Hemostatic factors and risk of coronary heart disease in general populations: new prospective study and updated meta-analyses

<p>Background: Activation of blood coagulation and fibrinolysis may be associated with increased risk of coronary heart disease. We aimed to assess associations of circulating tissue plasminogen activator (t-PA) antigen, D-dimer and von Willebrand factor (VWF) with coronary heart disease risk.</p> <p>Design: Prospective case-control study, systematic review and meta-analyses.</p> <p>Methods: Measurements were made in 1925 people who had a first-ever nonfatal myocardial infarction or died of coronary heart disease during follow-up (median 19.4 years) and in 3616 controls nested within the prospective population-based Reykjavik Study.</p> <p>Results: Age and sex-adjusted odds ratios for coronary heart disease per 1 standard deviation higher baseline level were 1.25 (1.18, 1.33) for t-PA antigen, 1.01 (0.95, 1.07) for D-dimer and 1.11 (1.05, 1.18) for VWF. After additional adjustment for conventional cardiovascular risk factors, corresponding odds ratios were 1.07 (0.99, 1.14) for t-PA antigen, 1.06 (1.00, 1.13) for D-dimer and 1.08 (1.02, 1.15) for VWF. When combined with the results from previous prospective studies in a random-effects meta-analysis, overall adjusted odds ratios were 1.13 (1.06, 1.21) for t-PA antigen (13 studies, 5494 cases), 1.23 (1.16, 1.32) with D-dimer (18 studies, 6799 cases) and 1.16 (1.10, 1.22) with VWF (15 studies, 6556 cases).</p> <p>Conclusions: Concentrations of t-PA antigen, D-dimer and VWF may be more modestly associated with first-ever CHD events than previously reported. More detailed analysis is required to clarify whether these markers are causal risk factors or simply correlates of coronary heart disease.</p&gt

Decision aids to assist Icelandic men with PSA testing and prostate cancer treatment decision-making

