This thesis presents the work done to implement new computational tools and methods dedicated to aircraft conceptual design sizing and optimization. These tools have been exercised on different aircraft concepts in order to validate them and assess their relevance and applicability to practical cases. First, a geometry construction protocol has been developed. It is indeed essential to have a geometry description that supports the derivation of all discretizations and idealizations used by the different analysis modules (aerodynamics, weights and balance, stability and control, etc.) for which an aircraft concept is evaluated. The geometry should also be intuitive to the user, general enough to describe a wide array of morphologies and suitable for optimization. All these conditions are fulfilled by an appropriate parameterization of the geometry. In addition, a tool named CADac (Computer Aided Design aircraft) has been created in order to produce automatically a closed and consistent CAD solid model of the designs under study. The produced CAD model is easily meshable and therefore high-fidelity Computational Fluid Dynamics (CFD) computations can be performed effortlessly without need for tedious and time-consuming post-CAD geometry repair.Second, an unsteady vortex-lattice method based on TORNADO has been implemented in order to enlarge to scope of flight conditions that can be analyzed. It has been validated satisfactorily for the sudden acceleration of a flat plate as well as for the static and dynamic derivatives of the Saab 105/SK 60.Finally, a methodology has been developed to compute quickly in a semi-empirical way the buffet envelope of new aircraft geometries at the conceptual stage. The parameters that demonstrate functional sensitivity to buffet onset have been identified and their relative effect quantified. The method uses a combination of simple sweep theory and fractional change theory as well as the buffet onset of a seed aircraft or a provided generic buffet onset to estimate the buffet envelope of any target geometry. The method proves to be flexible and robust enough to predict within mainly 5% (and in any case 9%) the buffet onset for a wide variety of aircrafts, from regional turboprop to long-haul wide body or high-speed business jets.This work was done within the 6th European framework project SimSAC (Simulating Stability And Control) whose task is to create a multidisciplinary simulation environment named CEASIOM (Computerized Environment for Aircraft Synthesis and Integrated Optimization Methods), oriented toward stability and control and specially suited for aircraft conceptual design sizing and optimization. / QC 20101104 / SimSAC

Background: Cardiovascular disease (CVD) is the leading cause of death globally since the turn of the century. One major risk factor is tobacco smoking with a particular risk associated with early initiation/greater duration. Research also indicates that alcohol use can offer both risk or protective cardiovascular benefits depending on consumption characteristics (intensity, frequency, dose, type). The purpose of this study is to examine the early onset of smoking, heavy smoking, and alcohol behavior as they relate to CVD risk. Methods: Using the data from the 2019 National Survey on Drug Use and Health (N=56,136), logistic regression analysis were conducted to examine trends in heavy substance use predictive of CVD risk (Independent variables of heavy substance use: number of cigarettes smoked per day, ≤ 12 years of tobacco smoking, ≥ 5 drinks for males or ≥ 4 drinks for females on each of 5 or more days in the past 30 days; and the dependent variable - ever told by a doctor or other health care professional that you had heart condition) while controlling for sociodemographic factors. Results: Overall, 19.7% of the study population reported CVD conditions, 5.9% heavy alcohol consumption, and 4.9% early onset of smoking. Overall, the odds of having heart condition among heavy alcohol drinkers was 23.6% less than those who were not heavy alcohol drinkers (odds ratio (OR): 0.76, 95% confidence interval (CI): (0.63-0.92), 44% more among those smoked 26 or more cigarettes per day than 25 or less 1.44 (1.01-2.05), 49% more among those with early onset of smoking than none 1.49 (1.15-1.93). By age, we found that heavy alcohol consumption could be either risk factor or protective factor of heart condition or no effect on heart condition across different age groups: for aged 12-18, OR 1.69 (CI 0.69-4.16); 19-25, 0.75 (0.48-1.15), 26-29, 1.21 (0.57-2.53); 30-34, 0.80 (0.36-1.77); 35-49, 0.61 (0.40-0.93); 50-64, 1.12 (0.77-1.62); >64, 0.93 (0.57-1.52). Based on gender, CVD risk was higher in males than females, 1.22 (1.13-1.32). In terms of race, the odds of CVD risk were lower for all groups when compared with non-Hispanic White. Based on income, the odds of CVD risk were higher in high-income earners with at least a college education when compared to low-income earners with high school education or less (≥$50k vs.Conclusion: Study findings demonstrate that the association of heavy alcohol consumption related to CVD risk varied by age. For heavy tobacco smoking, early onset of tobacco smoking, being male, white race, having above high school level education, high income, and advanced age were found to be significant predictors of CVD risk. Future observational studies should be performed to determine the combined effects of heavy alcohol consumption and heavy smoking as it relates to CVD risk by other behavioral risk factors such as types of alcohol consumed (i.e, spirits vs wine) and related behaviors.

