Dissertations / Theses on the topic 'Population-based birth cohort studies'

Abstract Somatization is a widespread phenomenon causing subjective suffering and disability. The aim of the study was to assess somatization disorder (SD) and somatization symptoms among young adult population and their associations with sociodemographic factors, alexithymia and temperament as well as psychiatric comorbidity. Various suggestions have been presented to operationalize somatization but none of them has been shown to be superior to others. In this study two definitions were used: SD by DSM-III-R classification diagnostic criteria and "somatization" meaning four or more symptoms of the 35 symptoms of DSM-III-R SD criteria. The study population was a subsample of the Northern Finland Birth Cohort 1966 (NFBC 1966), consisting of cohort members living in Oulu (N = 1,609) on January 1st 1997. The NFBC 1966 is a general population birth cohort of 12,058 live-born children covering 96.3% of all deliveries in the catchment area. The best-estimated procedure was used for assessment of psychiatric morbidity including SD and somatization. Data were collected from the Finnish Hospital Discharge Register and from all available outpatient and inpatient records. Data on education were gathered from Statistics Finland. Other sociodemographic variables, alexithymia and temperament scores were drawn from questionnaires of the field study conducted in 1997 and from earlier follow-up studies. The prevalence of SD was 1.1% (N = 18). Of the subjects 6.1% (N = 97) had somatization. The female-to-male ratio was 5:1 and 6:1, respectively. SD was not recognized by any of the treating physicians, at least not documented in case notes. The observed occurrences of SD and somatization were at a level comparable with earlier international population studies. Somatization did not associate with depression or alexithymia, and neither could a characteristic temperament profile be recognized. Somatization was associated with psychological distress. These results indicate a need for training physicians to recognize SD and somatization and its comorbidity. This will have implications both for psychiatry and other medical specialties regarding collaboration and underlines the importance of liaison-psychiatry at general hospitals. The results suggest a need for more studies about the etiology and development of SD and somatization
Tiivistelmä Somatisaatio on yleinen ilmiö, josta aiheutuu subjektiivista kärsimystä ja toimintakyvyn laskua. Tämän tutkimuksen tarkoitus oli arvioida somatisaatiohäiriön ja somatisaatio-oireilun yleisyyttä nuorilla aikuisilla sekä näiden ilmiöiden yhteyttä sosiodemografisiin tekijöihin, aleksitymiaan, temperamenttiin ja psykiatriseen sairastavuuteen. Somatisaation käsitteellistämiseksi on esitetty useita vaihtoehtoja mutta mikään niistä ei ole osoittautunut muita paremmaksi. Tässä tutkimuksessa käytetiin kahta määritelmää: DSM-III-R -diagnoosiluokituksen mukaista somatisaatiohäiriön diagnoosia tai somatisaatio-oireilua, jossa esiintyy neljä tai useampia DSM-III-R:n 35 somatisaatiohäiriön oireesta. Tutkimusaineiston muodostivat Pohjois-Suomen vuoden 1966 syntymäkohortin ne jäsenet, jotka asuivat Oulussa 1. tammikuuta 1997 (N = 1,609). Alkuperäinen kohortti koostuu 12,058 elävänä syntyneestä tutkittavasta, mikä kattaa 96.3 % kaikista synnytyksistä Pohjois-Suomessa. Niin kutsutun best-estimated -menettelyn avulla arvioitiin tutkittavien psykiatrista sairastavuutta mukaan lukien somatisaatiohäiriö ja -oireilu. Tietoa kerättiin sairaaloiden poistoilmoitusrekisteristä. Avohoidon sairauskertomustieto koottiin kattavasti. Koulutusasteesta saatiin tieto Tilastokeskukselta. Muita sosiodemografisia tekijöitä, aleksitymiaa ja temperamenttia arvioitiin vuoden 1997 kenttätutkimuksen ja aiempien seurantatutkimusten tietojen avulla. Somatisaatiohäiriön esiintyvyys oli 1.1 % (N = 18). Somatisaatio-oireita todettiin 6.1 % (N = 97) tutkittavista. Naisten osuus oli somatisaatiohäiriössä 5:1 ja somatisaatio-oireilussa 6:1. Osoittautui, että lääkärit eivät tunnistaneet somatisaatiohäiriötä, ainakaan sitä ei oltu kirjattu sairauskertomuksiin. Havaitut somatisaatiohäiriön ja -oireilun esiintyvyydet ovat sopusoinnussa aiempien kansainvälisten tutkimusten kanssa. Somatisaatio-oireilu ei liittynyt masennukseen tai aleksitymiaan eikä somatisaatio-oireilusta kärsiville tutkittavilla todettu tyypillistä temperamenttiprofiilia. Somatisaatio liittyi psyykkiseen stressiin. Johtopäätöksenä voidaan todeta, että lääkäreille tulisi tarjota koulutusta somatisaatiohäiriön ja -oireilun tunnistamisessa. On tärkeää tunnistaa somatisaatio ja siihen liittyvä oheissairastavuus. Havainnot korostavat yleissairaaloiden yhteistyöpsykiatrian ja muiden erikoisalojen yhteistyön merkitystä somatisaatiosta kärsivien potilaiden tutkimuksessa ja hoidossa. Somatisaatiohäiriön ja -oireilun etiologian ja kehittymisen selvittämiseksi tarvitaan uusia tutkimuksia

[Truncated abstract] Asthma is a chronic and complex disorder and despite our increase in the understanding of the genetics, pathology and mechanisms underlying asthma a gold standard definition of asthma does not exist. A criterion for recognising and diagnosing asthma in epidemiological studies is crucial in order to determine risk factors for disease. Prospective longitudinal birth cohort studies have increased our understanding of the natural history and risk factors for asthma, yet we are still not able to accurately predict which children will go on to have asthma as adults. It is during the transition from childhood to adolescence where factors underlying asthma change and the prevalence of asthma shifts between the sexes. There are inconsistencies regarding risk factors for the development and persistence of disease during this transitional period. Risk factors predicting the development and persistence of asthma and intermediate phenotypes (BHR, airway inflammation and atopy) may be influenced by gender and risk factors predicting disease may differ between childhood and adolescence. Aims 1. To identify risk factors for Asthma, BHR and Atopy at 14yrs of age. 2. To determine risk factors for persistence of asthma between 6 and 14 years. 3. To examine the influence of gender on risk factors during adolescence. Method The West Australian Pregnancy Cohort is a longitudinal birth cohort. The cohort initially consisted of 2868 live births with follow-ups at 1, 2, 3, 6, 8, 10 and 14 years of V age. ... Strong associations were seen with BHR and new diagnosis of wheeze and asthma in VI teenagers. Interestingly having either a cat or dog inside was protective for persistence of disease; in particular stronger associations were seen in teenage girls not in boys. During this transitional period the risk factors for asthma and intermediate phenotypes differ between the sexes. Different mechanisms are likely to be involved in determining asthma in boys and girls during adolescence and shed new light on the recognised switch in the gender balance in asthma prevalence from the male predominance in childhood to the female predominance in adult life. Our understanding of the natural course of disease from the prenatal period to adulthood and the identification of the various asthma phenotypes has the potential to change prognosis and planning of therapeutic strategies. Identifying those at high risk for persistence of disease in the early stages of life will allow therapeutic interventions to be more appropriately targeted.