Prostate cancer (PC) is the second most common cancer among men globally and the most common cancer among Icelandic men. Early detection of PC is possible with a prostate-specific antigen (PSA) test. Before making a decision about PSA testing and before deciding which treatment to choose for localized PC, shared decision-making (SDM) is encouraged as many uncertainties are associated with those decisions and it is important that patients understand the pros and cons of all options before making a decision. Decision aids (DAs) have been found to enhance SDM by, for example, affecting patient involvement and patient-physician communication. While it is known that Icelandic men, newly diagnosed with PC, lack information about the pros and cons of different treatment options, no study to date has examined how much information Icelandic men receive about the pros and cons of PSA testing prior to undergoing PSA testing. Furthermore, DAs for PSA testing decision and PC treatment decision are not available in Icelandic. To address these limitations, the aims of the current Thesis were to; 1) establish the need for an Icelandic PSA testing DA, 2) translate and culturally adapt a pre-existing PSA testing DA for Icelandic men, and 3) develop, culturally adapt and extend an interactive DA to assist men, diagnosed with localized PC, to make a treatment decision. In Paper I, all Icelandic men diagnosed with PC from 2015 to 2020 were invited to participate in a quantitative study evaluating how much information men receive about the pros and cons of PSA testing prior to undergoing a PSA test. Participants were 471 men aged 51 to 95 (M = 71.9, SD = 7.3). In Paper II, a pre-existing DA for PSA testing decision was translated and culturally adapted, and usability was tested in a mixed-methods study, first in a qualitative study and then in a quantitative study. Ten men, aged 51 to 66 (M = 59.9, SD = 5.6) participated in the qualitative study using a semi-structured interview and a questionnaire. Minor modifications were made to the DA following the qualitative study, whereafter, a quantitative study was conducted among 135 men aged 50 to 70 years (M = 59.7, SD = 5.2) to evaluate the final version of the DA. In Paper III, a DA for localized PC treatment decision was culturally adapted, modified and extended. The usability of the DA was evaluated in a mixed-methods study, first in a qualitative study and then in a quantitative study. The qualitative study included semi-structured interviews and a usability scale and participants were 12 men, aged 58 to 80 years (M = 70.66, SD=6.58), diagnosed with PC. A thematic analysis of the interviews led to minor revisions of the DA. Then a quantitative evaluation of the usability of the final version of the DA was conducted among 11 newly diagnosed men with PC, aged 60 to 74 (M = 66.18, SD = 4.79). Findings from Paper I underscored the need for an Icelandic PSA testing DA as Icelandic men lack information before making a PSA testing decision. Half of the participants received information about the pros and cons of PSA testing, a third did not receive any information and 22.2% did not even know they were being tested. Additionally, more than 80% of the men reported none or little knowledge of PSA testing. The findings of Paper II demonstrated that participants found the translation and cultural adaptation of the DA for PSA testing decision to be successful, as they found the DA helpful and comprehensible and almost all participants said they would recommend it to others. The results of Paper III demonstrated that the DA for treatment decision for localized PC was well received by participants. Participants were satisfied with the DA and the realistic information on side effects that was presented. They found the information about the pros and cons of treatment options helpful, and all noted they would recommend the DA to others facing the same decision. Currently, a randomized clinical trial is being conducted to evaluate the effectiveness of the DA for localized PC treatment decision. The main results from the overall Thesis were that men do not receive adequate information about the pros and cons of PSA testing and that the DAs for PSA testing and localized PC treatment decisions were successfully modified. DAs have been shown to enhance SDM, be cost-effective, and have a minimal burden on the healthcare system. Therefore, the usage of DAs is likely to benefit both patients and healthcare providers of the Icelandic healthcare system.Blöðruhálskirtilskrabbamein (BHKK) er annað algengasta krabbamein meðal karlmanna á heimsvísu og algengasta krabbameinið meðal íslenskra karlmanna. Mikilvægt er að skilja kosti og galla PSA (prostate-specific antigen) prófs, sem getur greint BHKK á frumstigi, og einnig kosti og galla mögulegra meðferðarúrræða við staðbundnu BHKK áður en ákvörðun