Bakgrund Upplevelserna hos närstående till en person som fått en tidigt debuterande demenssjukdom kan skilja sig från upplevelserna de närstående har vid en sent debuterande demenssjukdom. En tidig debut av demenssjukdom, till skillnad från en debut efter 65 års ålder, innebär större risk att närstående i yngre åldrar påverkas. Det behövs ökad kunskap kring vilka upplevelserna är hos de närstående, för att underlätta deras liv efter diagnosen tidigt debuterande demenssjukdom. Syfte Syftet var att belysa närståendes upplevelser av att leva med en person med tidigt debuterande demenssjukdom. Metod En icke-systematisk litteraturöversikt gjordes baserat på artiklar av en kvalitativ design. Genom sökorden demens, tidig diagnos, närstående samt upplevelser tillsammans med varianter av dessa begrepp, genomfördes sökningar i PubMed och CINAHL. Artiklarna sammanställdes därefter i en integrerad dataanalys. Resultat Utifrån de 16 artiklarna i litteraturöversikten framkom ett resultat som indikerade på att närstående upplevde svårigheter i vardagen, redan från tiden innan diagnostiseringen av en tidig demenssjukdom. I samband med att demenssjukdomen fortskred skapades nya varianter av roller och relationer. Dessa förändringar i livet påverkade på sikt ekonomin såväl som det sociala livet negativt. På det emotionella planet fanns rädslor som främst grundade sig i det otänkbara, att förlora någon i sin närhet för att senare fortsätta att leva på egen hand. Närstående upplevde även att tillgänglig information till personer som berörs av just en tidigt debuterande demenssjukdom var otillräcklig. Slutsats Brist på tillgänglig information minskade närståendes möjligheter till att hantera vardagen samt att få rätt sorts hjälp och stöd. Detta skapar svårigheter för närstående att hantera och uppleva meningsfullhet i livet tillsammans med personen med tidigt debuterande demenssjukdom. Mer kunskap hos personal inom vården behövs för att kunna ge ett personcentrerat stöd. / Background  The experiences of close family and friends to a person with a diagnosis of early-onset dementia can differ from the experiences the close family and friends has when it comes to a late onset dementia. An early-onset dementia diagnosis, unlike an onset after the age of 65, means that there is a bigger risk that relatives of a younger age are affected. There is a need for increased knowledge about the experiences of close family and friends, to make their lives easier after the diagnosis of early-onset dementia. Aim The aim of this study was to describe close families and friends’ experiences of living with a person with early-onset dementia. Method A non-systematic literature review was done based on articles of a qualitative design. Through the keywords dementia, early diagnosis, relatives and experience together with versions of these concepts, searches were conducted in PubMed and CINAHL. The articles were then compiled in an integrated data analysis. Results From the 16 articles in this literature review a result emerged that indicated that the family and friends experienced difficulties in everyday life, beginning even before the diagnosis of early-onset dementia. In connection to the progress of the dementia disease, new versions of roles and relations were formed. These changes in life eventually affected both the economy as well as the social life negatively. On the emotional level there were fears mainly based on the unthinkable, to lose someone standing close to oneself and to have to continue living life alone. Family and friends also experienced that the information available for the people affected by an early-onset dementia was insufficient. Conclusions  Lack of available information reduced the family and friends’ possibilities to cope with everyday life and to get the right kind of help and support. This creates difficulties for the family and friends to both cope with and experience meaningfulness in life together with the person with an early-onset dementia. More knowledge among care personnel is needed to be able to give person-centered care.

