeSH
• inaktivace chromozomu X genetika   MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé MeSH
• lidské chromozomy X * genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• Publikační typ
• tisková chyba MeSH

Importance: The APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly. Objective: To determine whether rare missense variants on APOE are associated with AD risk. Design, Setting, and Participants: Association with case-control status was tested in a sequenced discovery sample (stage 1) and followed up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (stages 2 and 3). This study combined case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Stage 1 included 37 409 nonunique participants of European or admixed European ancestry, with 11 868 individuals with AD and 11 934 controls passing analysis inclusion criteria. In stages 2 and 3, 475 473 participants were considered across 8 cohorts, of which 84 513 individuals with AD and proxy-AD and 328 372 controls passed inclusion criteria. Selection criteria were cohort specific, and this study was performed a posteriori on individuals who were genotyped. Among the available genotypes, 76 195 were excluded. All data were retrieved between September 2015 and November 2021 and analyzed between April and November 2021. Main Outcomes and Measures: In primary analyses, the AD risk associated with each missense variant was estimated, as appropriate, with either linear mixed-model regression or logistic regression. In secondary analyses, associations were estimated with age at onset using linear mixed-model regression and risk of conversion to AD using competing-risk regression. Results: A total of 544 384 participants were analyzed in the primary case-control analysis; 312 476 (57.4%) were female, and the mean (SD; range) age was 64.9 (15.2; 40-110) years. Two missense variants were associated with a 2-fold to 3-fold decreased AD risk: APOE ε4 (R251G) (odds ratio, 0.44; 95% CI, 0.33-0.59; P = 4.7 × 10-8) and APOE ε3 (V236E) (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9 × 10-6). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared with noncarriers. Conclusions and Relevance: In this genetic association study, a novel variant associated with AD was identified: R251G always coinherited with ε4 on the APOE gene, which mitigates the ε4-associated AD risk. The protective effect of the V236E variant, which is always coinherited with ε3 on the APOE gene, was also confirmed. The location of these variants confirms that the carboxyl-terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here suggest that protein chemistry and functional assays of these variants should be pursued, as they have the potential to guide drug development targeting APOE.

• MeSH
• alely MeSH
• Alzheimerova nemoc * epidemiologie   genetika   MeSH
• apolipoprotein E2 genetika   MeSH
• apolipoprotein E4 genetika   MeSH
• apolipoproteiny E genetika   MeSH
• genotyp MeSH
• lidé MeSH
• věk při počátku nemoci MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Genetic 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.

• MeSH
• Alzheimerova nemoc epidemiologie   genetika   patologie   MeSH
• amyloidový prekurzorový protein beta genetika   metabolismus   MeSH
• apolipoproteiny E genetika   MeSH
• celogenomová asociační studie MeSH
• datové soubory jako téma MeSH
• genetická predispozice k nemoci MeSH
• heterozygot MeSH
• hodnocení rizik metody   MeSH
• jednonukleotidový polymorfismus MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• multifaktoriální dědičnost * MeSH
• následné studie MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• věk při počátku nemoci MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• validační studie MeSH

• Konspekt
• Stomatologie
• NLK Obory
• zubní lékařství

Verifying the speaker of a speech fragment can be crucial in attributing a crime to a suspect. The question can be addressed given disputed and reference speech material, adopting the recommended and scientifically accepted likelihood ratio framework for reporting evidential strength in court. In forensic practice, usually, auditory and acoustic analyses are performed to carry out such a verification task considering a diversity of features, such as language competence, pronunciation, or other linguistic features. Automated speaker comparison systems can also be used alongside those manual analyses. State-of-the-art automatic speaker comparison systems are based on deep neural networks that take acoustic features as input. Additional information, though, may be obtained from linguistic analysis. In this paper, we aim to answer if, when and how modern acoustic-based systems can be complemented by an authorship technique based on frequent words, within the likelihood ratio framework. We consider three different approaches to derive a combined likelihood ratio: using a support vector machine algorithm, fitting bivariate normal distributions, and passing the score of the acoustic system as additional input to the frequent-word analysis. We apply our method to the forensically relevant dataset FRIDA and the FISHER corpus, and we explore under which conditions fusion is valuable. We evaluate our results in terms of log likelihood ratio cost (Cllr) and equal error rate (EER). We show that fusion can be beneficial, especially in the case of intercepted phone calls with noise in the background.

