Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic potentially life-threatening complication of assisted reproduction techniques (ART). It is caused by an increased sensitivity of ovaries to gonadotropins administered during the controlled ovarian hyperstimulation (COH). Thus, the degree of ovarian response can be gently tuned by genetic polymorphisms of gonadotropins and their receptors. The aim of this study is to ascertain the prevalence of polymorphisms Asn291Ser (rs1470652), Ser312Asn (rs2293275) and insLQ (insertion of leucine and glutamine, rs58356637) in the luteinizing hormone chorionic gonadotropin receptor (LHCGR) gene in 102 Czech fertile men, 149 fertile women and 58 patients with serious grade of OHSS. Detection of the Asn291Ser and Ser312Asn polymorphisms was performed using TaqMan SNP Genotyping Assays. The insLQ variation was detected by the capillary electrophoresis with fluorescence-labeled primers. This study ascertained the prevalence of studied variants in Czech fertile population. Obtained results are in concordance with the majority of data from other European populations. There is no difference in prevalence between control-men and control-women. No relation to the development of OHSS was disclosed. The number of analyzed samples is too small for haplotype analysis. These...

In 1981, no representative study of the medical and social conditions among elderly persons in northern Scandinavia was performed. Nor was there such a study in a smaller Swedish town than Gothenburg. This study was initiated to fill that knowledge gap. The aim of the study was to evaluate gender and age differences in medical and social conditions among elderly people, including the reference intervals of clinical chemistry parameters and characteristic features of the 24-hour electrocardiogram (ECG) in healthy elderly. By way of longitudinal design with birth cohorts stratified by gender, it was assumed that the effects could be demonstrated. Also, the death risk of various social and medical variables was to be assessed. During the study period 1981 to 1990, the subjects were between 70 and 88 years of age. The proportion of persons living in private housing decreased from almost all at the age of 70 to slightly more than half at 88 years of age. The number of socially active persons decreased considerably during the period. The need of help increased from almost none to 60 % of the persons. The proportions of persons with normal sight and hearing decreased from two thirds to around one tenth The most frequent symptoms were general tiredness, pains, dyspnoea, constipation and dryness of the mouth. Cardiovascular diseases were the most frequent. Hypertensive disease became less, and congestive heart failure more frequent with age. The frequency of dementia increased steeply among the oldest persons; at 88 years of age, 40 % were demented. Drug consumption increased; the oldest persons in both age cohorts used 5 different drugs or more per person regularly. The consumption increase was mainly due to the increasing morbidity accompanying age. The most common drugs taken were cardiovascular preparations, psychoactive agents, drugs to alleviate gastrointestinal symptoms, and analgesics. Drug intake and symptom prevalence were generally higher in women, despite the fact that there was no gender difference in the number of diseases. The reference intervals of many blood components in healthy elderly were shown to be broader than those of younger persons. The intervals of P(lasma)-folate and P- potassium were on a lower and those of the erythrocyte sedimentation rate, P-creati- nine and, in women, S(erum)-cholesterol, were on a higher level than among younger persons. Several features of the 24-hour ECG, e.g. the number of episodes of supraventricular tachycardia as well as supraventricular and ventricular premature beats in healthy elderly were more frequent than among younger persons. Between 80 and 88 years of age, many functions crucial to the chances of living a rich and vital life were found deteriorating in the elderly persons. High age, male sex, dementia, congestive heart failure, and low values of S-creatinine were shown to be independent factors connected with an increased death risk. / <p>S. 1-112: sammanfattning, s. 115-177: 5 uppsatser</p> / digitalisering@umu.se

Nowadays intensive research is conducted for application of genetic polymorphisms for degraded samples analysis, identification and kinship determination. Another area of research in forensic genetics is biogeographical and phenotypic traits (eye, hair and skin color) determination. First part of presented work dealt with population study on the Czech popu- lation using Investigator DIPplex (QIAGEN, Germany) marker set containing 30 autosomal insertion-deletion polymorphisms. Power of Discrimination (PD), which is the probability of random selection of two persons with different genotypes, was 99.9999999999% for the whole marker set. This part of study concluded that ana- lyzed marker set is suitable as an additional marker panel for identification and kinship determination in the Czech Republic. Second part of the presented study was devoted to population research of Cen- tral Croatia using Mentype Argus X-8 kit (QIAGEN, Germany) containing 8 short tandem repeat polymorhisms located on X choromosomes (X-STR) divided into 4 linkage groups. PD for the whole kit reached 99.9999% and 99.99999999% for males and females, respectively. This kit could be used in Central Croatian population for kinship analysis and for identification as an additional marker panel. The next part of the presented study was the...

L’objectif principal de l’étude était d’identifier les principaux médicaments associés aux hépatites aiguës (HA) associé aux médicaments (HAM) en France. Trois approches méthodologiques ont été définies. L’approche méthodologique principale est l’analyse cas-population. Les autres approches sont cas-propre témoin et cas témoins.Les cas ont été identifiés parmi les patients adultes présents dans le SNIIRAM, ayant une première hospitalisation entre 01/01/2010-31/12/2014 dont le diagnostic principal est une atteinte hépatique toxique (Classification Internationale des Maladies (CIM-10) K71.1, K71.2, K71.6, K71.9) ou une insuffisance hépatique(CIM-10 K72.0). La population de référence a été définie à partir de l’EGB. La date index (DI) considérée est la date de première hospitalisation pour HA. Les délivrances de l’ensemble des traitements précédant la DI ont été étudiées en considérant une exposition variant de 7 à 60 jours avant la DI. Les produits les plus fréquemment retrouvés sont classiques: antalgiques et en premier lieu le paracétamol, puis les produits à visée digestive symptomatique (inhibiteur de la pompe à protons, prokinétique, antispasmodique). Les suivants sont l’amoxicilline seule ou associée à l’acide clavulanique, l’ibuprofène, la codéine associée et le furosémide. L’ensemble de ces résultats pourra informer les autorités sanitaires, les praticiens et les patients sur le risque associé à chacune de ces molécules tant au plan individuel (risque absolu, risque attribuable), qu’au sein d’une famille de produits(risque relatif) ainsi que plus globalement pour la population et le système de santé(nombre absolu de cas attribuables). / The main objective of EPIHAM study is to identify the main drugs associated with drug induced liver injury leading to hospital admission (DILIH) in France and the event rates associated with DILIH. Three methodological approaches were defined. Principal approach is case-population. The others are case-crossover and case control analyses. Cases were identified among adult patients present in SNIIRAM database having a first hospitalization between 01/01/2010-2010/31/12/1204, the main diagnosis of which is toxic liver disease (diagnostic codes according to the International Classification of Diseases (ICD-10) K71.1, K71.2, K71.6, K71.9) orK72.0. Reference population was defined from the EGB. Index date (ID) was considered as the date of hospital admission for DILI. The dispensations of all treatments preceding the ID were studied by considering an exposure windowvarying from 7 to 60 days before ID. The most frequently found are classical: analgesics and firstly paracetamol, followed by drugs acting on digestive system (proton pump inhibitors, prokinetics, antispasmodics). The following were amoxicillinalone or combined with clavulanic acid, ibuprofen, codeine combinations, and furosemide. These results can inform health authorities, practitioners and patients about the acute hepatitis risk leading to hospitalisation associated with each of these molecules, both individually (absolute risk, attributable risk) and within a therapeutic drug family (relative risk) as well as more generally for the population and the health system (absolute number of attributable cases).

The purpose of this study is the development of an educational simulation game for use in college classes. The simulation game is based on selected aspects of the population problem. The panel approved or rejected objectives on the basis of their significance as goals for college students. Twelve objectives were approved by a majority of the panel. Upon completion of the exercise, students should be able to compute population increases, to predict population sizes, and to identify birth and death rates that cause a population to increase, decrease, or remain stable. Students should also be able to describe how the following factors affect population size: cultural and religious beliefs, pressure for economic growth, investments of capital, and financial losses. Students should understand the problems of governing a country with a rapidly growing population as compared to problems in governing a country with slower population growth, and they should recognize how rapid population growth can affect the quality of life. Students should recognize decreased birth rates, increased death rates, and increased economic production as possible solutions to the population problem. Finally, students should personalize the population problem and make commitments in seeking and participating in its solutions.

Under många år har det förekommit individer inom hälsovården som klagar på somatiska besvär. Ett koncept som förekommer för att kunna beskriva en underliggande mekanism är somatisering som innebär t ex trötthet och smärta i muskler. Dessa somatiska besvär kan orsakas av mentala hälsofaktorer som till exempel utbrändhet och ångest. I studien testades hypotesen att depression, ångest, utbrändhet och sömnproblem är relaterade till somatisering, och vidare undersöktes frågan i vilken utsträckning var och en av dessa fyra mentala hälsofaktorerna unikt förklarar grad av somatisering. För detta användes data från Västerbottens miljöhälsostudie som är en befolkningsstudie. Totalt deltog 3406 individer i studien, och av dessa var 1898 kvinnor och 1508 män mellan 18 och 79 år. Fyra separata multipla regressionsanalyser genomfördes för ångest, utbrändhet, depression och insomni samt en multipel regressionsanalys som inkluderade alla fyra mentala hälsofaktorer. Resultaten visade att alla fyra mentala hälsofaktorer var för sig var associerade med somatisering. Beträffande unik förklarad varians var den standardiserade beta-koefficienten störst för utbrändhet (0,546), lägre för ångest (0,468) och sömnstörning (0,382), och lägst för depression (0,379). Tillsammans förklarade de fyra faktorerna ca 38% av variansen i somatisering. Dessa resultat talar för att de undersökta typerna av mental ohälsa, och utbrändhet i synnerhet, bör undersökas och möjligen behandlas hos personer som är höga i somatisering. / For many years, there have been individuals in healthcare who complain of somatic symptoms. One concept that exists for describing an underlying mechanism is somatization, which involves, for example, fatigue and muscle pain. These somatic complaints can be caused by mental health factors such as burnout and anxiety. The study tested the hypothesis that depression, anxiety, burnout and sleep problems are related to somatization, and further investigated the extent to which each of these four mental health factors uniquely explains the degree of somatization. For this, data from the Västerbotten Environmental Health Study was used, which is a population study. A total of 3406 individuals participated in the study, of whom 1898 were women and 1508 men between the ages 18 and 79 years. Four separate multiple regression analyzes were performed for anxiety, burnout, depression and insomnia as well as a multiple regression analysis that included all four mental health factors. The results showed that all four mental health factors were individually associated with somatization. Regarding uniquely explained variance, the standardized beta coefficient was greatest for burnout (0.546), lower for anxiety (0.468) and sleep disturbance (0.382), and lowest for depression (0.379). Together, the four factors explained about 38% of the variance in somatization. These results suggest that the types of mental illness investigated, and burnout in particular, should be investigated in healthcare and possibly treated among people who are high in somatization.

Microarray technology is a promising approach for the simultaneous analysis of multiple single nucleotide polymorphisms (SNPs), which are the most abundant form of genetic variation. In this thesis enzyme-assisted microarray-based methods were developed to improve the accuracy and genotype discrimination power of the current methods for SNP genotyping. The improved technology was applied for analysing recessively inherited disease mutations, for Y-chromosomal SNPs in a population study, for an evolutionary analysis of SNPs in flycatchers and for multiplexed quantitative determination of SNP-allele frequencies in pooled DNA samples. A robust attachment chemistry for immobilising oligonucleotides on glass surface was established, based on an evaluation of eight covalent coupling methods. A four-colour fluorescence detection strategy, which enabled a multiplexed quantitative analysis for as little as 2% of a minority allele frequency in pooled samples was generated. Twenty-five Y-chromosomal SNPs were screened in a collection of 300 samples from five Finno-Ugric-speaking populations using minisequencing on microarrays. In these populations six distinct haplotypes were defined by the six SNPs that were polymorphic. Data from five microsatellite markers was combined with the SNP data, revealing shared Y-chromosomal haplotypes between the Finns and the Saami, indicating, in accordance with earlier data, at least two founding Y-chromosomal lineages in these populations. Database screening and subsequent validation of 125 potential SNPs in the highly repetitive type 1 interferon genes and genes coding for proteins in the interferon-related regulatory pathways revealed 25 informative SNPs in the Finnish and Swedish populations. These SNPs were included in a panel for microarray based genotyping that should find a variety of applications in genetic studies due to the important immunoregulatory functions of the IFN family. The significance of sex-chromosome evolution on speciation was investigated in two naturally hybridising flycatcher species (N=459) by analysing a panel of 20 SNPs using minisequencing on microarrays. A strong selection against gene flow across the species boundary of sex-linked genes was observed, as well as a sex-chromosomal influence on male plumage characteristics that have previously been shown to reinforce isolation in these birds. The results suggest a major role for sex-chromosome-mediated isolation of the two flycatcher species.

A automedicação retrata o princípio do próprio indivíduo buscar espontaneamente por algum medicamento, que considere adequado para resolver um problema de saúde. Esta prática, ainda, é pouco explorada em idosos, principalmente a partir de dados populacionais. Desse modo, o objetivo do presente estudo foi analisar a pratica de automedicação em idosos no Município de São Paulo. Trata-se de um estudo transversal, de base populacional, cujos dados foram obtidos do Estudo SABE - Saúde, Bem-estar e Envelhecimento. A amostra foi constituída de 1.257 idosos que utilizaram medicamentos com idade de 60 anos e mais. Para coleta de informações utilizaram-se as seções do questionário sobre Informações pessoais (A), Estado de saúde (C), Medicamento (E), Uso e Acesso a serviços (F) e Historia de trabalho e fontes de renda (H). Os medicamentos consumidos na automedicação foram classificados de acordo com a Anatomical Therapeutical Chemical Classification System (ATC). Na análise dos dados utilizou-se o pacote estatístico STATA com realização de regressão logística. Considerou-se nível de significância de p<0,05. A prevalência de automedicação foi de 42,3%. Entre os medicamentos mais usados estão os analgésicos/antiinflamatórios (40,0%) e vitaminas (8,7%). No grupo de idosos que usou automedicação 45,0% pertenciam ao sexo feminino, 44,4% apresentaram 60 a 74 anos, 46,2% utilizaram o serviço público de saúde, 50,8% não consultaram o médico nos últimos 12 meses, 48,4% consumiram cinco ou mais medicamentos e 50,7% relataram não possuir doenças cronicas. O idoso foi o principal responsável pela indicação da automedicação (65%). Na análise múltipla, observou-se que empregar cinco ou mais medicamentos (OR=1,75) e possuir baixa escolaridade aumentou a chance dos idosos usarem a automedicação e possuir plano de saúde privado (OR=0,72), ter uma e mais doenças (OR=0,57) e idade igual ou superior a 75 anos (OR=0,69) diminuiu a chance de usar a automedicação. As intervenções educativas com o objetivo de reduzir a automedicação na população geriátrica devem contemplar, especialmente os usuários de polifarmácia, aqueles com baixa escolaridade e indivíduos na faixa etária dos 60 74 anos, tendo em vista que o próprio idoso é o principal responsável pela decisão de praticar a automedicação. / Self-medication depicts the principle of the individual seeking spontaneously by some drug, which it deems appropriate to resolve a health problem. This practice, though, is little explored in the elderly, primarily using population data. Thus, the objective of this study was to analyze self-medication in the elderly in São Paulo. It is a cross-sectional, population-based, whose data were obtained from the SABE Study - Health, Welfare and Ageing. The sample consisted of 1,257 seniors who used drugs at the age of 60 years and more. To collect the information we used sections of the questionnaire on personal information (A) Health status (C), drug (E), Use and Access to services (F) and work history and income sources (H). The drugs used in self-medication were classified according to the Anatomical Therapeutic Chemical Classification System (ATC). In the data analysis used the STATA statistical package with performance of logistic regression. It was considered a significance level of p <0.05. The prevalence of self-medication was 42,3%. Among the most commonly used drugs are analgesics, anti-inflammatory drugs (40.0%) and vitamins (8.7%). In the elderly group that used self-medication 45.5% were female, 44.4% had 60 to 74 years, 50.8% did not consult the doctor in the last twelve months, 46.2% used public insurance, 48,4% used five or more drugs and 50.7% reported not having chronic diseases. The senior was the main responsible for the appointment of self-medication (65%). In the multivariate analysis, we observed that employ five or more medications (OR = 1.75) and have low education increased the likelihood of using self-medication and the elderly have private health insurance (OR = 0.72), and have a more diseases (OR = 0.57) and age less than 75 years (OR = 0.69) decreased the chance of using self-medication. Educational interventions aimed at reducing self-medication should include in the geriatric population, especially those using polypharmacy, those with low education and individuals aged 60 to 74 years, given that the elderly person is mainly responsible for the decision to practice self-medication.

In the development process of novel cancer drugs, one important aspect is to identify patient populations with a high risk of early death so that resources can be focused on patients with the highest medical unmet need. Many cancer types are heterogeneous and there is a need to identify patients with aggressive diseases, meaning a high risk of early death, compared to patients with indolent diseases, meaning a low risk of early death. Predictive modeling can be a useful tool for risk stratification in clinical practice, enabling healthcare providers to treat high-risk patients early and progressively, while applying a less aggressive watch-and-wait strategy for patients with a lower risk of death. This is important from a clinical perspective, but also a health economic perspective since society has limited resources, and costly drugs should be given to patients that can benefit the most from a specific treatment. Thus, the goal of predictive modeling is to ensure that the right patient will have access to the right drug at the right time. In the era of personalized medicine, Artificial Intelligence (AI) applied to high-quality data will most likely play an important role and many techniques have been developed. In particular, Graph Neural Network (GNN) is a promising tool since it captures the complexity of high dimensional data modeled as a graph. In this work, we have applied Network Representation Learning (NRL) techniques to predict survival, using pseudonymized patient-level data from national health registries in Sweden. Over the last decade, more health data of increased complexity has become available for research, and therefore precision medicine could take advantage of this trend by bringing better healthcare to the patients. However, it is important to develop reliable prediction models that not only show high performances but take into consideration privacy, avoiding any leakage of personal information. The present study contributes novel insights related to GNN performance in different survival prediction tasks, using population-based unique nationwide data. Furthermore, we also explored how privacy methods impact the performance of the models when applied to the same dataset. We conducted a set of experiments across 6 dataset using 8 models measuring both AUC, Precision and Recall. Our evaluation results show that Graph Neural Networks were able to reach accuracy performance close to the models used in clinical practice and constantly outperformed, by at least 4.5%, the traditional machine learning methods. Furthermore, the study demonstrated how graph modeling, when applied based on knowledge from clinical experts, performed well and showed high resiliency to the noise introduced for privacy preservation. / I utvecklingsprocessen för nya cancerläkemedel är en viktig aspekt att identifiera patientgrupper med hög risk för tidig död, så att resurser kan fokuseras på patientgrupper med störst medicinskt behov. Många cancertyper är heterogena och det finns ett behov av att identifiera patienter med aggressiv sjukdom, vilket innebär en hög risk för tidig död, jämfört med patienter med indolenta sjukdom, vilket innebär lägre risk för tidig död. Prediktiv modellering kan vara ett användbart verktyg för riskstratifiering i klinisk praxis, vilket gör det möjligt för vårdgivare att behandla patienter olika utifrån individuella behov. Detta är viktigt ur ett kliniskt perspektiv, men också ur ett hälsoekonomiskt perspektiv eftersom samhället har begränsade resurser och kostsamma läkemedel bör ges till de patienter som har störst nytta av en viss behandling. Målet med prediktiv modellering är således att möjliggöra att rätt patient får tillgång till rätt läkemedel vid rätt tidpunkt. Framför allt är Graph Neural Network (GNN) ett lovande verktyg eftersom det fångar komplexiteten hos högdimensionella data som modelleras som ett diagram. I detta arbete har vi tillämpat tekniker för inlärning av grafrepresentationer för att prediktera överlevnad med hjälp av pseudonymiserade data från nationella hälsoregister i Sverige. Under det senaste decennierna har mer hälsodata av ökad komplexitet blivit tillgänglig för forskning. Även om denna ökning kan bidra till utvecklingen av precisionsmedicinen är det viktigt att utveckla tillförlitliga prediktionsmodeller som tar hänsyn till patienters integritet och datasäkerhet. Den här studien kommer att bidra med nya insikter om GNNs prestanda i prediktiva överlevnadsmodeller, med hjälp av populations -baserade data. Dessutom har vi också undersökt hur integritetsmetoder påverkar modellernas prestanda när de tillämpas på samma dataset. Sammanfattningsvis, Graph Neural Network kan uppnå noggrannhets -prestanda som ligger nära de modeller som tidigare använts i klinisk praxis och i denna studie preserade de alltid bättre än traditionella maskininlärnings -metoder. Studien visisade vidare hur grafmodellering som utförs i samarbete med kliniska experter kan vara effektiva mot det brus som införs av olika integritetsskyddstekniker.

<p>Microarray technology is a promising approach for the simultaneous analysis of multiple single nucleotide polymorphisms (SNPs), which are the most abundant form of genetic variation. In this thesis enzyme-assisted microarray-based methods were developed to improve the accuracy and genotype discrimination power of the current methods for SNP genotyping. The improved technology was applied for analysing recessively inherited disease mutations, for Y-chromosomal SNPs in a population study, for an evolutionary analysis of SNPs in flycatchers and for multiplexed quantitative determination of SNP-allele frequencies in pooled DNA samples. </p><p>A robust attachment chemistry for immobilising oligonucleotides on glass surface was established, based on an evaluation of eight covalent coupling methods. A four-colour fluorescence detection strategy, which enabled a multiplexed quantitative analysis for as little as 2% of a minority allele frequency in pooled samples was generated. </p><p>Twenty-five Y-chromosomal SNPs were screened in a collection of 300 samples from five Finno-Ugric-speaking populations using minisequencing on microarrays. In these populations six distinct haplotypes were defined by the six SNPs that were polymorphic. Data from five microsatellite markers was combined with the SNP data, revealing shared Y-chromosomal haplotypes between the Finns and the Saami, indicating, in accordance with earlier data, at least two founding Y-chromosomal lineages in these populations.</p><p>Database screening and subsequent validation of 125 potential SNPs in the highly repetitive type 1 interferon genes and genes coding for proteins in the interferon-related regulatory pathways revealed 25 informative SNPs in the Finnish and Swedish populations. These SNPs were included in a panel for microarray based genotyping that should find a variety of applications in genetic studies due to the important immunoregulatory functions of the IFN family.</p><p>The significance of sex-chromosome evolution on speciation was investigated in two naturally hybridising flycatcher species (N=459) by analysing a panel of 20 SNPs using minisequencing on microarrays. A strong selection against gene flow across the species boundary of sex-linked genes was observed, as well as a sex-chromosomal influence on male plumage characteristics that have previously been shown to reinforce isolation in these birds. The results suggest a major role for sex-chromosome-mediated isolation of the two flycatcher species.</p>