Abstract Uterine leiomyomas are the most common benign tumours in females. They are myometrial neoplasms, may present single or multiple, and may be located in various sites of the uterus. Leiomyomas distort the uterine cavity and the uterus itself, causing abnormal vaginal bleeding, reduced fertility and also pelvic pressure and pain symptoms. The aim of this study was to elaborate current knowledge on familial uterine leiomyomas and to explore the possible association between uterine leiomyoma and cardiovascular disease risk factors, and also the association between leiomyomas and endometriosis. The natural history of familial uterine leiomyoma study showed significant differences between familial and non-familial leiomyoma cases, familial cases having more severe clinical characteristics. They presented with multiple uterine leiomyomas and were more often symptomatic. They were also diagnosed at a younger age. The prevalence study on uterine leiomyomas and endometriosis offered confirmation of an association between the diseases. Uterine leiomyomas and endometriosis seem to decrease female fertility independently of each other. Uterine leiomyomas related to the hereditary leiomyomatosis and renal cell cancer (HLRCC) tumour syndrome were studied in regard to their clinical characteristics and immunophenotype. The study provided evidence that women with HLRCC may be identified through distinct leiomyoma clinical characteristics, and routine-use IHC of CD34 and Bcl-2. Distinguishing these leiomyoma cases from sporadic ones may identify families affected by fumarate hydratase (fumarase, FH) mutation. Uterine leiomyoma and cardiovascular disease risk factors were studied in The Northern Finland Birth Cohort 1966 (NFBC1966). The study showed an association between leiomyomas and raised cardiovascular disease risk factors, serum lipids and metabolic syndrome in particular. These findings may suggest that there are shared predisposing factors underlying both uterine leiomyomas and adverse metabolic and cardiac disease risks, or that metabolic factors have a role in biological mechanisms underlying leiomyoma development. This study provides novel information on clinical characteristics of familial uterine leiomyomas and on the immunophenotype of HLRCC-related leiomyomas. The study also offers significant confirmation of associations between uterine leiomyomas and both endometriosis and several CVD risk factors
Tiivistelmä Kohdun leiomyoomat ovat naisten yleisin hyvänlaatuinen kasvain. Ne ovat myometriumin neoplastisia muutoksia ja ne ilmenevät joko yksittäisinä tai monilukuisina, ja ne voivat sijaita missä tahansa kohdun myometriumia. Leiomyoomat muuttavat kohdun ja kohtuontelon säännöllistä muotoa. Lisäksi ne aiheuttavat vuotohäiriöitä, alentunutta hedelmällisyyttä, ja lantion alueen painetta ja kipua. Tämän tutkimuksen tavoitteena oli laajentaa nykyistä tietämystä suvuittain esiintyvistä kohdun leiomyoomista ja selvittää mahdollista leiomyoomien ja kardiovaskulaaritautiriskin assosiaatiota, ja lisäksi selvittää leiomyoomien ja endometrioosin assosiaatiota. Suvuittain esiintyvien kohdun leiomyoomien taudinkulkua selvittävässä tutkimuksessa osoitettiin merkittäviä eroja suvuittain ja ei-suvuittain esiintyvien leiomyoomien välillä. Suvuittain esiintyvien leiomyoomien kliininen taudinkuva oli vaikeampi, leiomyoomia oli kohdussa useampia ja ne aiheuttivat useammin oireita ja lisäksi ne diagnosoitiin nuoremmalla iällä. Kohdun leiomyoomien ja endometrioosin yleisyyttä selvittävä tutkimus antoi lisävahvistusta sille havainnolle, että nämä taudit assosioivat keskenään. Tutkimustuloksen mukaan leiomyoomat ja endometrioosi vähentävät naisen hedelmällisyyttä toisistaan riippumatta. Perinnöllinen kohdun leiomyomatoosi ja munuaissyöpä (hereditary leiomyomatosis and renal cell cancer, HLRCC) -kasvainoireyhtymään liittyvän kohdun leiomyoomia selvittävän tutkimuksen tuloksien mukaan HLRCC-naisten kohdun leiomyoomien kliiniset ominaisuudet poikkeavat satunnaisesti esiintyvien leiomyoomien ominaisuuksista. Naisella HLRCC voitaisiinkin tunnistaa näiden poikkeavien ominaisuuksien perusteella, sekä immunohistokemiallisilla värjäyksillä CD34 ja Bcl-2. Fumaraattihydrataasi (fumaraasi, FH) -geenin mutaatiota kantava suku voitaisiin siten tunnistaa yksittäisen HLRCC leiomyoomatapauksen avulla. Pohjois-Suomen syntymäkohortti 1966 (Northern Finland Birth Cohort 1966, NFBC1966) tutkittiin kohdun leiomyoomia ja kardiovaskulaarisairauden riskitekijöitä. Tutkimustuloksien perusteella kohdun leiomyoomat assosioivat koholla olevien kardiovaskulaarisairauden riskien kanssa, erityisesti seerumin lipidien ja metabolisen syndrooman suhteen. Näiden tutkimustulosten perusteella voidaan esittää, että leiomyoomien ja terveydelle epäedullisen metabolian ja kardiovaskulaaritaudin riskien taustalla on mahdollisesti joitain yhteisiä altistavia tekijöitä, tai että metabolisilla tekijöillä on rooli kohdun leiomyoomien tautimekanismissa. Tämä tutkimus on tuottanut uutta tietoa suvuittain esiintyvien kohdun leiomyoomien kliinisestä taudinkuvasta ja HLRCC:n liittyvien leiomyoomien immunofenotyypistä. Lisäksi tämä tutkimus esittää lisävahvistusta kohdun leiomyoomien ja endometrioosin assosiaatiolle sekä useille kardiovaskulaaririskitekijöille

Abstract Study samples in medical research are selected according to the objectives of the studies. Researchers seek to collect data as extensively and reliably as possible. In practice, however, data are often missing or may be incorrect. This thesis covers some of the problems concerning missing data and data collection in psychiatric research. Methods for adjusting for missing data and for evaluating the reliability of data are presented. The data originate from the Northern Finland 1966 Birth Cohort (N = 12058). This study explored how participation in an epidemiologic study that includes questionnaires and a clinical examination is affected by mental health (N = 11540), and whether non-participants experience more severe clinical symptoms than participants in a psychiatric field study (N = 145) among subjects with a psychosis. Inverse probability weighting (IPW) was used to adjust for non-participation in comparisons of brain volumes between schizophrenia and control groups. The precision of self-reported medication use was also explored (N = 7625). In an epidemiologic study of all cohort members, subjects with a psychiatric disorder participated less actively than those without one. In the psychiatric field study, non participants were more often patients with schizophrenia than other psychoses. The psychiatric symptoms of non-participants were more severe and they needed more hospital care than participants. The use of IPW led to higher estimates of cerebrospinal fluid volume and lower estimates of grey and white matter volumes in schizophrenia patients, and increased the statistical significance of the differences in brain volume estimates between the schizophrenia and control groups. The precision of self-reported data on psychoactive medication use was substantial. Due to non-participation, the true prevalence of psychiatric disorders is probably higher than the prevalence estimates from field studies that are based on data provided by participants only. In order to reflect the true differences in the target population, weighting methods can be used to improve estimates affected by non-participation. Regarding psychoactive medication use, data collected by postal questionnaire can be assumed accurate enough for study purposes. However, it may underestimate the prevalence of medication use due to non-participation
Abstract Tutkimusaineisto valitaan tutkimuksen tavoitteiden perusteella. Tavoitteena on kerätä kattava ja virheetön aineisto. Käytännössä kuitenkin osa tiedoista voi puuttua tai olla virheellistä. Tässä väitöskirjassa esitellään yleisesti menetelmiä huomioida puuttuva tieto analyyseissä ja arvioida aineistojen luotettavuutta psykiatrisessa tutkimuksessa. Aineisto perustuu Pohjois-Suomen vuoden 1966 syntymäkohorttiin (N = 12058). Väitöskirjassa tutkittiin, miten psykiatrinen sairastavuus vaikuttaa osallistumiseen epidemiologisessa tutkimuksessa, joka sisälsi kyselyitä ja terveystutkimuksen (N = 11540), sekä erosiko psykiatriseen kenttätutkimukseen osallistuneiden ja osallistumattomien psykoosipotilaiden kliininen taudinkuva toisistaan (N = 145). Käänteisen todennäköisyyden painotusmenetelmää käytettiin korjaamaan puuttuvan tiedon aiheuttamaa virhettä aivovolyymien estimaateissa skitsofreniapotilailla. Lisäksi arvioitiin itse ilmoitetun lääkekäyttötiedon luotettavuutta (N = 7625). Epidemiologisessa tutkimuksessa ne kohortin jäsenet, joilla oli jokin psykiatrinen sairaus, osallistuivat passiivisemmin kuin ne, joilla ei ollut psykiatrista sairautta. Psykoosipotilaat, jotka eivät osallistuneet psykiatriseen kenttätutkimukseen, sairastivat tutkimukseen osallistuneita useammin skitsofreniaa kuin muita psykooseja ja heidän taudinkuvansa oli vakavampi. Painottaminen kasvatti aivonesteen ja alensi harmaan ja valkean aineen tilavuuksien estimaatteja skitsofreniapotilailla, ja lisäsi aivovolyymien erojen tilastollista merkitsevyyttä skitsofreniapotilaiden ja vertailuhenkilöiden välillä. Itse ilmoitetun psykoaktiivisten lääkkeiden käyttötiedon luotettavuus oli merkittävä. Kadosta johtuen psykiatristen sairauksien todellinen vallitsevuus on todennäköisesti korkeampi kuin vallitsevuuden estimaatit, jotka on laskettu tutkimukseen osallistuneiden tiedoista. Painotusmenetelmiä voidaan käyttää parantamaan puuttuvan tiedon vääristämiä estimaatteja, koska painottamalla huomioidaan todellisia eroja kohdeväestössä. Tutkittaessa lääkekäyttötietoa postikyselyillä kerätyn aineiston voidaan olettaa olevan laadultaan riittävä tutkimustarpeisiin

In this thesis I analysed population-based data on 22955 infants enrolled in a neonatal vitamin A supplementation trial in rural Ghana to investigate whether low birth weight (LBW: born weighing <2.50kg) was a risk factor for under-vaccination. I also investigated whether under-vaccination among LBW infants was occurring within a broader context of poorer health outcomes such as increased mortality, illness and health facility admissions and lower care-seeking. I additionally investigated how using routine contacts with health services (opportunities for vaccination) could be used to improve their vaccination. Compared to non-LBW (NLBW) infants, LBW infants were less likely to be vaccinated in both the neonatal and postneonatal period. The smaller the baby at delivery the less likely they were to be vaccinated (p-trend < 0.0001). By the end of the neonatal period, moderately LBW (MLBW) infants (1.50-1.99kg) were 1.6 times (adjusted odds ratio (aOR)=1.64; 95%CI:1.30-2.08), and very LBW (VLBW) infants (< 1.50kg) were 2.4 times (aOR=2.42; 95%CI:1.50-3.88) more likely to be BCG unvaccinated. In the postneonatal period, VLBW infants had an almost 40% lower DTP1 vaccination rate at age 10 weeks (adjusted rate ratio (aRR)=0.58; 95%CI:0.43-0.77) and 18 weeks (aRR=0.63; 95%CI:0.50- 0.80). MLBW infants had vaccination rates approximately 25% lower at these time points. Similar results were observed for DTP3. LBW infants had much higher mortality rates in infancy compared to NLBW infants. Infants weighing 2.00-2.50kg were > 2 times (adjusted hazard ratio (aHR)=2.13; 95%CI:1.76-2.59); MLBW infants were > 8 times (aHR=8.21; 95%CI:6.26-10.76), and VLBW infants were > 25 times (aHR=25.38; 95%CI:18.36-35.10) more likely to die. The trend of higher mortality with lower birth weight was seen in each of the neonatal, early and late infant periods, but the magnitude of the association declined over time. There was also some evidence that LBW infants had increased illness rates in the neonatal period, and in each of the neonatal and early infant periods. An absence of care seeking was found for MLBW infants in the first year of life (aOR=1.46; 95%CI:1.18-1.81), and in each of the neonatal (aOR=3.30; 95%CI:1.98-5.48) and early infant periods (aOR=1.74; 95%CI:1.26-2.39) respectively. No association was found in the late infant period (p-interaction=0.0002). Among all infants (NLBW and LBW) with opportunities for vaccination, most opportunities were missed. There was no association between birth weight and uptake of opportunities. In conclusion LBW infants are under-served by vaccination in Ghana. Given their poorer health outcomes, efforts to improve their access to care services, including vaccination are warranted. Further research into the barriers and facilitators of vaccination of LBW infants is warranted, including qualitative research targeting care givers and vaccine providers.

Mestrado em Biomedicina Molecular
Demência é uma síndrome clínica caracterizada pelo declínio progressivo das capacidades cognitivas, estando a tornar-se cada vez mais comum, devido ao envelhecimento da população mundial. Prevê-se que o número de doentes com demência aumente em cerca de 30 milhões nos próximos 15 anos, representando grandes gastos para os sistemas de saúde e sociais. Existem vários tipos de demência, sendo que a Doença de Alzheimer (DA) é a mais comum, afetando entre 20 a 30 milhões de pessoas em todo o mundo, das quais 90.000 são portuguesas. A compreensão das características genéticas e moleculares associadas a esta doença pode constituir um meio para descobrir novos métodos de diagnóstico e tratamento. A maior parte dos casos de Alzheimer tem início tardio, afetando indivíduos com 65 ou mais anos de idade. Até recentemente apenas o gene que codifica a Apolipoproteína E (APOE) foi associado com esta forma de DA. No entanto, estudos recentes de associação genómica identificaram o gene BIN1 como sendo o loci de risco associado ao Alzheimer tardio mais significativo depois do APOE. Além disso, vários SNPs do BIN1 foram associados a este tipo de Alzheimer, sendo que o polimorfismo rs744373 foi proposto como um dos mais relevantes para a DA. Dado que os SNPs mais significativos podem variar de população para população, o objetivo principal deste trabalho foi avaliar se o polimorfismo rs744373 do gene BIN1 pode ser associado a um aumento do risco de desenvolver DA, numa população portuguesa do distrito de Aveiro, que pertence a um estudo transversal baseado em populações, realizado na Universidade de Aveiro. Analisámos 63 indivíduos Portugueses, sendo 32 doentes e 31 controlos. Neste estudo conseguimos observar que, de uma forma geral, o alelo A é o mais frequente e que o alelo G (alelo de risco) foi o menos frequente, numa razão de 3:1. Não conseguimos encontrar uma forte evidência de associação entre o rs744373 e o risco de desenvolver DA (Razão de probabilidade [RP] = 0.733 , valor p = 0.464), o que está de acordo com estudos previamente publicados. Não foi detetada significância estatística entre o rs744373 e portadores do alelo APOE-Ԑ4 (valor p = 0.467) ou indivíduos com demência (CDR≥1) (valor p = 0.269). Foi detetada uma associação entre o alelo de risco do polimorfismo de estudo e a presença de Diabetes Mellitus (RP = 6.60, valor-p = 0.035). No entanto, como a nossa amostra era pequena, deve ser feito um novo estudo para avaliar se este resultado pode ser generalizado para a população Portuguesa.
Dementia is a clinical syndrome characterized by a progressive decline in cognitive skills, and is becoming increasingly common, due to the aging of the world’s population. It is expected that the number of patients with dementia will increase by 30 million in the next 15 years, representing a major factor of costs in health care and social systems. There are several types of dementia, and Alzheimer’s Disease (AD) is the most common, affecting 20 to 30 million people worldwide, of which 90.000 are Portuguese. Understanding the genetic and molecular characteristics associated with the disease may constitute a way to discover new diagnostic methods and treatments. Most cases of AD are late-onset (LOAD), affecting individuals with 65 or more years of age. Until recently only the Apolipoprotein E gene (APOE) had been associated with this form of AD. However, recent genome-wide association studies have identified Bridging Integrator 1 (BIN1) as the most significant LOAD-associated risk loci after APOE. Furthermore, several SNPs of BIN1 have been associated to this type of AD and rs744373 was proposed to be one of the most relevant for AD. Since the most significant SNP may vary from population to population, the main aim of this work was to evaluate if BIN1 polymorphism rs744373 can be associated with the risk of AD in a Portuguese population from the Aveiro district, belonging to a cross-sectional population-based study performed in Aveiro University. We analysed 63 Portuguese individuals comprising 32 cases and 31 controls. In this study we could observe that, overall, allele A was the most frequent and allele G (risk allele) was the least frequent, in a ratio of 3:1. We didn’t find strong evidence of association for rs744373 with the AD risk (odds ratio [OR] = 0.733 , p-value = 0.464), which is in agreement with some previous published studies. No statistical significance was detected between rs744373 and APOE-Ԑ4 carriers (p-value = 0.467) or individuals with dementia (CDR≥1) (p value= 0.269). We have detected an association between the risk allele of the study polymorphism and the presence of Diabetes Mellitus (odds ratio [OR] = 6.60, p-p-value = 0.035). Nevertheless, due to our small sample size, a follow-up study is required in order to evaluate if this result can be generalized to the Portuguese population.

Type 2 diabetes mellitus (T2DM) is associated with a high mortality risk, although the magnitude of this association remains unknown in Latin America (LA). We aimed to assess the strength of the association between T2DM and all-cause and cause-specific mortality in population-based cohort studies in LA. Systematic review and meta-analysis: inclusion criteria were (1) men and women 18 years old and above with T2DM; (2) study outcomes all-cause and/or cause-specific mortality; and (3) using people without T2DM as comparison group. Five databases (Scopus, Medline, Embase, Global Health, and LILACS) were searched. Risk of bias was evaluated with the ROBINS-I criteria. Initially, there were 979 identified studies, of which 17 were selected for qualitative synthesis; 14 were included in the meta-analysis (N = 416 821). Self-reported T2DM showed a pooled relative risk (RR) of 2.49 for all-causes mortality (I-squared [I 2 ] = 85.7%, p < 0.001; 95% confidence interval [CI], 1.96-3.15). T2DM based on a composite definition was associated with a 2.26-fold higher all-cause mortality (I 2 = 93.9%, p < 0.001; 95% CI, 1.36-3.74). The pooled risk estimates were similar between men and women, although higher at younger ages. The pooled RR for cardiovascular mortality was 2.76 (I 2 = 59.2%; p < 0.061; 95% CI, 1.99-3.82) and for renal mortality 15.85 (I 2 = 0.00%; p < 0.645; 95% CI, 9.82-25.57). Using available population-based cohort studies, this work has identified and estimated the strength of the association between T2DM and mortality in LA. The higher mortality risk compared with high-income countries deserves close attention from health policies makers and clinicians to improve diabetes care and control hence preventing complications and delaying death.
Revisión por pares

Physical inactivity is a major public health problem, and evidence suggests that it is a contributing factor in numerous chronic diseases and conditions. Along with smoking and poor dietary habits, physical inactivity is one of the main risk factor for chronic diseases that can be modified through behavior change Performing physical activity on a regular basis has been linked with positive effects on health and well-being, and physical activity improvement has been appointed as the leading health indicator for the next decades. The availability of health data is important for national discussions on health policies. Such data can highlight real variations in health status and the factors affecting health across communities. Moreover, it could be useful to guide policy-related discussions on best practices to improve the health of population. The objectives of this thesis are to describe changes on leisure time and occupational physical activity status at the community level and to evaluate sociodemographic, health related, and life style determinants of such changes, and also evaluate the association of different physical activity domains for women and men, with overall mortality. The thesis is composed by two original articles based on two population-based cohorts studies: the Cornellà Health Interview Survey Follow-Up Study and the Barcelona Health Interview Study. The studies included in this thesis suggest that there were changes in the population on the physical activity status whereas no clear determinants of such changes were recognized. Moreover the effects of all domains of physical activity were associated with a substantial decreased mortality. Therefore, promoting moderate levels of leisure time physical activity, occupational physical activity and walking seems to be essential in comprehensive health promotion programs at community levels.
La inactividad física o el sedentarismo es un problema central de la salud pública, la evidencia científica muestra que es un factor de riesgo para numerosas enfermedades de las denominadas crónicas o no transmisibles. Junto al hábito de fumar y a la alimentación es un factor de riesgo de enfermedad que puede ser modificado por cambios de comportamiento y hábitos. Se postula que realizar actividad física de manera regular permite lograr efectos positivos sobre el bienestar y la salud; además, el mejoramiento en los niveles de actividad ha sido señalado como un indicador líder de las ganancias en salud. En este sentido disponer de datos poblacionales es fundamental para discutir las políticas públicas sanitarias: las variaciones a nivel poblacional de los indicadores de salud son los que guían las discusiones para desarrollar guías que mejoren la salud comunitaria. Los objetivos de la presente tesis son: describir los cambios en la actividad física de ocio y la ocupacional a nivel comunitario y evaluar los determinantes de dichos cambios tales como los sociodemográficos, los relacionados con el status de salud, y los estilos de vida; Identificar la asociación de los distintos dominios de actividad física con la mortalidad general tanto en hombres como en mujeres en estudios de cohortes de base poblacional. La tesis se compone de artículos originales desarrollados en el marco de dos estudios de cohortes con base poblacional, el Estudio de Seguimiento de la Cohorte de Cornellà y el de La Encuesta de Salud de Barcelona año 2000. Los estudios analizados evidencian que hubo cambios en los niveles de actividad física a nivel poblacional, y que no se demostraron determinantes claros de esos cambios más que los sociodemográficos. También demostraron que todos los dominios de actividad física realizada tanto en mujeres como en hombres decrecen la mortalidad por todas las causas evaluada a nivel poblacional. Por lo tanto para el diseño de programas abarcativos de promoción de la salud a nivel comunitario deben incluirse recomendaciones apropiadas para la realización de actividad física de ocio y del caminar y laboral

Background: Venous thromboembolism (VTE) in one of the leading causes of maternal morbidity and mortality in high income countries. However there is a surprising shortage of evidence which allows us to accurately predict which women are at high risk which has hindered prevention to date. Therefore the aim of this thesis is to measure the occurrence of and risk factors for VTE during the antepartum and postpartum periods. Methods: Electronic health records from women of childbearing age (15-44 years) were identified from two separate databases; The Health Improvement Network (THIN) between 1995 and 2009 and the Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES) between 1997 and 2010. Five separate studies were then carried out to study the incidence and risk factors for VTE during antepartum and postpartum periods. In studies 1 and 2 I used the THIN database to assess the incidence of and risk factors for VTE during antepartum and postpartum periods separately. Studies 3, 4 and 5 incorporated the CPRD-HES linked data which enabled me to get better ascertainment of VTE and its potential risk factors. Using these data I externally validated my VTE definition which was followed by investigating the impact of non-delivery related hospitalisations on the incidence of antepartum VTE. I also examined the risk factors for postpartum VTE using a conceptual hierarchical analysis approach along with their impact on the timing of VTE during specific periods of postpartum. All results were presented in the form of absolute rates (AR) per 100,000 person-years and incidence rate ratios (IRR) were calculated using Poisson regression with adjustment for relevant covariates. Results: In THIN, there were a total of 1.7 million women of which 280,451 experienced 376,154 pregnancies resulting in live or stillbirths whereas the CPRD-HES linked data contained information on over 240,000 pregnancies among 204,929 women. Overall VTE rates were highest in the first few weeks postpartum. Women in their third trimester of antepartum were at a 5 fold increased risk of first VTE compared to their time outside pregnancy whereas in the first and second trimesters this rate was only marginally higher. However the use of CPRD-HES linked database gave me estimates of VTE risk with better precision in and around pregnancy that were comparable to the existing literature. For my risk factor analysis I found that the strongest risk factor for VTE during the antepartum period was hospitalisation corresponding to a 17-fold increase (IRR=17.7 95%CI=7.7-39.6) compared to time outside hospital. The rate of VTE was also high during the 28 days post-discharge (IRR=5.9; 95%CI=3.5-10.0; AR=646). These factors were not confounded by pregnancy related characteristics and complications, pre-existing medical co-morbidities or demographic or life style related characteristics. I also found that postpartum, women whose pregnancies resulted in stillbirth were at a 6- fold (IRR=6; 95%CI 3.17-14.6; AR=2570) increased risk of VTE. Those with caesarean delivery (elective or emergency), pre-term birth or postpartum haemorrhage had a 2-fold or higher risk of postpartum VTE compared to their respective baseline (AR>600/100,000 person-years). These findings were consistent across both the THIN and CPRD-HES linked data bases with respect women's risk factors for VTE. Finally the risk of VTE remains consistently high up to first six weeks postpartum (>700/100,000 person-years) for pregnancies of women complicated with BMI>30kg/m2 or caesarean delivery whereas risk of VTE was only high in the first three weeks postpartum (>1300/100,000 person-years) In those with pre-term birth or postpartum haemorrhage. Conclusion: I have provided some of the most precise estimates of absolute rates of VTE In and around pregnancy for better understanding of risks. The overall rate of antepartum VTE is substantially increased during non-delivery related hospitalisations and this increase is sustained in the 28 days post-discharge. Postpartum, delivery associated characteristics and complications including, stillbirth, caesarean delivery, BMI>30Kg/m2 postpartum haemorrhage are important risk factors for VTE particularly during the first three weeks postpartum. My analysis provides valuable information to clinicians for better decision making in terms of identifying high risk pregnant and postpartum women who may require some form of thromboprophylaxis.

Malgré les moyens importants de prévention et de lutte mis en place ces dernières années, le paludisme reste dévastateur avec près d’un demi-million de décès par an (405 000 en 2018, d'après le dernier rapport de l'OMS). Le rôle clé joué par les facteurs génétiques de l’hôte dans la susceptibilité et la sévérité de la maladie est admis aujourd'hui. Cependant, les bases moléculaires de la sensibilité/résistance au paludisme restent encore mal connues. Ces dix dernières années, les efforts de recherches pour l’identification de gènes impliqués dans la sensibilité au paludisme à P. falciparum se sont concentrés sur les formes graves de paludisme, avec plusieurs plusieurs études d’association sur l’ensemble du génome (Genome-Wide Association Study ou GWAS) publiées. Ce manuscrit porte sur l’extension de cette approche aux formes simples du paludisme, au travers de l’étude d’association génome entier de deux cohortes de nouveau-nés au Sud Bénin (au total 800 enfants), suivis pendant 18-24 mois par l’UMR261 (MERIT IRD/Université de Paris). Dans une première partie nous présentons les résultats de la première GWAS réalisée sur les formes simples de paludisme dans ces deux cohortes. L’association a été testée avec la récurrence des accès palustres et la récurrence de l’ensemble des infections (incluant les accès palustres et les infections asymptomatiques) en prenant en compte un risque environnemental estimé au niveau individuel. Elle met en évidence plusieurs signaux d’association forts, en lien avec des gènes dont la fonction biologique est pertinente pour le paludisme (notamment PTPRT, MYLK4, UROC1 et ACER3). La forte variabilité génétique présente au sein des populations africaines a nécessité de prendre en compte l’effet de confusion potentiel de la structure de population. Dans l’étude les formes simples de paludisme, une approche en deux étapes a été utilisée, le modèle de Cox mixte, utilisé pour l’analyse des données longitudinales, n’étant pas applicable à l’ensemble du génome du fait du temps de calcul nécessaire. Un modèle de Cox mixte a été appliqué pour construire un « effet individuel » ajusté sur les covariables, puis un modèle mixte linéaire pour tester l’association avec les polymorphismes du génome. Ceci nous a conduits à nous intéresser plus généralement aux modèles mixtes non-linéaires. Deux méthodes permettant l’estimation de l’effet des polymorphismes avec le modèle logistique mixte sont proposées, qui pourront être dans le futur généralisé à d’autres modèles, dont le modèle de Cox. Dans une dernière partie, le paludisme ayant constitué une des plus fortes pressions de sélection que l’homme ait connue dans son histoire récente, nous explorons la possibilité d’exploiter l’information de sélection naturelle pour augmenter la puissance de l’analyse, et améliorer la détection des signaux d’association. L’analyse des signaux de sélection positive récente sur l’ensemble du génome a été réalisée avec plusieurs méthodes basées sur les haplotypes longs ((iHS, nsL and XP-EHH). Celle-ci met en évidence plusieurs régions chromosomiques d’intérêt potentiel où les signaux d’association et de sélection co-localisent ; mais confirme également la difficulté à mettre en évidence les signaux de sélection liés au paludisme avec les outils disponibles actuellement
In spite of numerous prevention and control efforts in recent years, malaria remains a major global public health problem with nearly half a million deaths per year (405,000 in 2018). The key role played by genetic factors of the host in the susceptibility and severity of the disease is is admitted nowadays. However, the molecular basis of susceptibility / resistance to malaria has not been elucidated to date. Over the past decade, research efforts to identify genes involved in malaria susceptibility have focused on severe malaria, with several genome-wide association studies (GWAS) published. This manuscript concerns the extension of this approach to uncomplicated forms of malaria, through the genome wide association study of two birth cohorts in South Benin (800 children), followed for 18-24 months by UMR261 (MERIT IRD / University of Paris).In the first part, we present the results of the first GWAS performed on simple forms of malaria in these two cohorts. The association was tested with the recurrence of malaria attacks and the recurrence of all infections (including malaria attacks and asymptomatic infections) taking into account an environmental risk estimated at the individual level. It highlights several strong association signals, linked to genes whose biological function is relevant for malaria (in particular PTPRT, MYLK4, UROC1 and ACER3). The high genetic diversity within African populations has made it necessary to take into account the potential confounding effect of population structure. In this study we proceeded with a two-step strategy as the Cox mixed model, used for the analysis of longitudinal data, is not applicable to the whole genome due to computational burden. In a first step, an analysis was performed with a Cox mixed model to build an "individual effect" fitted on the covariates, then a linear mixed model were used to test the association with genome polymorphisms. This led us to focus more generally on non-linear mixed models. Two methods allowing the estimation of the effect of polymorphisms with the mixed logistic model are proposed, which may in the future be generalized to other models, including the Cox model.In a final part, malaria having been one of the strongest selection pressures that man has known in recent history, we explore the possibility of exploiting natural selection information to increase the power of analysis, and improve the detection of association signals. The analysis of recent positive selection signals were performed using several genome-scan methods focusing on patterns of long-range haplotype homozygosity (iHS, nsL and XP-EHH). This analysis revealed several chromosomic region of potential interest, where the signals of association and selection co-localized but confirms also the difficulty of highlighting the selection signals linked to malaria with tools currently available

Les taux de survie des enfants nés entre 22 et 26 semaines d’aménorrhée (SA), appelés extrêmes prématurés, sont plus faibles en France qu’en Angleterre, en Suède aux États-Unis ou au Japon. Ces différences de survie pourraient être liées à des différences de pratiques autour de la naissance et en particulier à des différences de pratiques anténatales. En cas de naissances prématurées les obstétriciens, premiers interlocuteurs des femmes, peuvent décider d’instaurer ou non des mesures anténatales pour améliorer le pronostic des enfants à naître : corticothérapie, césarienne d’indication fœtale ou sulfate de magnésium à visée neuroprotectrice. Le rôle des équipes obstétricales pourrait ainsi être déterminant pour le pronostic des extrêmes prématurés et les raisons qui incitent les obstétriciens, en accord avec les parents, à initier ou non une prise en charge active anténatale sont mal connues. L’âge gestationnel est un facteur décisionnel bien connu sans qu’il n’y ait d’âge gestationnel seuil consensuel de prise en charge active en France. Mais il se pourrait aussi que les prises en charge varient selon les centres voire même selon les praticiens ou encore selon d’autres facteurs individuels liés aux femmes ou à leur grossesse. L’objectif de notre travail était dans un premier temps d’identifier, pour les naissances extrêmement prématurées en France, les déterminants individuels ou organisationnels associés à une prise en charge active anténatale. Dans certaines circonstances, volontaires ou non, les extrêmes prématurés naissent sans avoir bénéficié d’une prise en charge active anténatale. La plupart des nouveau-nés décèdent alors à la naissance mais certains d’entre eux sont néanmoins admis en réanimation néonatale. Le devenir de ces enfants, qui posent des difficultés médicales et éthiques, est mal connu. Étudier leur devenir néonatal était le deuxième objectif de ce travail. Les données de la cohorte EPIPAGE 2 ont été utilisées pour répondre à ces deux questions. Nous avons montré que les pratiques anténatales en cas de naissances extrêmes prématurées variaient de manière importante selon les régions avec des taux régionaux de prise en charge active anténatale allant de 22% (IC95% 0.05-0.38) à 61% (IC95% 0.44-0.78). Une prise en charge active anténatale était aussi plus fréquente pour les naissances à 25 et 26 SA que pour les naissances à 24 SA. Même après ajustement sur les caractéristiques individuelles et organisationnelles, les taux de prise en charge active variaient selon les établissements (p=0.03). Nous avons également souligné que les enfants admis en réanimation sans avoir pu bénéficier d’une prise en charge active anténatale ont un risque augmenté de morbi-mortalité néonatale par rapport aux enfants qui en ont bénéficié (Odds Ratio (OR) brut de 2.60, (IC95% 1.44-4.66 et OR ajusté de 1.86, (IC95% 1.09-3.20)). Les différences de pratiques anténatales entre les maternités de naissance, soulève la problématique de l’équité de la prise en charge ce d’autant que ces pratiques ont un impact sur le devenir immédiat de l’enfant. Ces résultats ont conduit certaines équipes françaises à réévaluer les processus de décisions autour de ces naissances afin d’harmoniser les pratiques. Au décours de ces réflexions, les sociétés savantes françaises proposent un guide d’aide à la décision pour la prise en charge des naissances extrêmes prématurées qui s’appuie sur une cohérence des soins prodigués avant, pendant et après la naissance
Survival rates of extremely preterm neonates, infants born between 22 and 26 Weeks of Gestation (WG), are lower in France than in England, Sweden, the United States or Japan. This may be related to differences in the management of extreme preterm births and in particular to differences in antenatal practices. In the case of preterm births, obstetricians are the first to meet the mothers-to-be. They decide whether or not to implement antenatal measures to improve outcomes of these unborn children: corticosteroids, caesarean sections or magnesium sulphate for neuroprotective purposes. The provision of optimal antenatal care is key to the management and survival of extremely preterm births and obstetrical teams thus play a major role. Factors associated with active antenatal care have never been studied. The first objective of our work was to identify, for extreme preterm births in France, individual or organisational determinants associated with active antenatal care. Gestational age is a well-known decision-making factor, but care could also depend on individual factors related to women or their pregnancy, practitioners or maternity units. Some extremely preterm neonates are born without having received active antenatal care. For newborns who have not received such treatment, the risk of peripartum and delivery room death is high. However some extremely preterm neonates for whom active antenatal was either voluntarily withheld or not provided because of insufficient time are resuscitated and admitted to a Neonatal Intensive Care Unit (NICU). Neonatal outcomes for these children raise medical and ethical difficulties and are poorly known. Our second objective was to study neonatal outcomes of extremely preterm neonates admitted to NICU without prior active antenatal care. Data from the EPIPAGE 2 cohort were used to answer these questions. We have shown that antenatal management for extreme preterm births varies widely between regions with regional active antenatal care rates ranging from 22% (95% CI 0.05-0.38) to 61% (95% CI 0.44-0.78). Active antenatal care was more frequent for births occurring at 25 and 26 WG than for births occurring at 24 WG. Even after adjusting for individual and organisational characteristics, active antenatal care rates varied by maternity unit of birth (p = 0.03). We also underlined that children admitted to NICU without having received active antenatal care have an increased risk of neonatal morbidity and mortality compared to children who have (crude OR of 2.60, (95% CI 1.44-4.66), adjusted OR of 1.86, (95% CI 1.09-3.20)). Differences in antenatal management between maternity units raise the issue of equality of care, especially since these practices have an impact on neonatal outcomes. These findings have led French teams to reassess the decision-making process around extreme preterm births and to the elaboration of guidelines for the management of extreme preterm births

Antecedents: No hi ha gaire coneixement sobre el neurodesenvolupament de preescolars i la seva susceptibilitat enfront a factors ambientals.
Objectius: Avaluar les respostes del neurodesenvolupament en nens i les seves característiques psicomètriques, i, si factors ambientals primerencs (ex., duració de la lactància materna i mares que fumen) poden influir tals respostes.
Mètodes: Dues cohorts prospectives des del naixement en població general (Menorca (N=421) i Ribera d'Ebre (N=79)) van se seguides fins als 4 anys d'edat durant un període de dos anys (2001-2003). Els nens van ser avaluats per tres psicòlegs i els seus respectius mestres per les funcions neuropsicològiques (MCSA), els comportaments de dèficit d'atenció i d'hiperactivitat (TDAH-DSM-IV) i la competència social (CPSCS); junt amb l'administració (en persona) a les mares de qüestionaris generals.
Resultats: Les respostes van mostrar característiques psicomètriques acceptables i els patrons neuropsicològics del TDAH eren consistents amb altres troballes sobre TDAH. La lactància materna de llarga durada estava associada amb una millora de totes les àrees comportamentals avaluades. Fumar durant l'embaràs estava associat a puntuacions cognitives més baixes.
Conclusions: Avaluar el neurodesenvolupament a preescolars sans és factible i necessari per investigar efectes primerencs de factors ambientals i aplicar polítiques preventives de salut pública.
Background: Little is known about neurodevelopment among preschoolers and its susceptibility to environmental factors.
Objectives: Assess neurodevelopmental outcomes and their psychometric characteristics in children; and, if early environmental factors (i.e., duration of breastfeeding and maternal smoking) influence the neurobehavioral outcomes.
Methods: Two prospective population-based birth cohorts (Menorca (N=421) and Ribera d'Ebre county (N=79)) were followed up at the age of 4 years during a two year period (2001-2003). Children were assessed by three psychologists and their respective teachers for neuropsychological functions (MCSA), inattention-hyperactivity behaviors (ADHD-DSM-IV) and social behavior (CPSCS); in addition to maternal in person general questionnaires.
Results: Outcomes showed acceptable psychometric characteristics and ADHD neuropsychological patterns were consistent with other ADHD findings. Long-term breastfeeding was associated with the improvement of all behavioral areas assessed. Maternal smoking during pregnancy was associated with lower cognitive scores.
Conclusions: Assessing neurodevelopment in healthy preschoolers is feasible and necessary to investigate early effects of environmental factors and apply public health preventive policies.

碩士
臺北醫學大學
醫學資訊研究所
104
The potential risk of prostate cancer associated with statins use has been a focus of much interest. Japanese research combines both the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and a large organized database from The Japan Medical Data Center (JDMC) data to examine the association between statins and cancer. The FAERS is a computerized information database designed to support the FDA''s post-marketing safety surveillance program for all approved drugs and therapeutic biological products. In the FAERS database analysis, significant signals for colorectal cancer、pancreatic cancer and prostate cancer were found for “atorvastatin”、“rosuvastatin” and “pitavastatin”. The hypothesis in our research is certain statin related drugs displays high or low antitumor activity in prostate cancer. If the hypothesis is correct, cells treated with statin related drugs will show similar/reverse gene expressions as cancer cells do after analyzed by bioinformatics approach. This paper focuses on statin related drugs on prostate cancer. To testify whether the results will be concordant with the gene expression profiling and related cohort studies. Data part using prostate cancer RNA-seqV2 gene expression profiling from TCGA by R DESeq package. Tools part uses program Perl and R to analyze overall survival and disease free survival analysis. After survival analysis, LINCSCLOUD web platform get this differential gene expression data then calculate and offer connectivity score. The connectivity score can visualize the risk between statins and cancer by boxplot. In addition to TCGA data, we also using 1997 to 2013 NHIRD HV data to validate gene expression profiling by life table analysis and Cox proportional hazards model. Comparison with analysis of various type, Statin related drugs “atorvastatin” and ”pitavastatin” displays oncogenesis effects both in tumor v.s. normal analysis with TCGA by DESeq tool and NHIRD analysis. It imply that these statins possess potential oncogenesis ability and may lead oncogenesis effect in prostate cancer. In contrast, statins “pravastatin” displays anti-oncogenesis effects both in gene expression profiling and related cohort studies. It probably represent the opposite side of cell growth control, normally acting to inhibit cell proliferation and tumor development potentially.