• MeSH
• akustika řeči MeSH
• algoritmy MeSH
• lidé MeSH
• lingvistika MeSH
• pravděpodobnostní funkce MeSH
• řeč MeSH
• soudní vědy * metody   MeSH
• support vector machine MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• diferenciální diagnóza MeSH
• kožní nemoci patologie   diagnóza   MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• dermatovenerologie
• patologie
• dermatovenerologie

PURPOSE OF THE STUDY Aseptic loosening of endoprosthetic components is the most frequent reason for total hip arthroplasty revision. This paper aimed to verify the influence of the type of hip-component fixation of total hip replacement in correlation with the age of patients on aseptic loosening of components during mid-term survival. MATERIAL AND METHODS The retrospective, monocentric study statistically evaluated the data of 67 cases of implanted total hip replacements in 66 patients with the loosening of at least one of the components requiring a revision of the total number of 1,488 primary total hip replacements implanted during the 1995 to 2006 period at a single department. The study compares the implants by Johnson&Johnson (Ultima threaded cups, Duraloc sector, Ultima UHMWPE cups. Mecroblock MR, AML and Ultima straight stems, Charnley and Elite plus cups and stems), Fehling Medical AG (HPQ and Müller cups, Müller Geradschaft stems) and Biomet (Mallory-Head and Müller cups, Bi-Metric cemented and uncemented stems) with respect to the age of patients. First-generation and second-generation cementing techniques were used. Primary arthroplasty of revised endoprostheses were indicated for primary and post-dysplastic coxarthrosis not requiring skeletal reconstruction. In order to determine the influence of age, three age categories were considered: under 54 years of age, 55 to 64 years of age, and elderly individuals aged 65 and over. The data was statistically evaluated by the test for two proportions and the Student's t-test. RESULTS The mean age of patients with total hip replacement loosening was lower than the mean age of the other patients (p < 0.05). The age category 55-64 reported a significantly higher failure rate only for HPQ - Müller-Geradschaft endoprosthesis compared to the uncemented and hybrid version of Mallory-Head - Bi-Metric, Duraloc - AML and Charnley group (p < 0.05). Duraloc - Charnley showed worse results than Mallory-Head - Bi-Metric porous (p = 0.0437). Except for HPQ - Müller-Geradschaft endoprosthesis, there were no statistically significant differences in the achieved revision rate of components used in endoprostheses. In the younger age category, only uncemented and hybrid versions were assessed. Hybrid endoprostheses made by Fehling and Biomet failed more often than uncemented Mallory-Head - Bi-Metric porous (p < 0.05) and Duraloc - AML (p < 0.01). For the category of 65 plus, cemented and hybrid endoprostheses were assessed. A higher revision rate was seen only in HPQ - Müller-Geradschaft endoprosthesis compared to the cemented version of Biomet (p < 0.05). No difference was reported in mid-term survival of the applied cemented and uncemented cups. DISCUSSION Despite the development of uncemented versions of total hip arthroplasty components, the current literature includes opinions supporting the cemented technique of total hip replacement. Especially for elderly patients the implant of uncemented components is questionable. The presented study did not identify a higher mid-term revision rate of uncemented implants, namely with respect to acetabular components, not even in the elderly patients. CONCLUSIONS No difference was found in the mid-term revision rate of evaluated endoprostheses for the medium age category of 55-64 years, regardless of whether cemented or uncemented components were implanted. The only exception was represented by hybrid HPQ-Müller Geradschaft endoprosthesis with a higher revision rate of the femoral and acetabular components. The younger age category showed a lower revision rate for uncemented versions than for the used hybrid versions of endoprostheses. For the group of elderly patients, there was no difference between the survival rate of hybrid and cemented joint replacement. Key words:arthroplasty with total hip replacement, cemented joint replacement, uncemented joint replacement, joint replacement failure, aseptic loosening of total replacement, age, joint replacement survival. 046_053_kubinec 20.2.18 14:12 Stránka 46 47/ Acta Chir Orthop Traumatol Cech. 85, 2018, No. 1 PŮVODNÍ PRÁCE.

• MeSH
• hodnocení výsledků zdravotní péče MeSH
• kostní cementy * škodlivé účinky   terapeutické užití   MeSH
• kyčelní protézy škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• náhrada kyčelního kloubu * škodlivé účinky   přístrojové vybavení   metody   MeSH
• protézy - design metody   MeSH
• registrace MeSH
• reoperace * metody   statistika a číselné údaje   MeSH
• rizikové faktory MeSH
• selhání protézy etiologie   MeSH
• senioři MeSH
• věkové faktory MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH