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Background: Persistent Organic Pollutants (POPs) are chemicals that have negative impacts on the environment and biota and have been investigated as possible risk factors for Type 2 Diabetes Mellitus (T2DM). Other well-established risk factors for T2DM, for example, obesity, increased lipids, and age have been reported to influence human POP concentrations. Previous studies have reported positive associations between single POP measurement and prevalent and incident T2DM, although causality has not been established. Longitudinal studies with repeated pre-diagnostic POP measurements, which may help in addressing causality, are lacking. Aims: This thesis aimed to investigate if the different classes of POPs (perfluoroalkyl acids [PFAAs], polychlorinated biphenyls [PCBs], organochlorine pesticides [OCPs], and polybrominated diphenyl ethers [PBDEs]) are causal factors of T2DM using repeated POP measurements from the same individuals. We also assessed if T2DM status influences the body burden of POPs. Methods: We used questionnaire data and blood samples from two different population-based studies. The Norwegian Women and Cancer study was used to investigate PFAAs-T2DM associations and time trends in PFAAs (2001-2005/06) with two repeated measurements. The Tromsø study was used to study the associations between PCBs, OCPs, PBDEs, and T2DM, and time trends (1986-2016) in cases and controls using three to five repeated POP measurements per individual. Results: Among the PCBs and OCPs, only cis-heptachlor epoxide showed strong pre- and post-diagnostic associations. Further, PCBs and OCPs declined slower in cases compared to controls. PFAAs and PBDEs showed similar time trends in cases and controls, and these POPs were not associated with T2DM before or after diagnosis. Conclusion: The results from this thesis do not support POPs being causal factors of T2DM but suggest that T2DM-related physiological changes may cause retention of certain POPs already years before T2DM diagnosis leading to higher concentrations in prospective cases, and thus, positive associations with T2DM status.

Enterococci are gram-positive commensals in the human gut microbiota that may cause severe infections, especially in immunocompromised and hospitalised patients. Their ability to accumulate antimicrobial resistance and virulence genes has been vital in their evolution into leading pathogens. Vancomycin resistant enterococci (VRE) are among the most important resistant pathogens causing outbreaks worldwide. In this study, we aimed to examine recent developments in the epidemiology of VRE in Norway related to the occurrence of novel van-types and the increasing incidence of VRE since 2010. By analysing whole genome sequencing data produced in this project, we identified and described the first Norwegian vanD-type VRE isolates from two patients and reported a novel vanD-subtype and genomic islands harbouring the vanD gene clusters and reported vanD gene cluster in vancomycin resistant Enterococcus casseliflavus for the first time. Different vanD subtypes harbouring genomic islands and phylogenetic, genomic distance confirmed that the isolates of the two cases are clonally unrelated. Additionally, we identified the first vanE-type VRE isolates in Norway recovered from the same patient and described the mobile genetic element harbouring (MGE) the vanE gene cluster, its insertion site, and explained why one isolate expressed inducible low level and the other isolate constitutive low level vancomycin resistance. Moreover, we conducted the first comprehensive study on Norwegian VRE and vancomycin susceptible Enterococcus faecium (VSEfm) at the genomic level and identified the most prevalent cluster types (CTs), compared their virulomes, and MGEs harbouring the van gene clusters. In conclusion the population structure of E. faecium in Norway is shaped by globally prevalent clones, particularly concurrent European CTs, with similar dynamic ST sweeps. The dominant CTs of VREfm have acquired more virulence determinants than the more diverse local VSEfm population.

Current knowledge about the relationship between exercise and cardiac remodelling is mostly based on studies of athletes. Little is known about cardiac adaptations to moderate doses of exercise in the general adult and elderly population, and whether exercise-induced cardiac remodelling is a benign physiological adaption of exercise or part of a pathophysiological mechanism. The main objective of this thesis was to study the association between physical activity (PA) and the structure and function of the left side of the heart. Also, we wanted to explore if exercise-related left atrial (LA) remodelling was associated with adverse cardiac alterations and increased risk of incident atrial fibrillation (AF). In paper I, we applied a longitudinal design with repeated measures of self-reported PA and echocardiographic structural and functional data. In paper II, we applied a cross-sectional design to investigate the association between device-based PA and LA size. In paper III, we applied a prospective design to investigate the association between self-reported PA, LA size, and risk of AF. The main findings of this thesis are that exercise-induced cardiac remodelling also occurs with moderate levels of habitual PA, and not only in endurance-trained athletes. Moreover, our results indicate that exercise-induced LA remodelling is a benign physiological adaptation to exercise, without being associated with reduced left ventricular (LV) diastolic function or increased risk of incident AF. Higher levels of PA were associated with increased LA size in general, and increased LV size in females. However, no change in pump function or atrioventricular ratio at rest was observed with higher levels of PA. Moreover, moderate levels of habitual PA were associated with reduced risk of AF, and active individuals with LA enlargement did not have higher risk of AF than either active or inactive with normal LA size. Nåværende kunnskap om sammenhengen mellom trening og hjerteremodellering er for det meste basert på studier av idrettsutøvere. Lite er kjent om hjertetilpasninger til moderate doser trening i den generelle voksne- og eldre befolkningen, og om treningsindusert hjertemodellering er en normal fysiologisk tilpasning til trening, eller en del av en patofysiologisk mekanisme. Dessuten er sammenhengen mellom fysisk aktivitet (FA), hjerteremodellering, og langtidsrisiko for atrieflimmer (AF) kompleks og representerer et kunskapshull, spesielt i den generelle voksen og eldre befolkningen. Hovedmålet med denne avhandlingen var å studere sammenhengen mellom FA og hjertets venstre sides struktur og funksjon. Vi ønsket også å undersøke om treningsrelatert remodellering av venstre atrium (VA) var assosiert med uønskede hjerteendringer og økt risiko for AF. I artikkel I brukte vi et longitudinelt design med gjentatte mål av selvrapportert FA og ekkokardiografiske strukturelle og funksjonelle data. I artikkel II brukte vi et tverrsnittsdesign for å undersøke sammenhengen mellom monitormålt FA og VA-størrelse. I artikkel III brukte vi et prospektivt design for å undersøke sammenhengen mellom selvrapportert FA, VA-størrelse og risiko for AF. Hovedfunnene i denne avhandlingen er at treningsindusert hjerteremodellering også forekommer ved moderate nivåer alminnelig FA, og ikke bare hos utholdehetsutøvere. Dessuten indikerer resultatene våre at treningsindusert VA-remodellering er en normal fysiologisk tilpasning til trening, uten å være assosiert med redusert venstre ventrikkel (VV) diastolisk funksjon eller økt risiko for insidens av AF. Høyere nivåer FA var assosiert med økt VA-størrelse generelt, og økt VVstørrelse hos kvinner. Imidlertid ble ingen endring i pumpefunksjon aller atrioventrikulært forhold i hvile observert ved høyere nivåer FA. Moderate nivåer FA var assosiert med redusert risiko for AF, og aktive individer med VA-forstørrelse hadde ikke høyere risiko for AF enn hverken aktive- eller inaktive med normal VA-størrelse.

This is a pre-copyedited, author-produced version of an article accepted for publication in the European Journal of Preventive Cardiology following peer review. The version of record Hansen, K.W., Peytz, N., Blokstra, A., Bojesen, S.E., Celis-Morales, C., Chrysohoou, C, ... Prescott, E. (2021). Association of fatal myocardial infarction with past level of physical activity: a pooled analysis of cohort studies. European Journal of Preventive Cardiology, zwaa146, is available online at: https://doi.org/10.1093/eurjpc/zwaa146. Aims: To assess the association between past level of physical activity (PA) and risk for death during the acute phase of myocardial infarction (MI) in a pooled analysis of cohort studies. Methods and results: European cohorts including participants with a baseline assessment of PA, conventional cardiovascular (CV) risk factors, and available follow-up on MI and death were eligible. Patients with an incident MI were included. Leisure-time PA was grouped as sedentary (32 MET-hours) based on calculated net weekly energy expenditure. The main outcome measures were instant and 28-day case fatality of MI. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using multivariate random-effects models. Adjustments for age, sex, CV risk factors, alcohol consumption, and socioeconomic status were made. From 10 cohorts including a total of 1 495 254 participants, 28 140 patients with an incident MI comprised the study population. A total of 4976 (17.7%) died within 28 days—of these 3101 (62.3%) were classified as instant fatal MI. Compared with sedentary individuals, those with a higher level of PA had lower adjusted odds of instant fatal MI: low PA [OR, 0.79 (95% CI, 0.60–1.04)], moderate PA [0.67 (0.51–0.89)], and high PA [0.55 (0.40–0.76)]. Similar results were found for 28-day fatal MI: low PA [0.85 (0.71–1.03)], moderate PA [0.64 (0.51–0.80)], and high PA [0.72 (0.51–1.00)]. A low-to-moderate degree of heterogeneity was detected in the analysis of instant fatal MI (I2 = 47.3%), but not in that of 28-day fatal MI (I2 = 0.0%). Conclusion: A moderate-to-high level of PA was associated with a lower risk of instant and 28-day death in relation to a MI.

Venøs tromboembolisme (VTE), bestående av dyp venetrombose (DVT) og lungeemboli (PE), er en utbredt og multifaktoriell sykdom med langtidskomplikasjoner som negativt påvirker fysisk funksjon og livskvalitet. Sosioøkonomisk status (SES) er kjent for å påvirke både risiko og prognose for helsemessige og helserelaterte utfall. Selv om assosiasjoner mellom VTE og fysisk helse er godt dokumentert, finnes det lite forskning på psykososiale risikofaktorer og konsekvenser relatert til VTE. I denne avhandlingen ønsket vi å studere sammenhengen mellom SES og VTE i en befolkning i arbeidsfør alder. Vi ville videre se på sammenhengen mellom VTE og påfølgende uføretrygd i befolkningen i arbeidsfør alder, samt å vurdere om SES var assosiert med økt risiko for uføretrygd etter VTE. Vi ville også vurdere risikoen for depresjon etter VTE. Denne avhandlingen er basert på data samlet inn fra 1995 til 2016 fra danske nasjonale medisinske og administrative registre. Studiepopulasjonen inkluderte nesten 125 000 individer med VTE, i tillegg til en sammenligningskohorte fra den generelle befolkningen. Vi fant at at høyt utdanningsnivå, høy inntekt og høy sysselsettingsstatus, samt en høy sammensatt SES score, var assosiert med en 30-40% redusert risiko for VTE, samt at SES score modellen var bedre til å vurdere VTE risikoen sammenlignet med de individuelle indikatorene. Videre fant vi at VTE var assosiert med en 2 til 3 ganger forhøyet risiko for påfølgende uføretrygd, og at interaksjon stod for 45,6% av forekomsten av uføretrygd hos personer med lav SES og VTE. Avslutningsvis fant vi at VTE var assosiert med en 1.9-ganger forhøyet risiko for fremtidig depresjon. Våre funn kan bidra til en forbedret forståelse av psykososiale risikofaktorer og konsekvenser for VTE, og de kan danne grunnlag for helsemessige anbefalinger og nye strategier for identifisering av høyrisikogrupper for forebygging, oppfølging eller behandlingsprogrammer etter en VTE. Venous thromboembolism (VTE) is a prevalent and multifactorial disease with long-term complications that negatively affect physical functioning and quality of life. Socioeconomic status (SES) is known to affect the risk and prognosis of health and health behavioral outcomes. In this thesis, we used data collected from 1995 through 2016 from Danish national registries to investigate socioeconomic and psychosocial risk factors for and outcomes of VTE. We found that low SES increases the risk of VTE, that individuals with VTE, particularly those with low SES, are at increased risk of disability pension, and that VTE increases the risk of subsequent depression. Our findings provide an improved understanding of the psychosocial impact of VTE, and they can form the basis for health recommendations and novel strategies to identify high-risk groups that would benefit from programs for prevention, follow-up, or treatment after a VTE.

Important gaps in population-based epidemiological research on ovarian cancer include understanding how risk factors relate to cancer subtypes and anatomical sites, identifying safe and effective preventive measures, and getting a more detailed picture of the continuum of events during ovarian carcinogenesis. This thesis used prospective exposure information from the Norwegian Women and Cancer (NOWAC) Study and blood samples from the NOWAC Postgenome biobank to explore topics within these gaps. On the topic of risk factors, subtypes and anatomical sites, previous studies have shown that serous carcinomas of the ovary and fallopian tube cancers have similar risk factors. This thesis compared risk factors between the ovary/fallopian tube and uterine corpus. One risk factor association separated serous carcinomas of these sites, while no differences in risk factor associations were found for endometrioid and clear cell carcinomas. Possible alternative explanations of this result include few observations in the analysis of endometrioid and clear cell carcinomas, and histological misclassification of high-grade endometrioid carcinomas. Among preventive measures, combined oral contraceptives reduce the risk of both ovarian and uterine carcinoma. Current trends in female contraception include an increase in use of progestin-only long-acting reversible contraceptives, such as the levonorgestrel-releasing intrauterine system (LNG-IUS). In the NOWAC cohort, ever use of LNG-IUS reduced the risk of ovarian carcinoma by 53% (95% CI: 22% – 68%) and the risk of uterine carcinoma by 78% (95% CI: 60% – 87%) compared to never use. These results extend current knowledge to include postmenopausal women in a sample of the general population. The association with breast cancer was also investigated and discussed. To investigate the continuum of events during ovarian carcinogenesis, this thesis explores gene expression in peripheral blood in the years preceding ovarian cancer diagnosis. The presented study did not find strong associations. This could be because there is little association between ovarian cancer and prediagnostic gene expression in blood, but could also be due to a small sample size, or the analytic approach that was used. Kreft i eggstokkene er forholdsvis sjelden kreftform, som har høy dødelighet. Denne doktoravhandlingen bygger på spørreskjema fra 172000 kvinner i Kvinner og kreft-studien, og på blodprøver fra 50000 av deltakerne. Blodprøvene utgjør en unik biobank med bevart genuttrykk fra de hvite blodlegemene. Fra før vet man at kvinner som har brukt p-piller har lavere risiko for eggstokkreft. I dag har mange kvinner, også de yngre, begynt å bruke hormonspiral. Det er lite kunnskap om hvorvidt kvinner som bruker hormonspiral har lavere risiko for eggstokkreft slik som p-pillebrukerne. Blant de noe eldre deltakerne i Kvinner og kreft hadde kvinner som noen gang har brukt hormonspiral en halvert risiko for eggstokkreft. Fordi det var få tilfeller, har anslaget en usikkerhet som tilsvarer mellom 10% og 70% lavere risiko. Blodprøvene i biobanken gir mulighet til å undersøke endringer i genuttrykk i immunceller opptil sju år før diagnosen ble stilt, i håp om å forstå mer om sykdomsutviklingen. Vi gjorde en utforskende analyse av blodprøver fra kvinner som hadde fått eggstokkreft, men fant ikke entydige endringer i genuttrykket.

The physiological changes that occur during the pregnancy are known to affect women´s oral health. Pregnant women are more vulnerable to oral diseases when compared to non-pregnant. Better understanding of the relation between changing oral microbial milieu and risk of pregnancy complications and associated mechanisms could help to improve maternal and perinatal outcomes. Thus, we aimed to investigate the pregnancy associated changes in oral bacterial milieu with a focus on cariogenic bacterial load, oxidative stress and nitric oxide levels in the saliva, and their effect on pregnancy outcome. The study included a total of 146 participants, 96 healthy pregnant women at 18-20 weeks of gestation and 50 age-matched non-pregnant women for comparison. Saliva samples were collected from both groups under similar situation for investigating oral bacterial load of Streptococcus mutans (SM) and Lactobacillus (LB), and for determining salivary antioxidant capacity, oxidative stress (OS) and nitric oxide (NO) levels. We found an increase in salivary OS and a decrease in antioxidant capacity along with an increase in colonization by SM in pregnant women compared to non-pregnant. The salivary NO levels were also higher among the pregnant women compared to non-pregnant and the NO level increased with advancing gestational age. However, an association between dental caries and risk of preterm birth was not observed based on data obtained from the published literature. In conclusion, pregnant women had increased load of caries related bacteria, especially SM, in the saliva with higher OS levels and decreased antioxidant capacity compared to non-pregnant women. Likewise, there was an increase in salivary NO levels with advancing gestational age, and an increase in bacterial colonization by SM and LB among the pregnant women in their second and third trimesters. No significant association was observed between dental caries and increased risk of preterm birth.

Background: Sarcopenia is an age-related muscle disease primarily characterized by reductions in muscle strength that increases the risk of falls, fractures, cognitive impairment, and mortality. Exercise is currently preferred in prevention and treatment, but it is unknown how different habitual physical activity and sedentary behaviour patterns associate with sarcopenia status. The purpose of the present study was to compare associations of these patterns with probable sarcopenia in older adults. Methods: In 3653 community-dwelling participants (51% women) aged 60–84 years from the seventh survey of the Tromsø Study, we assessed objective physical activity and sedentary behaviour collected over 8 days (ActiGraph wGT3X-BT Accelerometer), grip strength (Jamar+ Digital Dynamometer), five-repetition chair stands, and self-reported disease. We combined tertiles of sedentary (SED) time and moderate-to-vigorous physical activity (MVPA) to create nine different activity profiles (SEDHIGH, SEDMOD, and SEDLOW combined with MVPAHIGH, MVPAMOD, or MVPALOW). Multiple logistic regression models were used to examine how these profiles associated with probable sarcopenia, defined by low handgrip strength and/or slow chair stands time according to the revised European Working Group on Sarcopenia in Older People criteria. Results: Probable sarcopenia was present in 227 (6.2%) participants. Men with probable sarcopenia had on average 35.3 min more SED time and 20 min less MVPA compared with participants without sarcopenia (P < 0.01 for all), while women with probable sarcopenia only had 18 min less MVPA (P < 0.001). Compared with the SEDHIGH–MVPALOW reference activity profile (714.2 min SED/day and 10.4 min MVPA/day), the SEDHIGH–MVPAMOD profile (697.1 min SED/day and 31.5 min MVPA/day) had significantly lower odds ratio (OR) for probable sarcopenia (OR 0.17, 95% confidence interval [CI] 0.08–0.35), while the SEDLOW–MVPALOW profile (482.9 min SED/day and 11.0 min MVPA/day) did not (OR 0.72, 95% CI 0.47–1.11). These findings were not influenced by age, sex, smoking, or self-reported diseases, and higher levels of MVPA did not further decrease ORs for probable sarcopenia. Conclusions: Older adults who achieve moderate amounts of MVPA have reduced odds for probable sarcopenia, even when they have high sedentary time. Those with low sedentary time did not have reduced odds for probable sarcopenia when they also had low amounts of MVPA. These findings need confirmation in longitudinal studies but suggest that interventions for preventing sarcopenia should prioritize increasing MVPA over reducing sedentary behaviour.

In this thesis, the relationship between vitamin D and health-related outcomes has been investigated. More than 21,000 individuals participated in the Tromsø Study 2015-16. The participants donated blood samples and filled in questionnaires regarding their health status, including questions about their sleep health. Using these data, the association between vitamin D and sleep duration, daytime sleepiness, and insomnia (sleeplessness) were explored. In women, a positive association was found between vitamin D and sleep duration, while the prevalence of insomnia was lower in women with a normal vitamin D level compared to women with higher vitamin D levels. To further explore this relationship, the effect of vitamin D supplementation on sleep duration, daytime sleepiness, and prevalence of insomnia was explored. A sleep questionnaire was implemented as part of an ongoing intervention study, originally designed to evaluate the effect of vitamin D supplementation for the prevention of cardiovascular disease. In total, 189 participants with low vitamin D levels at baseline filled in the sleep questionnaire. After four months of treatment, there were no differences in sleep duration, daytime sleepiness, or prevalence of insomnia between the group taking vitamin D versus placebo, neither when stratified by sex, nor by vitamin D level or sleep status at baseline. It was further investigated in another intervention study whether vitamin D supplementation without additional calcium could have a positive effect on bone mineral density, as a preventive measure against deteriorated bone health. In this intervention study, originally designed to evaluate vitamin D for the prevention of type 2 diabetes, it was found that vitamin D supplementation alone had a positive effect on bone mineral density in men, and that the effect appeared to vary according to measurement site. I denne doktorgraden har sammenhengen mellom vitamin D og helserelaterte endepunkter blitt undersøkt. I 2015-16 deltok mer enn 21,000 personer i Tromsøundersøkelsen. Deltakerne donerte blodprøver og svarte på spørreskjema om helsetilstanden, inkludert spørsmål om søvnhelsen. I dette materialet ble sammenhengen mellom vitamin D nivå og søvnlengde, trøtthet på dagtid og insomni (også kjent som søvnløshet) undersøkt. Det ble funnet en positiv sammenheng mellom vitamin D nivå og søvnlengde blant kvinner, samt lavere forekomst av insomni blant kvinner med normale vitamin D nivå sammenlignet med kvinner med høyt vitamin D nivå. For å vite mer om denne sammenhengen, var det ønskelig å undersøke effekten av vitamin D tilskudd på søvnlengde, trøtthet på dagtid og forekomst av insomni. Det ble derfor inkludert et spørreskjema om søvnhelsen i en pågående intervensjonsstudie, som opprinnelig undersøkte effekten av vitamin D tilskudd i forebygging av hjerte- og karsykdom. Totalt 189 deltakere med lave vitamin D nivå ved studiestart fylte ut spørreskjemaet. Etter fire måneders behandling var det ingen forskjell i søvnlengde, trøtthet på dagtid eller forekomst av insomni mellom deltakere som hadde fått vitamin D og deltakere som hadde fått placebo (narremedisin). Det var heller ingen forskjeller stratifisert på kjønn, vitamin D nivå- eller søvnproblemer ved studiestart. Videre ble det i en annen intervensjonsstudie undersøkt om vitamin D tilskudd uten tillegg av kalsium kunne ha en positiv virkning på beintettheten, som et forebyggende tiltak mot forringet beinhelse. I denne studien, som opprinnelig undersøkte om vitamin D kunne forebygge utvikling av type 2 diabetes, hadde vitamin D en positiv effekt på beintettheten hos menn, og effekten varierte avhengig av hvor beintettheten ble målt.

Background/Aims: Prostate cancer (PCa) is the most common cancer among men in Norway as well as world-wide, and a major cause of health loss and death with 1.4 million new cases and 375 000 deaths world-wide in 2020. Biological mechanisms involved in PCa development are mainly unknown, but chronic inflammation, one hallmark of cancer development, has been questioned to play a key role in PCa development. This thesis aimed to explore whether markers that may be linked to inflammation, such as high sensitive-C-reactive protein (hs-CRP) and white blood cell count (WBC), systolic and diastolic blood pressure (BP) and miR-24-1-5p, a subtype of microRNA, may play a role in PCa development, recurrence and mortality. Materials and methods: The Prostate Cancer Study throughout Life (PROCA-life) is a population-based cohort study, a sub study of the Tromsø Study and the present thesis includes all men, who were enrolled in the Tromsø Study between 1994 and 2016 (Tromsø 4-7). The procedures were almost identical, and assessments were done by trained research technicians. By linkage to the Cancer Registry of Norway and Norwegian Cause of Death Registry, all PCa cases and death among the participating men were identified. Detailed histopathological and medical records were obtained. Cox proportional hazard regression models were used to study the association between prediagnostic WBC and hs-CRP in serum (Paper I), prediagnostic blood pressure (Paper II) and PCa risk and prognosis. We collected prostatectomy tissue from 142 PCa patients, and we studied the influence of miR-24-1-5p regarding aggressiveness and prognosis in men diagnosed with PCa. Results: We observed a positive dose-response relationship between hs-CRP and PCa risk. Men with an increase in hs-CRP between two measurements had a 36% increased risk of PCa, compared to men with no change or decrease in hs-CRP. Men with a high systemic inflammatory score (combination of WBC and hs-CRP) had a 68% higher risk of being diagnosed with metastatic disease compared to men with lower scores. Men (> 45 years) with a systolic BP > 150 mmHg had a 35% increased risk of PCa compared to men with a normal systolic BP (< 130 mmHg). Among PCa cases, men with systolic BP > 150 mmHg had a 49% increased overall mortality compared to men with a normal systolic BP. PCa patients with a high miR-24-1-5p expression in the tissue had a doubled risk of recurrence compared to patients with low miR-24-1-5p expression. Conclusion: Our results suggest that hs-CRP alone or in combination with WBC may be a useful inflammation-related biomarker for PCa risk and prognosis, and systolic and diastolic BP may be important factors when balancing disease management in PCa patients. Moreover, a high expression of miR-24-1-5p is associated with an increased risk of recurrence of PCa after radical prostatectomy. Systemic inflammation might be the common link between these factors, but further research is needed.

This is an Accepted Manuscript of an article published by Taylor & Francis in Chronobiology International on 28 May 2020, available online: https://doi.org/10.1080/07420528.2020.1764011. Seasonality is evident in several aspects of human health and behavior, whereas seasonality in chronic pain is less well studied. We examined seasonal variation in pain severity and pain dissemination, as well as in pain-associated conditions, such as sleep impairment, sleep timing, mental distress, fatigue and physical activity. We also examined if any of these associated conditions moderated the seasonality in pain. This prospective study was conducted in the subarctic municipality of Tromsø, Norway (69º North), on a sample of patients with chronic musculoskeletal pain (N = 56). Data were collected with self-report questionnaires and objective actigraphy measures (7 days) twice: winter and summer. Mixed linear regression models were fitted. A modest seasonality effect was observed in pain severity (highest in summer), but not in pain dissemination. Seasonality with increased physical activity and delayed sleep timing in the summer was also present. The remaining pain-associated self-report or objective measures indicated no seasonality. The season–pain association was not significantly moderated by any of the pain-associated conditions. Previous studies on healthy individuals residing in polar areas have suggested an opposite seasonal effect with delay of the sleep–wake rhythm in winter. Our results based on a clinical sample thus represent a novel finding that needs to be examined further with regard to seasonal circadian entrainment and alignment in pain populations. These results may have clinical value for the treatment of patients with musculoskeletal pain as seasonality may require seasonal adjustments of pain treatment strategies.

I de senere år har antibiotikaresistente bakterier blitt et økende medisinsk problem. Slike bakterier har smittet medisinske turister, og blitt bragt hjem til Norden. Det er beregnet at det i verden er nærmere 20 millioner pasienter som reiser internasjonalt, og at kostnadene er over 50 milliarder US dollar. I Europa er det pasienter som ønsker billig tannbehandling som utgjør hovedmengden av medisinske turister, og Ungarn og Polen er de prefererte land for odontologiske tjenester. Med disse landene er også høyt på listen over land i Europa som har høy grad av sykdomsfremkallende antibiotikaresistente bakterier, i Polen er 15 % av S. aureus MRSA og i Ungarn hele 22%. Dette i kontrast til de nordiske land som er blant de i Europa med lavest frekvens med patogene, antibiotikaresistente bakterier. De nordiske land har i 15 år testet helsearbeidere og pasienter som kommer fra sykehus utenfor Norden for MRSA – og det har gjort at Norden har få slike bakteriene i våre sykehus, fra 1–2,5 % av S. aureus er MRSA. Ettersom tannhelsepasienter ikke har vært inkludert i tidligere tiltak for beskyttelse av pasienter mot infeksjoner med resistente bakterier fra utlandet, er det grunn til se på odontologiske turistreiser til Ungarn og Polen som et potensielt problem. Norske helsemyndigheter har nå bedt også tannhelsepasienter om å avlyse planlagt behandling i utlandet, grunnet smittefare med resistente bakterier. Infections with antibiotic resistant bacteria have during the last 20 years become an increasing medical problem. Medical tourism has developed into a great marked; 20 million patients yearly to a cost of 50 billion US dollars. Dental tourists who want cheap dental services constitutes most of medical tourism in Europe, and Poland and Hungary are among the most frequently visited countries by European dental patients. However, Poland and Hungary have very high levels of antibiotic resistant bacteria, compared to the Nordic countries, who are among those with lowest frequency of antibiotic resistant infectious bacteria. One important factor has been a common Nordic effort to protect our hospitals by having a mandatory MRSA testing of health workers and patients coming from hospitals outside of the Nordic countries; from 1–2,5 % of S. aureus strains are MRSA in The Nordic, compared to Poland 15 % and Hungary 22%. Dental patients and health workers have not been included in this 15-year old program. As antibiotic resistance is becoming an increasing medical problem, we probably should regard dental tourism to Poland and Hungary as a potential problem. Norwegian health authorities did this summer issue a warning recommending medical and dental patients to cancel planned treatment outside the Nordic countries due to risk of becoming infected with antibiotic resistant bacteria.

Background Vibrio cholerae is a water-borne pathogen with a global burden estimate at 1.4 to 4.0 million annual cases. Over 94% of these cases are reported in Africa and more research is needed to understand cholera dynamics in the region. Cholera data are lacking, mainly due to reporting issues, creating barriers for widespread research on cholera epidemiology and management in Africa. Main body Here, we present datasets that were created to help address this gap, collating freely available sub-national cholera data for Nigeria and the Democratic Republic of Congo. The data were collated from a variety of English and French publicly available sources, including the World Health Organization, PubMed, UNICEF, EM-DAT, the Nigerian CDC and peer-reviewed literature. These data include information on cases, deaths, age, gender, oral cholera vaccination, risk factors and interventions. Conclusion These datasets can facilitate qualitative, quantitative and mixed methods research in these two high burden countries to assist in public health planning. The data can be used in collaboration with organisations in the two countries, which have also collected data or undertaking research. By making the data and methods available, we aim to encourage their use and further data collection and compilation to help improve the data gaps for cholera in Africa.

Background: Fibromyalgia is a common condition in the general population and is recognized as one of the most common conditions related to chronic pain and rheumatology. Fibromyalgia is a condition with severe burden on those affected, and furthermore an economical burden on society. Nevertheless, the etiology is yet to be fully clarified. It has been suggested that inflammation could be a part of the development and maintenance of fibromyalgia, and it has been proven that diet affect inflammation. Therefore, it would be interesting to investigate the relationship between the inflammatory potential of the diet and risk of fibromyalgia. Aim: To investigate the association between the inflammatory potential of the diet, measured by The Dietary Inflammatory Index (DII), and risk of fibromyalgia. Methods and material: Self-reported data on diet, characteristics and fibromyalgia were included from 21 814 women in the Norwegian Women and Cancer (NOWAC) study. The DII and energy-adjusted DII (E-DII) derived from a food frequency questionnaire (FFQ) were calculated and divided into quartiles. Cox proportional hazards were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the association between the DII and risk of fibromyalgia. Results: During an average 14.2 years of follow up a total of 692 cases of fibromyalgia were identified. Women in the third (DII HRQ3-Q1:1.27, CI: 1.03,1.57) and fourth (E-DII HRQ4-Q1:1.23, CI: 0.99,1.52) quartile were associated with an increased risk of fibromyalgia compared to women in the first quartile. When further adjusted for smoking status, education, gross household income, self-perceived health status, alcohol consumption and menopause status no significant associations were observed. Conclusion: Overall, no evident association was found between DII and risk of fibromyalgia and further studies are required to establish the relationship between DII and fibromyalgia.

During the past decades, extensive data from the general population have revealed that patients with acute myocardial infarction (MI) are at increased risk of venous thromboembolism (VTE, i.e., deep vein thrombosis [DVT] and pulmonary embolism [PE]). The risk is highest in the initial 0-6 months following an acute MI, and declines rapidly thereafter. The explanation for the observed association between MI and future risk of incident VTE is yet unknown. The overall aim of the present thesis was to identify triggers and risk factors of VTE in patients with MI that potentially can be used to identify MI patients with high risk of VTE. In Paper I, we used a case-crossover designed study with the incident VTE cases recruited from the fourth survey of the Tromsø Study. A case-crossover design is well-suited for studying transient risk factors or triggers on the risk of acute events. The study populations for Paper II and Paper III were recruited from the fourth, fifth and sixth surveys of the Tromsø Study. In Paper II, the participants consisted of a subgroup with extended genetic information. Study subjects in Paper II and Paper III were followed from the first survey they attended to the date of an incident VTE, the date of death or migration, or until administrative censoring at the end of follow-up. First, we found that an MI is a strong trigger factor for VTE, and that indirect risk factors related to the MI, in particular acute infections and immobilization, may to a large extent explain the observed association between MI and VTE. Second, we showed that five prothrombotic genotypes did not explain the increased risk of VTE in MI patients, implying that the prothrombotic genotypes may not play a crucial role in the development of VTE after MI. Third, we demonstrated that the combined effect of MI and obesity on overall VTE risk exceeded the sum of the separate effects. In non-obese subjects, MI was not associated with DVT and unprovoked VTE. Thus, the increased risk of these subtypes of outcomes in MI patients appeared to be dependent on the presence of obesity. Our findings imply that an acute MI is a strong trigger factor for VTE, and that indirect factors related to hospitalization for MI (i.e., acute infections and immobilization) and concomitant obesity could be essential in the risk assessment of VTE after MI.

BackgroundCurrent knowledge about the relationship between physical activity (PA) and cardiac remodeling is mainly derived from cross-sectional studies of athletes, and there is a knowledge gap of this association in the general adult and elderly population. Therefore, we aimed to explore the longitudinal association between cumulative PA and change in cardiac structure and function in a general adult and elderly population.MethodsThis longitudinal study includes 594 participants from the sixth (Tromsø6, 2007–08) and seventh (Tromsø7, 2015–16) survey of the Tromsø Study. Cardiac structure and function were assessed by echocardiography at two time points, and PA was self-reported by questionnaire at both time points. PA volume was expressed as cumulative PA (Low, Moderate, and Hard) and the association with left atrial (LA) and left ventricular (LV) structure and function was assessed using ANCOVA.ResultsOverall, LA diameter index (LADi) increased significantly more in Hard compared to Moderate PA (+0.08 cm/m2, 95% CI 0.01–0.15, p = 0.020) from Tromsø6 to Tromsø7. When stratified by sex or age, higher levels of cumulative PA were associated with increased LADi in males and in participants 2.7, 95% CI 0.23–7.57, p = 0.037). When stratified by sex or age, these changes in LVMi and indexed LV diameter (LVDi) were only significant in females. No significant associations were observed between cumulative PA and change in relative wall thickness, E/e' ratio, e' velocity, LV ejection fraction, and LADi/LVDi ratio.ConclusionHigher levels of cumulative PA were associated with increased LADi in males and participants

Staphylococcus aureus (S. aureus) is a human pathogen that can colonize skin and mucosa. Nasal carriage is associated with increased risk of autoinfection and transmission and it is therefore important to identify possible targets for prevention of carriage. Sex and age are the most important risk factors for S. aureus carriage, and hypotheses about sex-steroids as major host determinants have therefore emerged. We investigated if hormonal contraceptives and endogenous sex-steroids were associated with S. aureus carriage. We studied the transmission of S. aureus carriage in social networks and examined if known host risk factors for carriage were associated with social contact, indicating potential confounding or indirect transmission. We used data from the cross-sectional health surveys Fit Futures 1&2 and the sixth Tromsø Study. Females taking combination hormonal contraceptives (containing both estrogen and progestin) had doubled odds of nasal carriage compared to non-users. Users of progestin-only contraceptives had half the odds of nasal carriage compared to non-users. An increase in endogenous testosterone in women gave reduced odds of S. aureus nasal carriage. We found similar associations in adult men, but data were inconclusive. We demonstrate transmission of S. aureus and specific S. aureus genotypes in a social network of youths. We found higher risk of transmission with female friendships, while male friendships had no influence on transmission, although men were more frequent carriers. Use of alcohol more than twice a month, normal BMI, and moderate/high physical activity were associated with transmission. The results suggest that both exogenous and endogenous sex-steroid exposures are relevant in carriage of S. aureus. We show for the first time that the male predominance in carriage is determined by sex-specific predisposing host characteristics as S. aureus social transmission is less frequent than in females. We need more prospective studies to clarify causal relationships and targets for prevention.

Background: Health anxiety (HA) concerns worry of disease, and has mostly been examined in people with severe HA/hypochondriasis. However, HA can be conceptualised as a continuous construct, with levels ranging from low to severe. There is little knowledge on the distribution of HA as a continuous construct in the general population, nor the association between different levels of HA and healthcare use, physical disease and cardiovascular risk factors. Aim: To study the distribution of HA as a continuous construct in the general population, examine sociodemographic and social network factors associated with HA, and examine the association between HA and healthcare use, physical disease and cardiovascular risk factors. Methods: This thesis used cross-sectional data from the Tromsø study: Tromsø7 (2015-2016). 21 083 persons aged 40 years or older gave self-reported information on physical diseases, cardiovascular risk factors, and healthcare use in the last 12 months. HA was measured with Whiteley Index; possible scores ranged from 0-24. Sociodemographic and social network factors included age, gender, education, household income, friendship, and participation in organised activities. Results: HA was highly skewed in our sample of the general adult population, with an exponential distribution. Of the sociodemographic and social network variables, friendship had the highest association with HA level. HA as a continuous construct was associated with increased level of use of all types of healthcare services. HA was also consistently higher in the population reporting current or previous physical disease and cardiovascular risk factors, than in the healthy reference group. Conclusion: Our results support conceptualising HA as a continuous construct. Mean HA in the study sample was low, but all levels of HA were associated with increased healthcare use. Having physical disease and cardiovascular risk factors were consistently associated with increased HA. This indicates that all levels of HA deserve attention in future research. Bakgrunn: Forskning på temaet helseangst (HA) har i stor grad fokusert på alvorlig helseangst; personer som har symptombyrde likt de med hypokondri. HA er samtidig foreslått som et kontinuerlig fenomen, med alvorlighetsgrader som varierer fra lite til alvorlig. Alvorlig, eller høy grad av HA, er assosiert med høyt helsetjenesteforbruk og redusert livskvalitet. HA som et kontinuerlig fenomen har vi lite kunnskap om, heller ikke hvordan dette fordeler seg i den generelle befolkningen. I Norge og i verden er helsetjenesteforbruk økende, sammen med økende forekomst av fysisk sykdom og kardiovaskulære risikofaktorer. Sammenhengen mellom HA som et kontinuerlig fenomen og disse faktorene er derfor viktig å undersøke. Formål: Formålet med denne doktorgraden var å undersøke fordelingen av HA som et kontinuerlig fenomen i en voksen, generell befolkning, samt undersøke hvordan ulike faktorer var assosiert med HA; sosiodemografiske og sosiale faktorer, ulike typer helsetjenesteforbruk, fysisk sykdom og kardiovaskulære risikofaktorer. Metode: Doktorgraden brukte spørreskjemadata fra 21 083 personer som var 40 år eller eldre, som deltok på Tromsøundersøkelsen (Tromsø7) i 2015-2016, og hadde et tverrsnittdesign. HA ble målt med to versjoner av måleverktøyet Whiteley Index (WI-6 og WI-6-R), med en totalscore 0 til 24 der høyere score indikerer høyere HA. Sosiodemografiske faktorer inkluderte alder, kjønn, utdanning, husholdningsinntekt, vennskap og deltakelse i organisert aktivitet. Helsetjenesteforbruk inkluderte bruk av primærhelsetjenesten, somatisk spesialisthelsetjeneste og psykiatrisk spesialisthelsetjeneste de siste 12 måneder. Deltakerne rapporterte også om de hadde ulike somatiske sykdommer, nå eller tidligere, og om de hadde kardiovaskulære risikofaktorer. Resultat: HA var skjevfordelt i den generelle voksne befolkningen og hadde en eksponentiell fordeling. Av de sosiodemografiske variablene var vennskap den variabelen som var sterkest assosiert med HA. Alle grader av HA var assosiert med alle typer helsetjenesteforbruk. Grad av HA var gjennomgående høyere hos deltakere med fysisk sykdom sammenlignet med deltakere uten sykdom. Dette gjaldt både personer med nåværende og tidligere sykdom, samt de med kardiovaskulære risikofaktorer. Konklusjon: Våre resultater, med utgangspunkt i Tromsø7, viser HA som et kontinuerlig fenomen. Selv om gjennomsnittsscoren av HA var lav, var alle grader av HA assosiert med helsetjenesteforbruk. Sammenhengen mellom HA og fysisk sykdom var også konsekvent. Jeg mener våre funn indikerer at alle grader av HA er viktig og fortjener økt oppmerksomhet, både i fremtidig forskning og klinisk praksis.

High rates of cesarean section are associated with increased mortality and morbidity. To decrease cesarean sections without medical indication is complex and requires in-depth knowledge of local context and which groups to target for possible interventions. Our aim was to assess the role of maternal risk factors in relation to cesarean section in Georgia and Norway, two countries with diverging rates of cesarean sections. In addition, we wanted to assess the impact of a financial punitive policy with the aim to curb the high cesarean section rate in Georgia. The thesis consists of three studies, all of which used data from national birth registries. The first study assessed the relationship between maternal factors and cesarean section among primiparous women in Georgia. The second study assessed the prevalence of maternal risk factors for cesarean section over time and their relationship with the observed increase in cesarean sections in Norway. The third study assessed the impact of a financially punitive policy on rates of CS and perinatal outcomes in Georgia. Among primiparous women in Georgia, age ≥35 years, obesity, and birthweight ≥4000 g were strongly associated with cesarean section, while the proportion of women with risk factors for cesarean section was not unusually high. In Norway, the proportion of women with risk factors for cesarean section increased over time. Despite this development, the national cesarean section rate has remained stable since 2005. The financial policy did reduce the cesarean section rate in Georgia, mainly among primiparous women. We could not find that the policy impacted transfer to neonatal intensive care units or perinatal mortality. Our findings from Georgia and Norway indicate that maternal risk factors are not an important contributor to the increasing proportions of cesarean section. Financial regulations may play a role in reducing high rates of cesarean section but should be implemented with caution.

Chronic pain is a major health challenge, and musculoskeletal pain is among the main contributors to years lived with disability worldwide. Earlier research found an association between cold exposure at work and musculoskeletal pain. However, the literature is scarce, especially regarding chronic pain. It is a common belief that weather affects pain experience, but the literature on this topic is conflicting, and many researchers have concluded that there is no association. Therefore, the aims of this thesis are to study whether cold exposure at work is associated with chronic pain, and if weather affects pain tolerance. The results indicate that cold exposure at work is a risk factor for chronic pain and musculoskeletal complaints. Those working in a cold environment ≥25% of the time had more chronic pain, and the association was strongest for those who felt cold often. Those working in cold environment ≥25% of the time also had an increased risk of future musculoskeletal complaints. Cold pain tolerance was highest in the winter. There was a non-random variation in pressure pain tolerance. The timescale of this variation was 5.1 days (95% confidence interval: 4.0-7.2), which is similar to that of the meteorological variables studied. Further, both pressure pain tolerance and cold pain tolerance correlated with meteorological variables. These correlations changed over time and temperature and barometric pressure predicted future values of pressure pain tolerance. Taken together, these findings suggest that weather affects pain tolerance in a dynamic non-linear way.

Background/aims: Testicular cancer (TC) is the most common cancer among young men aged 20-40 years. The cure rates are excellent, an important factor being the chemotherapeutic agent cisplatin. This thesis aimed to investigate how TC treatment influenced the subsequent risk for metachronous contralateral (second) TC, non-TC second cancer (SC) and non-TC mortality. Methods: The Cancer Registry of Norway (CRN) identified all men diagnosed with TC 1980-2009. Complete TC treatment information was retrieved from medical journals for all eligible men (n=5724) and linked with the CRN and the Norwegian Cause of Death Registry. Crude cumulative incidences were estimated, and standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) were calculated to compare rates with the general population. Adjusted hazard ratios (HRs) were estimated to investigate the effect of treatment intensity. Results: Median follow-up time in the three papers was 16.6-18.7 years. Second TC developed in 218 (3.9%) men, and the 20-year cumulative incidence was 4% (95% CI 3.5-4.6). Treatment with cisplatin-based chemotherapy (CBCT) at first TC was associated with a significantly reduced second TC risk compared with surgery (HR 0.55). A dose-dependent relationship was observed, with a risk reduction for each additional CBCT cycle after 3, 4 and >4 cycles (HRs 0.53, 0.41 and 0.21, respectively). Additionally, older age at first TC was associated with a reduced second TC risk. Overall, 572 (10.2%) men developed a non-TC SC, and compared with the general population the risk was increased after treatment with surgery (SIR 1.28, 95% CI 1.05-1.56), CBCT (SIR 1.62, 95% CI 1.39-1.88) and radiotherapy (SIR 1.64, 95% CI 1.46-1.85). In total, 665 (12%) men died due to non-TC causes during follow-up, and the risk was increased after CBCT (SMR 1.23, 95% CI 1.07-1.43) and radiotherapy (SMR 1.28, 95% CI 1.15-1.43), but not after surgery. Compared with the general population, increased risk for suicide was observed after treatment with CBCT. The highest risk for SC and non-TC mortality was observed in those with young age at TC diagnosis. Compared with surgery, treatment with 1 CBCT cycle was not associated with increased risks, while increased risks were observed after ≥2 (SC) and ≥3 (mortality) CBCT cycles in those with >10 years follow-up. Conclusions: Previous TC treatment as well as age at diagnosis influenced the subsequent risks for second TC, SC and premature non-TC mortality. This information is important for all TC survivors and for health personnel involved in the follow-up. Bakgrunn: Testikkelkreft er den vanligste kreftsykdommen blant unge menn. Heldigvis kureres de aller fleste, og cellegiften cisplatin er en viktig årsak til dette. Målsetninga med denne avhandlinga var å undersøke hvordan testikkelkreftbehandling påvirker den seinere risiko for å utvikle metakron kontralateral testikkelkreft (ny testikkelkreft), sekundærkreft (ikke testikkelkreft) og risiko for død av andre årsaker enn testikkelkreft. Metode: Kreftregisteret identifiserte alle menn diagnostisert med testikkelkreft i perioden 1980-2009. Komplett informasjon om behandling ble samla fra medisinske journaler for alle menn inkludert i studien (n=5724) og koblet med data fra Kreftregisteret og Dødsårsaksregisteret. Kumulativ insidens ble estimert. For å sammenligne med den generelle befolkning kalkulerte vi standardisert insidensratio (SIR) og standardisert mortalitetsratio (SMR). Justerte hasard ratio (HR) ble estimert for å undersøke effekten av behandlingsintensitet. Resultater: Median oppfølgingstid i de tre arbeidene var 16.6-18.7 år. Det var 218 (3.9%) menn som utviklet en ny testikkelkreft, og 20 års kumulativ insidens var 4% (95% konfidensintervall (KI) 3.5-4.6). Behandling med cisplatin-basert cellegift (CBCT) ved første testikkelkreft var assosiert med en signifikant reduksjon i risiko for ny testikkelkreft sammenligna med kirurgi (HR 0.55). Vi observerte en dose-respons-sammenheng med en risikoreduksjon for hver påfølgende kur med CBCT etter 3 (HR 0.53), 4 (HR 0.41), >4 (HR 0.21). Alder >30 år ved første testikkelkreft var også assosiert med redusert risiko for en ny testikkelkreft. Totalt var det 572 (10.2%) menn som utviklet sekundærkreft, og sammenligna med den generelle befolkning var risikoen økt etter kirurgi (SIR 1.28, 95% KI 1.05-1.56), CBCT (SIR 1.62, 95% KI 1.39-1.88) og strålebehandling (SIR 1.64, 95% KI 1.46-1.85). Det var 665 (12%) menn som døde av andre årsaker enn testikkelkreft, og risikoen var forhøyet etter behandling med CBCT (SMR 1.23, 95% KI 1.07-1.43) og strålebehandling (SMR 1.28, 95% KI 1.15-1.43), men ikke etter kun kirurgi. Sammenligna med generell befolkning fant vi en økt risiko for selvmord etter behandling med CBCT. Den høyeste risikoen for sekundærkreft og død (ikke testikkelkreft) ble observert blant de som var yngst ved testikkelkreftdiagnosen. Konklusjon: Testikkelkreftbehandling og alder ved diagnose påvirker den seinere risikoen for ny testikkelkreft, sekundærkreft og for tidlig død. Dette er viktig informasjon for testikkelkreft-overlevere og helsepersonell involvert i oppfølginga av denne gruppa kreftoverlevere.

Intracerebral hemorrhage (ICH) is the second most common subtype of stroke. The prognosis is poor. However, it is to a large degree a preventable disease. The aim of our study was to analyse the association between cardiovascular risk factors and risk of ICH, and to assess the impact of changes in risk factor levels over time on incidence rates of ICH. In addition, we aimed to analyse short- and long-term mortality after ICH. The Tromsø study is an ongoing, longitudinal population-based study with repeated health surveys, with >45,000 attendees, providing an unique opportunity to assess longitudinal data on ICH epidemiology in a general population in a well-defined geographical area. Age, male sex, systolic and diastolic blood pressure were significantly associated with increased risk of ICH. Incidence rates were stable in the overall population in the period 1995-2013. In women incidence rates decreased, whereas incidence rates in men were stable. Lower blood pressure levels, and a steeper decrease in blood pressure in women may have contributed to the difference in trends. Despite an increase in treatment of hypertension, less than half of attendees of the last survey who had hypertension were on blood pressure-lowering drugs. Of these, two-thirds had uncontrolled hypertension. One-month case fatality and 5-year mortality rates remained stable. Participants who survived the first 30 days after ICH had a more than 60% increased 5-year risk of death compared with controls matched by birth-year and sex. The main cause of death was cardiovascular disease. Smoking, serum cholesterol and use of anticoagulant drugs at time of ICH were associated with increased risk of 5-year mortality after ICH. Our results indicate that there is a need for improved primary prevention of ICH. The stable short- and long-term mortality rates probably reflect the limited treatment possibilities of ICH and emphasize the urge for improved treatment strategies in the acute phase and a need for better knowledge on secondary prevention after ICH. Intracerebral blødning (ICB) er den nest hyppigste type av hjerneslag. Prognosen etter ICB er alvorlig, men det er en sykdom som i stor grad kan forebygges. Vi ønsket å undersøke hvilke risikofaktorer som øker risikoen for ICB, og om endringer i risikofaktorer over tid har påvirket forekomsten av ICB. I tillegg ønsket vi å undersøke kort- og langtidsdødelighet etter ICB. Tromsøundersøkelsen er en pågående longitudinell populasjonsbasert studie med repeterte målinger med over 45,000 deltakere. Undersøkelsen gir en unik mulighet til å analysere endringer over tid i insidens og dødelighet og risiko-faktorer for ICB i befolkningen. Vi fant at alder, mannlig kjønn, systolisk og diastolisk blodtrykk var signifikant assosiert med risikoen for ICB. Insidensraten av ICB var stabil i den samlede befolkningen i perioden 1995-2013. Vi observerte imidlertid en nedgang i insidens av ICB hos kvinner. Insidensratene hos menn var stabile. Lavere blodtrykksnivåer og en større nedgang i blodtrykk hos kvinner kan ha bidratt til forskjellen i trend. Blant deltakere med hypertensjon økte andelen som ble behandlet og hadde velregulert blodtrykk. Til tross for dette var mindre enn halvparten av deltakere med hypertensjon i siste del av studien medikamentelt behandlet. To tredeler av disse hadde ukontrollert hypertensjon. Det var ingen endring i 30-dagers fatalitet og 5-års dødelighet. Blant deltakere som var i live 30 dager etter ICB var risikoen for død i løpet av 5 år mer enn 60% høyere sammenlignet med kontroller matchet for fødselsår og kjønn. Forskjellen kunne forklares av en økt risiko for død av kardiovaskulær sykdom hos pasienter med ICB. Røyking, serum kolesterol og bruk av antikoagulantia på blødningstidspunktet var assosiert med økt risiko for 5-års dødelighet. De stabile insidensratene viser at det er behov for en forbedret forebygging av ICB. Stabile trender i kort- og langtidsdødelighet indikerer at det er et behov for mer effektiv behandling av ICB. I tillegg er det behov for økt kunnskap om sekundærprofylakse etter ICB.

Venous thromboembolism (VTE) is the formation of a blood clot in, most commonly, the deep veins of the lower extremities and the pulmonary circulation. VTE is a prevalent disease associated with severe short- and long-term complications. Negatively charged procoagulant phospholipids (PPL), and phosphatidylserine (PS) in particular, are vital to efficient coagulation activation, and found expressed on the surface of extracellular vesicles (EVs) and activated platelets. The overall aim of the present thesis was to develop an easily available and reproducible FXa-dependent clotting assay to measure PPL activity in plasma, and further use the assay to investigate the association between plasma PPL activity and the risk of VTE. In paper I, we investigate the impact of several pre-analytical conditions on EV concentration and size measured by Nanoparticle Tracking Analysis (NTA) and scanning electron microscopy (SEM). In paper II, we developed a modified FXa-dependent clotting assay by substituting the chemically phospholipid depleted plasma with PPL-depleted plasma obtained by ultracentrifugation. In paper III, we used our modified PPL assay to investigate the association between PPL clotting time (PPLCT) and the risk of incident VTE in a nested case-control study derived from a population based cohort (the Tromsø study). Previous studies have suggest that statin treatment reduced the risk of recurrent VTE. In paper IV, we investigated the impact of statin treatment (rosuvastatin) on PPL activity, using the modified PPL assay and plasma samples from the STAtins Reduce Thrombophilia trial. The impact of pre-analytical conditions (i.e. anticoagulants, centrifugation protocols, and fasting status) on EV measurements was demonstrated, and the obstacle of post-prandial lipoproteins interfering with NTA analysis was particularly highlighted. We found that the modified PPL assay displayed similar sensitivity and reproducibility compared to commercial assays based on chemically phospholipid-depleted plasma. We observed an inverse association between plasma PPLCT, assessed by the modified assay, and the risk of future VTE in a population-based nested case-control study. Additionally, rosuvastatin treatment caused a substantial decrease in plasma PPL activity in subjects with a history of VTE. The development of the modified PPL assay enabled us to perform high-quality measurements in large-scale studies. The inverse association between PPLCT and VTE risk supports an important role of plasma PPL in the pathogenesis of VTE and may partly explain the reduced risk of VTE recurrence observed by statin treatment.

Clustering of certain cardiometabolic risk factors is known as metabolic syndrome (MetS). MetS is associated with an unhealthy lifestyle and the prevalence is increasing alongside the obesity epidemic, making it an important public health issue. Both MetS and obesity are common in the adult population in rural Northern Norway, which comprises an ethnically mixed population. MetS is defined using ethnicity-specific cut-offs for waist circumference (WC), but there is much uncertainty with respect to obesity and ethnicity. Using various regression models we analysed data from the SAMINOR Study, comprising SAMINOR 1 (2003–2004) and SAMINOR 2 (2012–2014). We examined the change in prevalence of MetS between these two time points by sex and Sami/non-Sami ethnicity, and estimated the mortality of MetS, obesity-metabolic phenotypes, and continuous obesity measures. Next, we modelled the ethnic-specific relationships between metabolic markers and obesity measures. Finally, we examined the correlation between body mass index (BMI) and height, estimated a sample-specific height-corrected weight index and compared it in Sami and non-Sami. The prevalence of MetS increased over time and was present in more than one third of the population in 2012–2014. The increase differed by sex, but not ethnicity. MetS was associated with a 50% increased cardiovascular disease (CVD) mortality. In men, metabolically healthy obesity was associated with a three-fold increase in CVD mortality compared to metabolically healthy non-obesity. The association was linear and positive for all obesity measures regardless of metabolic health status in men. However, there were only weak associations between metabolically healthy obesity and mortality in women. We found no evidence of ethnic-specific relationships between obesity measures and metabolic markers. Because height differs in Sami and non-Sami, BMI comparisons are biased. Cardiometabolic health is deteriorating in rural Northern Norway. This development is not influenced by ethnicity. Previous findings of ethnic differences in obesity may be invalid.

Background Patients with wake-up ischemic stroke who have evidence of salvageable tissue on advanced imaging can benefit from intravenous thrombolysis. It is not known whether patients who do not fulfil such imaging criteria might benefit from treatment, but studies indicate that treatment based on non-contrast CT criteria may be safe. Tenecteplase has shown promising results in patients with acute ischemic stroke. The aim of the Tenecteplase in Wake-up Ischemic Stroke Trial (TWIST) is to compare the effect of thrombolytic treatment with tenecteplase and standard care versus standard care alone in patients with wake-up ischemic stroke selected by non-contrast CT. Methods/design TWIST is an international, investigator-initiated, multi-centre, prospective, randomized-controlled, open-label, blinded end-point trial of tenecteplase ( n = 300) versus standard care ( n = 300) in patients who wake up with an acute ischemic stroke and can be treated within 4.5 h upon awakening. Seventy-seven centres in 10 countries (Denmark, Estonia, Finland, Latvia, Lithuania, New Zealand, Norway, Sweden, Switzerland, and the United Kingdom) participate. The primary outcome is the modified Rankin Scale on the ordinal scale (0–6) at three months. Discussion TWIST aims to determine the effect and safety of thrombolytic treatment with tenecteplase in patients with wake-up ischemic stroke selected by non-contrast CT. Trial registration ClinicalTrials.gov NCT03181360. EudraCT Number 2014-000096-80.

Objective - Overweight, defined as excessive fat mass, is a long-standing worldwide public health challenge. Traditional anthropometric measures used to identify overweight and obesity do not assess body composition. The aim of this study was to examine population trends in general and abdominal fat mass during the past two decades. Methods - This study included participants from one or more consecutive surveys of the population-based Tromsø Study, including Tromsø 5 (conducted in 2001, n = 1,662, age 40-84 years), Tromsø 6 (2007-2008, n = 901, age 40-88 years), and Tromsø 7 (2015-2016, n = 3,670, age 40-87 years), with total body dual-energy x-ray absorptiometry scans. Trends in total fat and visceral adipose tissue (VAT) were analyzed by generalized estimation equation models in strata of sex and age groups. Results - Total fat and VAT mass increased during 2001 to 2016, with a larger increase during 2007 to 2016 than from 2001 to 2007 and among the youngest age group (40-49 years), particularly in women. Women had higher total fat mass than men, whereas men had higher VAT mass than women. Conclusions - General and abdominal dual-energy x-ray absorptiometry-derived fat mass increased during the past two decades in this general population. Of particular concern is the more pronounced increase in the past decade and in the younger age groups.

Background This study investigated cause of death, mortality rates and explored if baseline characteristics were associated with risk of death in patients with alcohol use disorder alone or poly-substance use disorders. Methods This was a prospective, longitudinal study of patients followed for 19 years after entering specialized treatment for substance use disorders. At baseline 291 patients (mean age 38.3 years, standard deviation 11.4 years, 72% male) with high psychiatric co-morbidity were recruited; 130 (45%) had lifetime alcohol use disorder alone, while 161 (55%) had poly-substance use disorders. Time and causes of death were gathered from the Norwegian Cause of Death Registry. Lifetime psychiatric symptom disorders and substance use disorders at baseline were measured with The Composite International Diagnostic Interview and personality disorders at baseline were measured with The Millon Clinical Multiaxial Inventory II. Results Patients with alcohol use disorder alone more often died from somatic diseases (58% versus 28%, p = 0.004) and more seldom from overdoses (9% versus 33%, p = 0.002) compared with patients with poly-substance use disorders. The crude mortality rate per 100 person year was 2.2 (95% confidence interval: 1.8–2.7), and the standardized mortality rate was 3.8 (95% confidence interval: 3.2–4.6) in the entire cohort during 19 years after entering treatment. Having lifetime affective disorder at baseline was associated with lower risk of death (Hazard Ratio 0.58, 95% confidence interval: 0.37–0.91). Older age was associated to increased risk of death among men (p

Introduction: HIV/AIDS continues to be amongst the leading causes of morbidity and mortality in Sub-Saharan Africa. There is no approved cure for HIV, but the disease can be managed using Anti-Retroviral Therapy (ART). If drug adherence of about 95% is achieved, odds for a better clinical outcome increase. The level of education as a marker for many socio- economic status indicators has an impact on an individual ́s health. If a country is devasted by the virus, the nation faces both macro and micro economic effects. HIV is the leading cause of reduced disability adjusted life years in eSwatini, and the country has the highest HIV prevalence in the world. However, through donor agencies like United States President Emergency Plan for AIDS Relief (PEPFAR) and Global Fund, eSwatini can provide free ART. Purpose: To determine if the level of education lowers the risk for VLS failure in eSwatini to a population that has universal access to ART. Material and Methods: The present study included a representative sample of 2025 HIV positive participants with traces of ART in blood-samples who have used ART for at least 6 months aged 15 years or older from the SHIMS 2 study in eSwatini 2016-2017. This cross- sectional survey includes data from blood samples analyses Viral Load Suppression (VLS) and Viral Load Count VLC) and self-administered questionnaires. Multi-variate logistic regression models were used to estimate the un-biased association between level of education and VLS- Failure. Results: The study included 620 (30.6%) males and 1405 (69.4%) females. The mean age was 40.25 years (range 15 - 80 years). 92.9% of the participants had achieved VLS. In a multivariate regression analysis, increased level of education was associated with lower risk of VLS- failure. After adjusting for confounders (adherence, age, and wealth quintile) people with tertiary education had 76 % less risk of VLS failure compared to people with primary education (OR, 0.24; CI, 0.05-1.03; P, 0.05). For Secondary and High-school levels of education, the ORs were 0.65 (CI, 0.43-0.99; P, 0.05) and 0.55 (CI, 0.33-0.92; P, 0.02) compared to the reference group (Primary education). Conclusion: This population-based survey is, to the best of our knowledge, the first study to provide data on the association of level of education and VLS-Failure in eSwatini in a population with blood traces of ART. This study reveals that people who have completed tertiary education have lower risks of VLS-Failure.

We estimate the weekly excess all-cause mortality in Norway and Sweden, the years of life lost (YLL) attributed to COVID-19 in Sweden, and the significance of mortality displacement. We computed the expected mortality by taking into account the declining trend and the seasonality in mortality in the two countries over the past 20 years. From the excess mortality in Sweden in 2019/20, we estimated the YLL attributed to COVID-19 using the life expectancy in different age groups. We adjusted this estimate for possible displacement using an auto-regressive model for the year-to-year variations in excess mortality. We found that excess all-cause mortality over the epidemic year, July 2019 to July 2020, was 517 (95%CI = (12, 1074)) in Norway and 4329 [3331, 5325] in Sweden. There were 255 COVID-19 related deaths reported in Norway, and 5741 in Sweden, that year. During the epidemic period of 11 March–11 November, there were 6247 reported COVID-19 deaths and 5517 (4701, 6330) excess deaths in Sweden. We estimated that the number of YLL attributed to COVID-19 in Sweden was 45,850 [13,915, 80,276] without adjusting for mortality displacement and 43,073 (12,160, 85,451) after adjusting for the displacement accounted for by the auto-regressive model. In conclusion, we find good agreement between officially recorded COVID-19 related deaths and all-cause excess deaths in both countries during the first epidemic wave and no significant mortality displacement that can explain those deaths.

Aims: The objectives of this study are to identify the proportion and characteristics of people with type 1 and 2 diabetes treated in primary, specialist and shared care and to identify the proportion of persons with type 2 diabetes reaching HbA1c treatment targets and the clinical risk factors and general practitioner and practice characteristics associated with treatment in specialist care. Methods: Population-based cross-sectional study including all adults ≥18 years diagnosed with diabetes in primary and specialist care in Salten, Norway. We used multivariable mixed-effects logistic regression models with level of care as outcome variable and population, general practitioner, and practice characteristics as exposure variables. Results: Of 2704 people with type 2 diabetes, 13.5% were treated in shared care and 2.1% in specialist care only. Of 305 people with type 1 diabetes, 14.4% received treatment in primary care only. The HbA1c treatment target of 53 mmol/mol (7.0%) was reached by 67.3% of people with type 2 diabetes in primary care versus 30.4% in specialist care. HbA1c, use of insulin, coronary heart disease, retinopathy and urban practice location were positively associated with treatment in specialist care. General practitioners’ use of a structured form and a diabetes nurse were negatively associated with specialist care. Conclusions: Of people with type 2 diabetes, 16% were treated in specialist care. They had higher HbA1c and more vascular complications, as expected from priority guidelines. The use of a structured diabetes form and diabetes nurses seem to support type 2 diabetes follow-up in primary care.

This is the peer reviewed version of the following article: Abeler, K., Bergvik, S. & Friborg, O. (2021). Daily associations between sleep and pain in patients with chronic musculoskeletal pain. Journal of Sleep Research, e13237, which has been published in final form at https://doi.org/10.1111/jsr.13237. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Patients with chronic pain commonly report sleep problems, and the evidence for a relationship between sleep disturbance and pain seems robust. The day‐to‐day associations between these constructs are less well studied, particularly with objective sleep measures such as actigraphy. Moreover, the concurrent presence of negative affective symptoms, as well as seasonality effects at extreme latitudes may complicate it further. Here, we studied 56 patients with chronic primary musculoskeletal pain conditions, contributing data in two separate 7‐day data‐collection periods during the summer and winter, respectively. The effect of self‐reported sleep quality, and actigraphy measured sleep duration, efficiency and timing on next‐day pain, as well as the effect of pain on the same sleep indices were estimated by generalised linear mixed regression models. The models were additionally adjusted for age, sex, education, data collection period, weekend, season and mental distress, with the latter two also specified as moderators. We observed a significant effect of pain as a predictor of next‐night sleep quality (p = .003) and marginally of next‐night sleep duration (p = .079). Conversely, sleep quality tentatively predicted next‐day pain (p = .063). No other day‐to‐day associations were present. Mental distress was the strongest predictor of pain, but it did not modify the sleep–pain associations, nor did season. In conclusion pain, sleep quality and mental distress are closely related, underscoring the importance of encompassing this complexity in assessment and treatment of patients with chronic pain.

Background The EuroQol EQ-5D is one of the most widely researched and applied patient-reported outcome measures worldwide. The original EQ-5D-3L and more recent EQ-5D-5L include three and five response categories respectively. Evidence from healthy and sick populations shows that the additional two response categories improve measurement properties but there has not been a concurrent comparison of the two versions in patients with low back pain (LBP). Methods LBP patients taking part in a multicenter randomized controlled trial of lumbar total disc replacement and conservative treatment completed the EQ-5D-3L and 5L in an eight-year follow-up questionnaire. The 3L and 5L were assessed for aspects of data quality including missing data, floor and ceiling effects, response consistency, and based on a priori hypotheses, associations with the Oswestry Disability Index (ODI), Pain-Visual Analogue Scales and Hopkins Symptom Checklist (HSCL-25). Results At the eight-year follow-up, 151 (87%) patients were available and 146 completed both the 3L and 5L. Levels of missing data were the same for the two versions. Compared to the EQ-5D-5L, the 3L had significantly higher floor (pain discomfort) and ceiling effects (mobility, self-care, pain/discomfort, anxiety/depression). For these patients the EQ-5D-5L described 73 health states compared to 28 for the 3L. Shannon’s indices showed the 5L outperformed the 3L in tests of classification efficiency. Correlations with the ODI, Pain-VAS and HSCL-25 were largely as hypothesized, the 5L having slightly higher correlations than the 3L. Conclusion The EQ-5D assesses important aspect of health in LBP patients and the 5L improves upon the 3L in this respect. The EQ-5D-5L is recommended in preference to the 3L version, however, further testing in other back pain populations together with additional measurement properties, including responsiveness to change, is recommended. Trial registration: retrospectively registered: https://clinicaltrials.gov/ct2/show/NCT01704677.

Bakgrunn De siste tiårene har det skjedd en endring i nordmenns inntak av sukkersøtet drikke (SSD) og kunstig søtet drikke (KSD). I 2019 var totalomsetningen for første gang større for kunstig søtet brus enn for sukkersøtet brus. Formålet med masteroppgaven var å få ny kunnskap om inntaket av KSD og SSD i en generell ungdomsbefolkning og undersøke hvordan inntaket varierte mellom kjønn og studieprogram, samt om brus/saft-vanene var assosiert med andre livsstils- og kostholdsfaktorer. Materiale og metode Studien er en tverrsnittsanalyse med datagrunnlag fra Fit Futures 1 (FF1). Studiepopulasjon inkluderer 874 deltakere fra de videregående skolene i Tromsø og Balsfjord. Disse deltakerne var mellom 15-17 år når FF1 ble gjennomført, og de hadde svart på alle variablene som inkluderes i oppgaven. Statistiske analyser ble gjennomført i SPSS. Resultater For begge kjønn, var det flere deltakere som drakk SSD enn KSD daglig. Det var signifikant forskjell mellom kjønn for begge drikketypene, der en større andel gutter enn jenter var dagligdrikkere. Det var klare forskjeller for begge kjønn i daglig inntak av SSD mellom elevene på yrkesfag og elevene på studiespesialisering inkludert idrettslinjer, der en større andel SSD-dagligdrikkere gikk yrkesfag. Det var signifikante assosiasjoner mellom drikketypene for begge kjønn. Daglig snusbruk for jenter hadde en sterk positiv assosiasjon med daglig inntak av SSD og en negativ assosiasjon med daglig inntak av KSD. For begge kjønn var det en sterk positiv assosiasjon mellom å spise junkfood ofte og drikke SSD daglig. Konklusjon Studien har gitt ny kunnskap om brus/saft-vaner hos en generell ungdomsbefolkning. Analysene har identifisert grupper av befolkningen med høyt inntak av SSD og KSD og andre livsstils- og kostholdsfaktorer som er assosiert med disse brus/saft-vanene. Resultatene kan brukes i videre kartlegging og som bidrag til å målrette forebyggende tiltak som eventuelt kan bidra til endring av disse vanene i positiv retning

Objectives - Dental caries is a major oral health problem among indigenous people worldwide, but knowledge on this issue among the indigenous Sámi people in Norway is scarce. The aim of the study was to describe dental caries experience in an adult population in core Sámi areas of Northern Norway and to assess the corresponding associations with socio‐demographic, socioeconomic and oral health‐related behavioural factors. Methods - This cross‐sectional study is based on data from the Dental Health in the North study (2033 participants aged 18‐75 years). A questionnaire was used to collect data on socio‐demographic, socioeconomic and oral health‐related behavioural factors. Clinical examinations were performed by dentists and dental hygienists at Public Dental Service (PDS) clinics in core Sámi areas of Northern Norway. Results - About 68% (n = 1380) of participants reported Sámi ethnicity, and the mean number of decayed (D), missed (M) and filled (F) teeth (T) was 16.2 (standard deviation [SD] = 6.7). The mean DMFT was 15.7 (SD = 6.7) among Sámi and 17.0 (SD = 6.7) among non‐Sámi. The mean DT among Sámi was 1.0 (SD = 1.6), with a significant, higher prevalence among coastal Sámi (DT = 1.3, SD = 1.8) than inland Sámi (DT = 0.8, SD = 1.5). Living in the coastal region, consumption of sugary soft drinks several times a week or daily, toothbrushing less than daily and irregular dental visits were associated with DT. Conclusions - Caries experience among adults in core Sámi areas of Northern Norway was common. Dental caries were more common in the coastal than the inland region, with minor differences in caries experience between Sámi and non‐Sámi people within these regions.

The increase of obesity coincides with a substantial decrease in cigarette smoking. We assessed post-cessation weight change and its contribution to the obesity epidemic in a general population in Norway. A total of 14,453 participants (52.6% women), aged 25–54 years in 1994, who attended at least two of four surveys in the Tromsø Study between 1994 and 2016, were included in the analysis. Hereof 77% participated in both the first and the last survey. Temporal trends in mean body mass index (BMI), prevalence of obesity (BMI ≥ 30 kg/m2) and daily smoking were estimated with generalized estimation equations. We assessed BMI change by smoking status (ex-smoker, quitter, never smoker, daily smoker), and also under a scenario where none quit smoking. In total, the prevalence of daily smoking was reduced over the 21 years between Tromsø 4 (1994–1995) and Tromsø 7 (2015–2016) by 22 percentage points. Prevalence of obesity increased from 5 – 12% in 1994–1995 to 21–26% in 2015–2016, where obesity in the youngest (age 25–44 in 1994) increased more than in the oldest (p We conclude that smoking cessation contributed to the increase in obesity in the population, but was probably not the most important factor. Public health interventions should continue to target smoking cessation, and also target obesity prevention.

The prevalence of cardiovascular disease is reportedly high in Russia; this thesis focuses on the prevalence of unrecognized myocardial infarction and self-reported health (mental health and physical health) as well as the association between both variables using data from the know your heart study. This survey is a cross sectional study from two Russian cities- Novosibirsk and Arkhangelsk (2015-2018). The study population was 4542 men and women aged 35-69 years recruited from the general population. The study composes of two parts 1) Base line interview at participants’ resident and 2) Health check at primary health care clinic.

Decisions on uptake of medicines and medical devices on health insurance schemes are increasingly based ona health technology assessment (HTA) process. In Norway, the process has included reimbursement of outpatientmedicines for two decades. During the past years, in-patient medicines, medical devices and morerecently vaccines are all included in the HTA system. In the present article, we outline the Norwegian HTAsystem including its central components and partners. HTA as a scientific approach puts evidence on efficacy,safety and value of interventions into a broader perspective, explicitly considering relevant factors, among theselegal, ethical and organisational aspects of the intervention. Although several combinations of aspects arepossible, the most common is an assessment of the relative effectiveness and cost-effectiveness of theintervention. Randomised controlled trials have long been considered the mainstay for assessment of clinicaleffectiveness pre-launch, while registry data have been used to inform safety post-lunch, by pharmacovigilance.Recently, we have seen a move towards more use of “real world evidence”, i.e. data from non-RCT sources,mainly from registries. A model-based approach is often used to assess cost-effectiveness, in this context,different types of evidence from different sources are often synthesized. In this paper we describe the centralcomponents of HTA with special emphasis on different observational data sources, such as the unique Norwegianhealth registries. We finally speculate on future directions for use of observational data in HTA, both in aglobal and Norwegian setting.

ObjectiveTo investigate conceptual knowledge about mammographic screening among Norwegian women.DesignWe administered a cross-sectional, web-based survey. We used multiple-choice questions and a grading rubric published by a research group from Australia.SettingOur Norwegian-language survey was open from April to June 2020 and targeted women aged 45–74 years.Participants2033 women completed our questionnaire. We excluded 13 women outside the target age range and 128 women with incomplete data. Responses from 1892 women were included in the final study sample.Primary and secondary outcome measuresThe questionnaire focused on women’s knowledge about the breast cancer mortality reduction, false positive results and overdiagnosis associated with mammographic screening. The primary outcome was the mean number of marks assigned in each of the three themes and overall. There were three potential marks for questions about breast cancer mortality, one for false positives and six for overdiagnosis.ResultsMost women (91.7%) correctly reported that screened women are less likely to die of breast cancer than non-screened women. 39.7% of women reported having heard of a ‘false positive screening result’ and 86.2% identified the term’s definition; 51.3% of women had heard of ‘overdiagnosis’ and 14.8% identified the term’s definition. The mean score was 2.59 of 3 for questions about breast cancer mortality benefit and 0.93 of 1 for the question about false positive screening results. It was 2.23 of 6 for questions about overdiagnosis.ConclusionsMost participants correctly answered questions about the breast cancer mortality benefit and false positive results associated with screening. The proportion of correct responses to questions about overdiagnosis was modest, indicating that conceptual knowledge about overdiagnosis was lower. Qualitative studies that can obtain in-depth information about women’s understanding of overdiagnosis may help improve Norwegian-language information about this challenging topic.

Venous thromboembolism (VTE), a collective term for deep vein thrombosis and pulmonary embolism, is a severe and multifactorial disease. Heritability has been found to explain up to 60% of VTE events, however, the role of genetics on VTE in cancer is scarcely studied. VTE occurs frequently in cancer patients and is a common cause of morbidity and mortality in this patient group. The aim of the present thesis was to investigate the impact of individual prothrombotic genotypes and the combination of genotypes in a genetic risk score (GRS) on the risk of VTE in cancer patients. Further, VTE may be the first sign of an underlying malignancy, and therefore we also aimed to investigate the effect of prothrombotic genotypes on VTE risk in subjects with an occult (i.e. undetected) cancer. All four papers in the present thesis utilize data from the fourth survey of the Tromsø Study (Tromsø 4), conducted in 1994-1995. The study populations in Paper I and III are also recruited from the second survey of the Nord-Trøndelag Health Study (HUNT 2), conducted in 1995-1997. Paper IV is based on the Scandinavian Thrombosis and Cancer (STAC) Cohort, which consists of merged data from the Tromsø 4 Study, the HUNT 2 Study and the Danish Diet, Cancer and Health (DCH) Study. Participants were followed from date of enrollment (1993-1997) in the different surveys to the date of an incident VTE event, the date of death or migration, or until end of follow-up (2007-2012). All potential cases of incident VTE events and cancer diagnoses during this time-period were recorded. We reported the effect of several single nucleotide polymorphisms (SNPs) on VTE risk in subjects with and without cancer. A SNP of the GP6 gene (rs1613662), affecting platelet adhesion and activation, displayed a decreased risk of VTE in cancer-free subjects, while an increased risk was observed in cancer patients homozygous for GP6 SNP. The genotype was also found to be associated with prothrombotic and metastatic cancers. These findings support a role of platelet reactivity in the pathogenesis of VTE, which may differ according to cancer status. The risk of VTE was also found to increase by the presence of ABO (rs8176719), and risk alleles in F5 (rs6025), F2 (rs1799963), FGG (rs2066865), and F11 (rs2036914) in both cancer-free subjects and in cancer patients. Moreover, a synergistic effect was discovered for the genetic variants of FGG, FVL and ABO in combination with cancer on the VTE risk. We found a dose-response relationship between number of risk alleles in the 5-SNP score (genetic risk score, GRS) and VTE risk in subjects with and without cancer, and the combined effect of cancer and high-number of risk alleles (≥4 risk alleles) yielded a supra-additive effect for the risk of VTE. However, the five prothrombotic genotypes, alone or combined, did not increase the risk of VTE in occult cancer. Our findings suggest that the genetic risk score and prothrombotic genotypes may be useful for identifying cancer patients at increased risk of VTE.

Although the problem of cardiovascular disease (CVD) in Russia has been the subject of attention for decades, a definitive and comprehensive explanation of why the CVD burden there is so high and generally greater than in many other countries has still not been found. In this thesis, I have attempted to advance research on these issues by examining the role of blood lipids, heart damage biomarkers (high sensitivity cardiac Troponin T and NT-proBNP), alcohol use, and diabetes. The methodological approach that I have chosen for Paper 1 and Paper 3 was to compare the biomarker levels in two population-based studies: Know Your Heart (Russia) and Tromsø 7 (Norway). There were no substantial differences in lipid profiles between Know Your Heart and Tromsø 7, however, higher mean high sensitivity C-reactive protein reflected higher pro-inflammatory status in Russian sample. Moreover there was evidence of higher levels of cardiac wall stretch (NT-proBNP) and heart damage (high sensitivity cardiac Troponin T) biomarkers in Know Your Heart compared to Tromsø 7. This work is the first time that levels of these heart damage biomarkers in two population-based studies in Russia and elsewhere have been undertaken. In Paper 3, I compared diabetes prevalence defined as self-reported diabetes and/or medication use for diabetes and/or glycated haemoglobin (HbA1c) ≥ 6.5 % between Know Your Heart and Tromsø 7. Obesity (measured as BMI and waist circumference) explained a substantial proportion of differences in diabetes prevalence between KYH and Tromsø 7 in women but not in men. The analysis in Paper 2 was based on data from Know Your Heart study only and was a comparison of biomarker levels in extremely heavy drinkers in Russian addiction treatment centers to those in the general population of Arkhangelsk (Russia). The levels of NT-proBNP, high sensitivity cardiac Troponin T, and high sensitivity C-reactive protein were much higher in extremely heavy drinkers compared to non-problem drinkers. This thesis implicates non-atherosclerotic pathways as a possible explanation for high cardiovascular disease burden in Russia. This conclusion is supported by higher levels of NT-proBNP and high sensitivity cardiac Troponin T in Know Your Heart compared to Tromsø 7, while atherogenic lipoproteins are at similar levels in both studies. The biomarker profile of extremely heavy drinkers in Russian addiction treatment centers supports the non-ischemic damage as an aetiological pathway leading to heart disease as a consequence of heavy alcohol use. High prevalence of diabetes mellitus in Russia, including a higher proportion of undiagnosed and untreated cases, contributes to cardiovascular disease burden of both atherosclerotic and non-atherosclerotic origin. Strategies to reduce the burden of high cardiovascular disease in Russia should include steps to reduce the prevalence of heavy drinking as well as tackling the high burden of diabetes.

Background Dental caries is the most prevalent non-communicable health condition globally. The surface-based susceptibility hierarchy indicates that surfaces in the same group have similar susceptibility to caries, where the most susceptible group consists of occlusal surfaces of first molars and buccal surfaces of lower first molars, and the least susceptible surfaces are smooth and proximal surfaces of first premolars, canines and incisors. Therefore, fluoride in the drinking water could impact one group more than the other group. The present study examined the association between fluoride levels in the drinking water and dental caries experience in adults in the context of varying tooth surface susceptibility. Methods Data from the cross-sectional National Lithuanian Oral Health Survey conducted in 2017–2019 included a stratified random sample of 1398 35–74-year-olds (52% response rate). Dental caries experience in dentine was measured at a surface level. The surfaces were grouped according to their caries susceptibility (group 1 being the most and group 4 the least susceptible), and dental caries experience was calculated separately for each susceptibility group, creating four outcomes. Information about explanatory variable, fluoride levels in the drinking water, was provided by the water suppliers. The questionnaire inquired about potential determinants: sociodemographic characteristics and oral health-related behaviors. Chi-square, Mann–Whitney U and Kruskal Wallis tests were used for descriptive statistics, and linear regression analyses to examine the association between fluoride levels and four outcomes. Results The proportions of median decayed, missing, filled surfaces decreased following the surface-based susceptibility hierarchy (group 1–33%, group 2–28%, group 3–24%, group 4–15%). When adjusted for potential determinants, higher-level fluoride (≥ 0.7 ppm vs Conclusions The higher-level fluoride in the drinking water associated with lower dental caries experience in adults and this was observed in all surface-based susceptibility groups. However, there is a need to validate the surface-based susceptibility hierarchy in longitudinal adult studies.

Aim - To assess the adherence to medication therapy for secondary prevention and achievement of treatment goals in persons with coronary heart disease (CHD) in a general population. Methods - This project used data from the seventh wave of the Tromsø Study, alone and linked with data from the Norwegian Prescription database (NorPD). Participants self-reporting CHD were included (n = 1483). In Paper I, the associations between guideline adherence and achievement of treatment goals were assessed using logistic regression. Paper II validated the self-reported medication use by comparing by it to pharmacy dispensings from NorPD. In Paper III medication adherence was calculated based on pharmacy dispensings from NorPD, and the associations between medication adherence and blood pressure and low-density-lipoprotein (LDL)-cholesterol were explored using linear regressions. Results - Use of lipid-lowering drugs (LLDs) was reported by 76% of the study population, antihypertensive drugs by 72% and acetylsalicylic acid (ASA) by 66%. Agreement between self-reported medication use and pharmacy dispensings was high for all three medication groups (kappa ≥0.61). Average medication adherence (proportion of days covered) was 0.94 for both LLDs and antihypertensive drugs and 0.97 for ASA. The recommended treatment goal for LDL-cholesterol was reached by 9% of the population. Achieving this treatment goal was associated with use of LLDs. Lower LDL-cholesterol was also associated with higher adherence to LLDs. The blood pressure goal was reached by 58% of the population, but achieving this goal was not significantly associated with using antihypertensive drugs. There was also no statistically significant association between adherence to antihypertensive drugs and lower systolic or diastolic blood pressure. Conclusions - Use of and adherence to medications for secondary prevention of CHD was high, but achievement of treatment goals for blood pressure and especially LDL-cholesterol was low. Our results indicate that the lipid-lowering and antihypertensive therapy is not sufficiently intense. The prescription level might be a potential target to improve achievement of treatment goals among persons with CHD and hence prevent new CHD events.

Background - Almost all health care interventions have the potential to be associated with risk to patient safety. Different terminologies are used to define treatment induced risk to patient safety and a common definition is the term adverse effect. Beyond the concept of adverse effect and specific to homeopathy is the concept of homeopathic aggravation. Homeopathic aggravation describes a transient worsening of the patients’ symptoms, which is not understood as an adverse effect. In order to ensure patient safety within a homeopathic treatment setting, it is important to identify adverse effects, as well as homeopathic aggravations, even though it may be challenging to distinguish between these two concepts. To date there is an obvious lack of systematic information on how adverse effects and homeopathic aggravations are reported in studies. This systematic review and meta-analysis focuses on observational studies, as a substantial amount of the research base for homeopathy are observational. Method - Eight electronic databases, central webpages and journals were searched for eligible studies. The searches were limited from the year 1995 to January 2020. The filters used were observational studies, human, English and German language. Adverse effects and homeopathic aggravations were identified and graded according to The Common Terminology Criteria for Adverse Effects (CTCAE). Meta-analysis was performed separately for adverse effects and homeopathic aggravations. Results - A total of 1,169 studies were identified, 41 were included in this review. Eighteen studies were included in a meta-analysis that made an overall comparison between homeopathy and control (conventional medicine and herbs). Eighty-seven percent (n = 35) of the studies reported adverse effects. They were graded as CTCAE 1, 2 or 3 and equally distributed between the intervention and control groups. Homeopathic aggravations were reported in 22,5% (n = 9) of the studies and graded as CTCAE 1 or 2. The frequency of adverse effects for control versus homeopathy was statistically significant (P < 0.0001). Analysis of sub-groups indicated that, compared to homeopathy, the number of adverse effects was significantly higher for conventional medicine (P = 0.0001), as well as other complementary therapies (P = 0.05). Conclusion - Adverse effects of homeopathic remedies are consistently reported in observational studies, while homeopathic aggravations are less documented. This meta-analysis revealed that the proportion of patients experiencing adverse effects was significantly higher when receiving conventional medicine and herbs, compared to patients receiving homeopathy. Nonetheless, the development and implementation of a standardized reporting system of adverse effects in homeopathic studies is warranted in order to facilitate future risk assessments.

Adherence to treatment for tuberculosis (TB) has been a concern for many decades, resulting in the World Health Organization's recommendation of the direct observation of treatment in the 1990s. Recent advances in digital adherence technologies (DATs) have renewed discussion on how to best address nonadherence, as well as offering important information on dose-by-dose adherence patterns and their variability between countries and settings. Previous studies have largely focussed on percentage thresholds to delineate sufficient adherence, but this is misleading and limited, given the complex and dynamic nature of adherence over the treatment course. Instead, we apply a standardised taxonomy – as adopted by the international adherence community – to dose-by-dose medication-taking data, which divides missed doses into 1) late/noninitiation (starting treatment later than expected/not starting), 2) discontinuation (ending treatment early), and 3) suboptimal implementation (intermittent missed doses). Using this taxonomy, we can consider the implications of different forms of nonadherence for intervention and regimen design. For example, can treatment regimens be adapted to increase the “forgiveness” of common patterns of suboptimal implementation to protect against treatment failure and the development of drug resistance? Is it reasonable to treat all missed doses of treatment as equally problematic and equally common when deploying DATs? Can DAT data be used to indicate the patients that need enhanced levels of support during their treatment course? Critically, we pinpoint key areas where knowledge regarding treatment adherence is sparse and impeding scientific progress.

Traumatic brain injury (TBI) is a significant cause of disability, but little is known about sex and gender differences after TBI. We aimed to analyze the association between sex/gender, and the broad range of care pathways, treatment characteristics, and outcomes following mild and moderate/severe TBI. We performed mixed-effects regression analyses in the prospective multi-center Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, stratified for injury severity and age, and adjusted for baseline characteristics. Outcomes were various care pathway and treatment variables, and 6-month measures of functional outcome, health-related quality of life (HRQoL), post-concussion symptoms (PCS), and mental health symptoms. The study included 2862 adults (36% women) with mild (mTBI; Glasgow Coma Scale [GCS] score 13–15), and 1333 adults (26% women) with moderate/severe TBI (GCS score 3–12). Women were less likely to be admitted to the intensive care unit (ICU; odds ratios [OR] 0.6, 95% confidence interval [CI]: 0.4-0.8) following mTBI. Following moderate/severe TBI, women had a shorter median hospital stay (OR 0.7, 95% CI: 0.5-1.0). Following mTBI, women had poorer outcomes; lower Glasgow Outcome Scale Extended (GOSE; OR 1.4, 95% CI: 1.2-1.6), lower generic and disease-specific HRQoL, and more severe PCS, depression, and anxiety. Among them, women under age 45 and above age 65 years showed worse 6-month outcomes compared with men of the same age. Following moderate/severe TBI, there was no difference in GOSE (OR 0.9, 95% CI: 0.7-1.2), but women reported more severe PCS (OR 1.7, 95% CI: 1.1-2.6). Men and women differ in care pathways and outcomes following TBI. Women generally report worse 6-month outcomes, but the size of differences depend on TBI severity and age. Future studies should examine factors that explain these differences Ana Mikolic´ et al., 2020; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.

Aerosolutvikling i sammenheng med behandling i munnhulen kan innebære risiko for smitteoverføring mellom pasienter og tannhelsepersonell. Denne artikkelen (Del 1) beskriver hva aerosol er og mulig innvirkning for helse. Hovedfokus i denne artikkelen er mikrobielle aerosoler, og hvilke situasjoner og prosedyrer som forårsaker mikrobielle aerosoler i tannhelseklinikken. Det produseres forskjellige former for mikrobielle aerosoler i en tannhelseklinikk, og mest aerosol blir utviklet ved bruk av roterende instrumenter, treveissprøyte og maskinell scaling. Smitterisiko fra infeksiøs aerosol omtales med eksempler fra noen bakterielle og virus-overførbare sykdommer i tannhelseklinikken. Tannhelsepersonell bør kjenne til mulige helsemessige konsekvenser fra aerosol i tannhelseklinikken for å kunne forebygge luftsmitte. Denne kunnskapen er avgjørende for å ivareta både pasientens og tannhelsepersonellets helse.

Aerosoler blir generert i sammenheng med flere behandlingsprosedyrer og situasjoner i tannhelseklinikken. Aerosoler i tannhelseklinikken kan være infeksiøse og føre til smitte mellom tannhelsepersonell og pasienter. Forskjellige tiltak for å begrense smitte fra infeksiøs aerosol, beskrives og diskuteres. Det er urealistisk å forvente at lokale aerosoler kan elimineres i sammenheng med behandling i munnhulen. Eksponering fra aerosol kan begrenses med tekniske tiltak. Aerosolgenerering og smitterisiko fra mikrobielle aerosoler, kan begrenses ved administrative og organisatoriske tiltak. Personlig verneutstyr som munnbind, øyebeskyttelse og hansker vil, forutsatt riktig bruk, også kunne bidra til å redusere faren for potensiell smitteoverføring. Spesielle tiltak under covid-19 pandemien i forhold til aerosoler samt risikovurdering og råd for hvordan tannhelsepersonell kan holde seg oppdatert faglig, omtales i artikkelen. Tannhelsepersonell må kjenne til og forstå konsekvensene av mikrobiell aerosol i tannhelseklinikken, og hvordan man kan minimere uønsket helseskade for pasienter og klinikkpersonale.

Bakgrunn: Det metabolske syndrom (MetS) brukes om en gruppering av risikofaktorer assosiert med en fordobling av risiko for kardiovaskulære sykdommer og fem ganger økt risiko for utvikling av diabetes mellitus type-2. Prevalensen øker globalt og utviklingen relateres til økning i prevalensen av fedme og nedgang i fysisk aktivitet. Formål: Formålet med studien er å beskrive assosiasjonen mellom MetS og fysisk aktivitet i fritid blant deltakere i den syvende Tromsøundersøkelsen (Tromsø 7, 2015-2016), i kjønns- og aldersgrupper. Materiale og metode: Totalt 21 083 kvinner og menn deltok i Tromsø 7, hvorav 19 789 deltakere (52 % kvinner) med valide data ble brukt til videre analyser i 10-års aldersgrupper fordelt etter kjønn. Forhold mellom alder og risikofaktorer/kriterier for MetS ble testet med Pearson’s kjikvadrattest. Assosiasjonen mellom MetS og fysisk aktivitet ble undersøkt etter kjønn med binomial logistisk regresjon (odds ratio (OR) og 95% konfidensintervall (KI)), ujustert og justert for alder, røyking og alkoholforbruk. Resultater: Blant stillesittende menn var prevalensen av MetS 47,0 % i gruppen 40-49 år og 65,3 % i gruppen 70+ år, mens blant de aktive var tilsvarende prevalens 10,6 % og 27,3 %. Blant stillesittende kvinner var prevalensen 28,7 % i gruppen 40-49 år og 64,4 % i gruppen 70+ år, mens blant de aktive var tilsvarende prevalens 3,6 % og 40,0 %. MetS og fysisk aktivitet var inverst korrelert både i justerte og ujusterte modeller. Aktivitetsnivåene lett, moderat og aktiv var assosiert med OR på hhv. 0,64 (0,57-0,73), 0,38 (0,33–0,43) og 0,18 (0,13–0,24) for menn og 0,55 (0,48-0,62), 0,32 (0,27-0,38) og 0,24 (0,16-0,36) for kvinner ved justering for alder. Konklusjon: MetS var inverst assosiert med selvrapportert aktivitetsnivå. Stillesittende og aktivt aktivitetsnivå hadde hhv. høyest og lavest andel MetS. Det anbefales å øke bevisstheten rundt viktigheten av fysisk aktivitet i fritids rolle i forhold til MetS.

Innledning: Posttraumatisk stresslidelse (PTSD) kan være forbundet med eksponering for traumer, og det har de senere år blitt etterspurt mer forskning om veteraners psykiske helse etter tjenestegjøring. Denne oppgaven tar for seg forekomst av PTSD-symptomer blant norske veteraner som har tjenestegjort i Libanon som en del av UNIFIL i årene 1978 -1998. Hypotesen er at veteraner som kan ha vært utsatt for en større mengde konflikter og potensielt traumer, kan ha en høyere forekomst av PTSD-symptomer. Metoder: Oppgaven bygger på data om selvrapporterte PTSD-symptomer blant 10063 veteraner, som en del av Forsvarets UNIFIL-studie som i år 2014 - 2015 fulgte opp alle norske UNIFIL-soldater fra den aktuelle tidsperioden. Utvalget er inndelt i «høykonfliktseksponerte» og «lavkonfliktseksponerte» basert på konfliktnivået i periodene de har tjenestegjort. Resultatene bygger på sjekklisten PCL-17-M, hvor en cut-off på ≥ 44 er ansett som en prediktor for sannsynlig PTSD. Deskriptive analyser og Pearson Chi-square test er utført i SPSS, signifikansnivå er satt til p < 0,05. Resultater: Av det totale utvalget på 10063 veteraner har 6 % PTSD-symptomer. I den høykonfliktseksponerte gruppen er forekomsten 6,8 % og i den lavkonfliktseksponerte 5,1 %. Denne forskjellen er signifikant (p < 0,01). Fordelt etter kjønn, hvor kvinner utgjør 3 % av det totale utvalget, har 3,4 % av disse PTSD-symptomer og det er liten forskjell mellom høy – og lavkonfliktseksponerte. Mennene utgjør 97 % av utvalget, her er forekomsten 5,1 % og 6,9 % for henholdsvis for lav – og høykonfliktseksponerte, og denne forskjellen er signifikant (p < 0,01). Forskjellen mellom kjønnene er ikke signifikant (p = 0,056). Konklusjon: Høykonfliktseksponerte veteraner har 33 % høyere relativ risiko for PTDS-symptomer sammenliknet med de lavkonfliktseksponerte. Forekomsten er 6 ganger høyere enn i den generelle norske befolkningen der den er 1 %, men lavere enn i internasjonale studier hvor opp mot 10 % av veteranene har PTSD. Kvinnelige veteraner har noe lavere forekomst av PTSD-symptomer enn menn, og relativt lik andel blant høy- og lavkonfliktseksponerte. For menn er det en signifikant høyere forekomst av selvrapporterte PTSD-symptomer blant høykonfliktseksponerte enn blant lavkonfliktseksponerte. Dette samsvarer med forskning om at alvorlige hendelser med fare for liv og helse, eller gjentakende traume kan være en utløsende faktor for PTSD.

Cesarean section rates remain high in Georgia. As a cesarean section in the first pregnancy generally lead to a cesarean section in subsequent pregnancies, primiparous women should be targeted for prevention strategies. The aim of the study was to assess factors associated with cesarean section among primiparous women. The study comprised 17,065 primiparous women with singleton, cephalic deliveries at 37–43 weeks of gestation registered in the Georgian Birth Registry in 2017. The main outcome was cesarean section. Descriptive statistics and logistic regression analysis were used to identify factors associated with cesarean section. The proportion of cesarean section was 37.1% with regional variations from 14.2% to 57.4%. Increased maternal age, obesity and having a baby weighing ≥4000 g were all associated with higher odds of cesarean section. Of serious concern for newborn well-being is the high proportion of cesarean section at 37–38 weeks of gestation. Further research should focus on organizational and economical aspects of maternity care to uncover the underlying causes of the high cesarean section rate in Georgia. The first author received a PhD grant from UiT The Arctic University of Norway to carry out the study.