Alzheimer’s disease (AD) is a multifactorial neurological condition associated with genetic profiles that are still not completely understood. We performed a family-based low-density genome-wide association analysis of age at onset (AAO) in AD (244 patients and their relatives) using Illumina 6 K single-nucleotide polymorphisms (SNPs) panel and the FBAT-logrank statistic. We observed 10 SNPs associated with AAO in AD with p < 2 × 10−3. The most significant hit within a known gene, the neuronal protein astrotactin 2 (ASTN2), was SNP rs1334071 (p = 8.74 × 10−4). ASTN2 has been implicated in several neuropsychiatric disorders, including cognitive disorders, autism and schizophrenia. We then conducted a replication study focusing on ASTN2 gene in a Canadian sample of 791 AD patients and 782 controls using the logrank test. Five ASTN2 SNPs (highest association is rs16933774 with p = 0.0053) showed associations with AAO in this Canadian sample (p < 0.05). Furthermore, Kaplan–Meier survival analysis of SNP rs16933774 showed that the AAO of AD in individuals heterozygous for AG genotype of rs16933774 (median of AAO = 68.5 years) was approximately 4.5 years earlier than those individuals having the AA genotype (median of AAO = 73 years). In conclusion, a significant association of ASTN2 genetic variants with AAO of AD in two independent samples demonstrates a role for ASTN2 in the pathogenesis of AD. Future functional studies of this gene may help to characterize the genetic architecture of the AAO of AD. Genetic factors in AAO may be a critical factor for early AD intervention and prevention efforts.

The Neuregulin 3 (NRG3) gene at 10q22-q24 has been implicated in multiple psychiatric traits such as cognitive impairment. We therefore hypothesized that NRG3 gene polymorphisms may play a role in Alzheimer disease (AD). This present study explored the association of NRG3 with the age at onset (AAO) of AD and the risk of developing AD. Secondary data analysis of 257 single-nucleotide polymorphisms (SNPs) in NRG3 gene was performed in 806 Alzheimer's disease patients and 782 controls using logistic regression and linear regression analyses. Eight SNPs were associated with the risk of AD (p < 0.05), while linear regression analysis showed 33 SNPs associated with the AAO of AD (p < 0.05). Two-SNP haplotype analyses based on UNPHASED revealed that the G-C haplotype from rs17685233 and rs17101017 was significantly associated with AD (p = 0.0031) and the A-G haplotype from rs504522 and rs474018 as well as the A-G haplotype from rs504522 and rs2483295 were more significantly associated with the AAO of AD (p = 6.72 × 10-5). Using an independent family-based sample, we found one SNP rs11192423 associated with AAO both in the case-control sample (p = 0.0155) and in the family sample (p = 0.0166). In addition, we observed nominally significant associations with AD and AAO for several flanking SNPs (p < 0.05). This is the first study demonstrating that genetic variants in the NRG3 gene play a role in AD. Our results also revealed that SNPs in the NRG3 genes were more strongly associated with AAO of AD.

We performed a genome-wide association analysis to identify genetic variants influencing age at onset (AAO) and examine gene×gender interactions for AAO in schizophrenia (SCZ) using a European-American sample (1,162 cases). Linear regression model in PLINK was used to test for associations with AAO while the GxE option was chosen to test for the influence of gene×gender interactions. The most significant association with AAO was observed with SNP rs7819815 (P=3.10×10-7) at 8q24.22. The next best signal was at 4q25 in COL25A1 gene (rs17039583, P=4.30×10-6) and the third region was at 4p16.1 (rs17407555, P=4.56×10-6, near RAF1P1, and rs4697924, P=1.23×10-5 within WDR1 gene). Conditional analysis on chromosome 4 indicated that 4p16.1 and 4q25 loci were independent. Furthermore, 2 SNPs (rs16834822 and rs16834824) at 1q43 in RYR2 showed strong associations in the female sample (P=2.10×10-6 and 2.33×10-6, respectively) and strong gene×gender interactions in influencing AAO (P=9.23×10-7 and 1.15×10-6, respectively) while the second best region showing gene×gender interaction was at 7q22.3 (rs179863, P=2.33×10-6). Using an independent sample of 1,068 cases, we could not replicate the associations for above top SNPs; however, we found nominal significance associations for their flanking SNPs (P<0.05). These findings provide evidence of several genetic variants influencing AAO of SCZ.

The MAPT gene has been shown to be associated with several neurodegenerative disorders, including forms of parkinsonism and Parkinson disease (PD), but the results reveal population differences. We investigated the association of 10 single-nucleotide polymorphisms (SNPs) in the region of MAPT on chromosome 17q21 with PD and age at onset, by using 443 discordant sib pairs in PD from a public dataset (Mayo-Perlegen LEAPS Collaboration). Association with PD was assessed by the FBAT using generalized estimating equations (FBAT-GEE), while the association with age at onset as a quantitative trait was evaluated using the FBAT-logrank statistic. Five SNPs were significantly associated with PD (P < 0.05) in an additive model, and 9 SNPs were associated with PD (P < 0.05) in dominant and recessive models. Interestingly, 8 PD-associated SNPs were also associated with age at onset of PD (P < 0.05) in dominant and recessive models. The SNP most significantly associated with PD and age at onset was rs17649641 (P = 0.015 and 0.021, respectively). Two-SNP haplotypes inferred from rs17563965 and rs17649641 also showed association with PD (P = 0.018) and age at onset (P = 0.026). These results provide further support for the role of MAPT in development of PD.

Although multiple susceptibility loci for late-onset Alzheimer's disease (LOAD) have been identified, a large portion of the genetic risk for this disease remains unexplained. LOAD risk may be associated with single-nucleotide polymorphisms responsible for changes in gene expression (eSNPs). To detect eSNPs associated with LOAD, we integrated data from LOAD genome-wide association studies and expression quantitative trait loci using Sherlock (a Bayesian statistical method). We identified a cis-regulatory eSNP (rs2927438) located on chromosome 19q13.32, for which subsequent analyses confirmed the association with both LOAD risk and the expression level of several nearby genes. Importantly, rs2927438 may represent an APOE-independent LOAD eSNP according to the weak linkage disequilibrium of rs2927438 with the 2 polymorphisms (rs7412 and rs429358) defining the APOE-ε2, -ε3, and -ε4 alleles. Furthermore, rs2927438 does not influence chromatin interaction events at the APOE locus or cis-regulation of APOE expression. Further exploratory analysis revealed that rs2927438 is significantly associated with tau levels in the cerebrospinal fluid. Our findings suggest that rs2927438 may confer APOE-independent risk for LOAD.

The human receptor-type protein-tyrosine phosphatase kappa (PTPRK) gene is highly expressed in human brain and was previously associated with an increased risk of neuropsychiatric disorders and cancer. This study investigated the association of 52 single nucleotide polymorphisms (SNPs) in PTPRK with the risk and age at onset (AAO) of Alzheimer's disease (AD) in 791 AD patients and 782 controls. Our data analysis showed that five SNPs (top SNP rs4895829 with p = 0.0125) were associated with the risk of AD based on a multiple logistic regression (p < 0.05); while six SNPs (top SNP rs1891150 with p = 8.02 × 10−6) were associated with AAO by using a multiple linear regression analysis. Interestingly, rs2326681 was associated with both the risk and AAO of AD (p = 4.65 × 10−2 and 5.18 × 10−3, respectively). In a replication study, the results from family-based association test - generalized estimating equation (GEE) statistics and Wilcoxon test showed that seven SNPs were associated with the risk of AD (top SNP rs11756545 with p = 1.02 × 10−2) and 12 SNPs were associated with the AAO (top SNP rs11966128 with p = 1.39 × 10−4), respectively. One additional sample showed that four SNPs were associated with risk of cancer (top SNP rs1339197 with p = 4.1 × 10−3), 12 SNPs associated with LDL-cholesterol (top SNP rs4544930 with p = 3.47 × 10−3), and eight SNPs associated with total cholesterol (top SNP rs1012049 with p = 6.09 × 10−3). In addition, the AD associated rs4895829 was associated with the gene expression level in the cerebellum (p = 7.3 × 10−5). The present study is the first study providing evidence of several genetic variants within the PTPRK gene associated with the risk and AAO of AD, risk of cancer, LDL and total cholesterol levels.

The neuron navigator 2 (NAV2) gene is highly expressed in brain and involved in the nervous system development and may play a role in Alzheimer's disease (AD). We aimed to investigate the associations of 317 single-nucleotide polymorphisms (SNPs) in the NAV2 gene with the risk and age at onset (AAO) of AD using a family-based sample (1266 AD cases and 1279 healthy relatives). Association with the risk of AD was assessed using family-based association test -generalized estimating equations (FBAT- GEE) statistics while the association with AAO as a quantitative trait was evaluated using the FBAT-Wilcoxon statistic. Single marker analysis showed that 20 SNPs were significantly associated with the risk of AD (top SNP rs7112354 with p = 8.46 × 10− 4) and 11 SNPs were associated with AAO (top SNP rs1354269 with p = 2.87 × 10− 3). Interestingly, two SNPs rs17614100 and rs12364788 were associated with both the risk (p = 1.7 × 10− 2 and 2.71 × 10− 2; respectively) and AAO (p = 1.85 × 10− 3 and 6.06 × 10− 3; respectively). Haplotype analyses further supported the results of single marker analyses. In addition, functional analysis showed that NAV2 mRNA had significant expression across ten human brain regions examined and significantly correlated with APOE expression in four of ten regions. The present study is the first study providing evidence of several genetic variants within the NAV2 gene influencing the risk and AAO of AD.