er tekin þar sem ýmsir óvissuþættir fylgja þessum ákvörðunum. Ákvörðunartæki geta stuðlað að sameiginlegri ákvörðunartöku sjúklings og heilbrigðisstarfsfólks en slík ákvörðunartaka hefur jákvæð áhrif á þátttöku sjúklings í ákvörðuninni sem og á samskipti sjúklings og heilbrigðisstarfsfólks. Rannsóknir sýna að íslenska menn sem nýgreindir eru með BHKK, skortir upplýsingar um kosti og galla þeirra meðferðaleiða sem í boði eru. Hinsvegar hefur ekki verið rannsakað hvort íslenskir menn fái nægar upplýsingar um kosti og galla PSA prófs áður en þeir fara í slíkt próf. Hvorki ákvörðunartæki sem aðstoðar menn við að taka ákvörðun varðandi PSA próf né ákvörðunartæki sem aðstoðar menn við að taka ákvörðun um meðferðarleið fyrir BHKK eru í boði á íslensku. Því var markmið þessarar doktorsrannsóknar að 1) sýna fram á að það væri þörf fyrir íslenskt ákvörðunartæki sem aðstoðar menn áður en þeir taka ákvörðun varðandi PSA próf, 2) þýða yfir á íslensku og staðfæra ákvörðunartæki sem aðstoðar við ákvarðanatöku varðandi PSA próf, 3) þróa og staðfæra gagnvirkt ákvörðunartæki til að aðstoða menn, sem hafa greinst með staðbundið BHKK, við að taka ákvörðun um hvaða meðferðarúrræði henti þeim best. Fyrsta rannsóknin var megindleg rannsókn þar sem kannað var hversu miklar upplýsingar menn fengu um PSA próf áður en þeir fóru í slíkt próf. Þátttakendur voru íslenskir menn, 471 talsins, á aldrinum 51 til 95 ára (M = 71.9, SD = 7.3) sem höfðu greinst með BHKK á árunum 2015 til 2020. Í næstu rannsókn var ákvörðunartæki, sem aðstoðar menn við ákvörðunartöku varðandi PSA próf, þýtt og staðfært. Síðan var blandaðri aðferð beitt til að kanna notagildi ákvörðunartækisins, fyrst í eigindlegri rannsókn og síðan megindlegri. Samtals tóku 10 menn á aldrinum 51 til 66 ára (M = 59.9, SD = 5.6) þátt í eigindlegu rannsókninni þar sem notuð voru hálfstöðluð viðtöl og spurningalistar til að meta upplifun þátttakenda af ákvörðunartækinu. Niðurstöður eigindlegu rannsóknarinnar leiddu til smávægilegra breytinga á ákvörðunartækinu sem síðan var notendaprófað í megindlegri rannsókn meðal 135 manna á aldrinum 50 til 70 ára (M = 59.7, SD = 5.2). Í þriðju rannsókninni var ákvörðunartæki fyrir meðferðarákvörðun fyrir staðbundið BHKK staðfært og umfang þess aukið. Samtals tóku 12 menn á aldrinum 58 til 80 ára (M = 70.66, SD=6.58) þátt og allir höfðu þeir verið greindir með BHKK. Notendaprófun var gerð með hálfstöðluðum viðtölum og þátttakendur beðnir um að svara kvarða sem metur notandaupplifun. Þemagreining á viðtölunum leiddi í ljós að gera þurfti minniháttar breytingar á ákvörðunartækinu. Lokaútgáfa ákvörðunartækisins var síðan notendaprófuð í megindlegri rannsókn meðal 11 manna á aldrinum 60 til 74 ára (M = 66.18, SD = 4.79) sem voru nýgreindir með BHKK. Niðurstöður fyrstu rannsóknarinnar leiddu í ljós að íslenskir menn fá ekki nægar upplýsingar áður en þeir fara í PSA próf og þar af leiðandi er þörf fyrir íslenskt ákvörðunartæki sem aðstoðar menn með ákvörðun varðandi PSA próf. Um helmingur þátttakenda fékk upplýsingar um kosti og galla PSA prófs áður en þeir fóru í prófið, þriðjungur fékk engar upplýsingar og 22.2% þátttakenda vissu ekki fyrirfram að það væri verið að mæla PSA gildin þeirra. Þar að auki greindu 80% þátttakenda frá að þeir hefðu litla eða enga þekkingu haft á kostum og göllum PSA prófs áður PSA gildið þeirra var mælt. Niðurstöður annarar rannsóknarinnar, á ákvörðunartæki fyrir PSA ákvörðun leiddi í ljós að bæði þýðing og staðfærsla ákvörðunartækisins að íslenskum aðstæðum tókst vel. Þátttakendum fannst ákvörðunartækið hjálplegt og auðskiljanlegt og nánast allir þátttakendur sögðust myndu mæla með því við aðra í sömu sporum. Niðurstöður þriðju rannsóknarinnar, á ákvörðunartæki fyrir meðferðarákvörðun fyrir staðbundið BHKK sýndi sömuleiðis fram á að þátttakendur voru ánægðir með tækið og þær upplýsingar sem þar var að fá. Sérstaklega voru þeir ánægðir með þær raunsæju upplýsingar um aukaverkanir sem voru gefnar í tækinu og þeim fannst einnig upplýsingar um kosti og galla hverrar meðferðar gagnlegar. Að auki sögðu allir þátttakendur að þeir myndu mæla með ákvörðunartækinu við aðra í sömu sporum. Nú fer fram slembiröðuð klínísk rannsókn til að meta virkni ákvörðunartækisins fyrir meðferðarúrræði við staðbundnu BHKK. Á heildina litið eru niðurstöður doktorsrannsóknarinnar þær að íslenska karlmenn fá ekki nægar upplýsingar áður en þeir fara í PSA próf og að þátttakendur voru ánægðir með bæði ákvörðunartækin. Niðurstöður benda til þess að ákvörðunartækin geti komið að góðum notum fyrir menn sem standa frammi fyrir þessum ákvörðunum. Rannsóknir hafa sýnt að ákvörðunartæki auka þátttöku sjúklinga í ákvörðunartöku, eru hagkvæm og auka ekki álag innan heilbrigðiskerfisins. Ákvörðunartæki ættu því að nýtast vel innan íslenska heilbrigðiskerfisins bæði fyrir sjúklinga og heilbrigðisstarfsfólk en jafnframt fyrir heilbriðiskerfið allt

Long-term interleukin-6 levels and subsequent risk of coronary heart disease: Two new prospective studies and a systematic review

Background The relevance to coronary heart disease (CHD) of cytokines that govern inflammatory cascades, such as interleukin-6 (IL-6), may be underestimated because such mediators are short acting and prone to fluctuations. We evaluated associations of long-term circulating IL-6 levels with CHD risk (defined as nonfatal myocardial infarction [MI] or fatal CHD) in two population-based cohorts, involving serial measurements to enable correction for within-person variability. We updated a systematic review to put the new findings in context. Methods and Findings Measurements were made in samples obtained at baseline from 2,138 patients who had a first-ever nonfatal MI or died of CHD during follow-up, and from 4,267 controls in two cohorts comprising 24,230 participants. Correction for within-person variability was made using data from repeat measurements taken several years apart in several hundred participants. The year-to-year variability of IL-6 values within individuals was relatively high (regression dilution ratios of 0.41, 95% confidence interval [CI] 0.28-0.53, over 4 y, and 0.35, 95% CI 0.23-0.48, over 12 y). Ignoring this variability, we found an odds ratio for CHD, adjusted for several established risk factors, of 1.46 (95% CI 1.29-1.65) per 2 standard deviation (SD) increase of baseline IL-6 values, similar to that for baseline C-reactive protein. After correction for within-person variability, the odds ratio for CHD was 2.14 (95% CI 1.45-3.15) with long-term average ("usual'') IL-6, similar to those for some established risk factors. Increasing IL-6 levels were associated with progressively increasing CHD risk. An updated systematic review of electronic databases and other sources identified 15 relevant previous population-based prospective studies of IL-6 and clinical coronary outcomes (i.e., MI or coronary death). Including the two current studies, the 17 available prospective studies gave a combined odds ratio of 1.61 (95% CI 1.42-1.83) per 2 SD increase in baseline IL-6 (corresponding to an odds ratio of 3.34 [95% CI 2.45-4.56] per 2 SD increase in usual [long-term average] IL-6 levels). Conclusions Long-term IL-6 levels are associated with CHD risk about as strongly as are some major established risk factors, but causality remains uncertain. These findings highlight the potential relevance of IL-6-mediated pathways to CH

Serum Uric Acid and Coronary Heart Disease in 9,458 Incident Cases and 155,084 Controls: Prospective Study and Meta-Analysis

BACKGROUND: It has been suggested throughout the past fifty years that serum uric acid concentrations can help predict the future risk of coronary heart disease (CHD), but the epidemiological evidence is uncertain. METHODS AND FINDINGS: We report a “nested” case-control comparison within a prospective study in Reykjavik, Iceland, using baseline values of serum uric acid in 2,456 incident CHD cases and in 3,962 age- and sex-matched controls, plus paired serum uric acid measurements taken at baseline and, on average, 12 y later in 379 participants. In addition, we conducted a meta-analysis of 15 other prospective studies in eight countries conducted in essentially general populations. Compared with individuals in the bottom third of baseline measurements of serum uric acid in the Reykjavik study, those in the top third had an age- and sex-adjusted odds ratio for CHD of 1.39 (95% confidence interval [CI], 1.23–1.58) which fell to 1.12 (CI, 0.97–1.30) after adjustment for smoking and other established risk factors. Overall, in a combined analysis of 9,458 cases and 155,084 controls in all 16 relevant prospective studies, the odds ratio was 1.13 (CI, 1.07–1.20), but it was only 1.02 (CI, 0.91–1.14) in the eight studies with more complete adjustment for possible confounders. CONCLUSIONS: Measurement of serum uric acid levels is unlikely to enhance usefully the prediction of CHD, and this factor is unlikely to be a major determinant of the disease in general populations

Mannan binding lectin as an adjunct to risk assessment for myocardial infarction in individuals with enhanced risk

Inflammation can predispose to myocardial infarction (MI), and mannan binding lectin (MBL) promotes phagocytic clearance of inflammatory agents, but the predictive value of MBL levels for MI is not known. MBL was analyzed in subgroups of the population-based Reykjavik study, a cohort of 19,381 participants recruited from 1967. MBL levels were very stable over time (self correlation: 0.86). In a cross-sectional group from the original cohort (n = 987), high MBL (>1,000 μg/L) was associated with a greatly lowered odds ratio for MI (0.64, P < 0.001). To verify this finding, a nested case control sample (n = 1,309) was randomly selected from the cohort. High MBL at recruitment was also associated with decreased MI risk in this follow-up group, but to a lesser extent and not significant for the whole group, smokers, or hypertensive individuals. However, high MBL was as in the cross-sectional group, associated with greatly decreased MI risk in diabetic (P = 0.02) or hypercholesterolemic individuals (P = 0.004). This also applied to raised erythrocyte sedimentation rate (P = 0.007). Diabetic patients with high MBL did not have a higher MI risk than nondiabetic individuals. Our findings indicate that high MBL may predict decreased likelihood of MI, particularly in diabetics, and are consistent with the possibility that MBL may promote clearance of atherogenic agents

Loss of heterozygosity at chromosome 11 in breast cancer: association of prognostic factors with genetic alterations.

We examined DNA from 116 female and four male breast cancer patients for loss of heterozygosity (LOH). DNA was analysed by polymerase chain reaction using ten microsatellite markers on chromosome 11. Three distinct regions of LOH were identified: 11p15.5, 11q13 and 11q22-qter with a LOH frequency of 19, 23 and 37-43% respectively. The marker D11S969 showing the highest frequency of LOH (43%) is located at the 11q24.1-q25 region. No previous molecular genetic studies have shown frequent LOH at the region telomeric to q23 on chromosome 11. Southern analysis revealed that LOH at 11q13 was due to amplification, whereas LOH at 11q22qter was due to deletion. LOH at 11p15.5 was associated with paucity of hormone receptor proteins, high S-phase and positive node status. An association was found between LOH at 11q13 and positive node status. LOH at the 11q22-qter region correlated with a high S-phase fraction. A significant association was found between LOH at 11p15 and chromosome regions 17q21 (the BRCA1 region) and 3p

Chromosome alterations and E-cadherin gene mutations in human lobular breast cancer

We have studied a set of 40 human lobular breast cancers for loss of heterozygosity (LOH) at various chromosome locations and for mutations in the coding region plus flanking intron sequences of the E-cadherin gene. We found a high frequency of LOH (100%, 31/31) at 16q21–q22.1. A significantly higher level of LOH was detected in ductal breast tumours at chromosome arms 1p, 3p, 9p, 11q, 13q and 18q compared to lobular breast tumours. Furthermore, we found a significant association between LOH at 16 q containing the E-cadherin locus and lobular histological type. Six different somatic mutations were detected in the E-cadherin gene, of which three were insertions, two deletions and one splice site mutation. Mutations were found in combination with LOH of the wild type E-cadherin locus and loss of or reduced E-cadherin expression detected by immunohistochemistry. The mutations described here have not previously been reported. We compared LOH at different chromosome regions with E-cadherin gene mutations and found a significant association between LOH at 13 q and E-cadherin gene mutations. A significant association was also detected between LOH at 13q and LOH at 7q and 11q. Moreover, we found a significant association between LOH at 3 p and high S phase, LOH at 9p and low ER and PgR content, LOH at 17p and aneuploidy. We conclude that LOH at 16q is the most frequent chromosome alteration and E-cadherin is a typical tumour suppressor gene in lobular breast cancer. © 1999 Cancer Research Campaig

Incidence and prevalence of total joint replacements due to osteoarthritis in the elderly: risk factors and factors associated with late life prevalence in the AGES-Reykjavik Study.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Total joint replacements (TJRs) should be considered as one of few definite endpoints in osteoarthritis research. We analyzed factors associated with late-life prevalence and risk factors for incidence of TJRs due to osteoarthritis in a population based cohort.After exclusion of inflammatory arthritis and fractures as causes of TJR, 5170 participants in the AGES-Reykjavik Study (mean age (SD) 76.4(6), 58 % females) were included for osteoarthritis studies. Three thousand one hundred thirty-three of them had a follow-up visit 5 years later.The prevalence of having at least one joint replacement operation due to OA was 13.6 % and the yearly incidence was 1.4 %/year during the five-year follow-up. Factors positively associated with late life prevalence of TJR included BMI, hand OA severity, female gender, finger length ratio and spine BMD. Risk factors for TJRs in the incidence group were symptoms at initial visit, prior TJR in the contralateral joint and BMI. Much stronger associations were seen for TKR than for THR with discriminatory analysis showing an AUC 0.71 for late life prevalence and 0.84 for the incidence.This study illustrates the importance of the different information expressed by late life prevalence vs. incidence on the factors associated with severe osteoarthritis of the knee and hip. The observation that prior TJR is a risk factor for subsequent TJR in the contralateral joint has not been described previously. The high power predictions for TKR suggest that a predictive model may be feasible, particularly if it can be extended by the addition of further predictive variables, perhaps through genetic, biomarker or imaging data.NIH N01-AG-12100 NIA Intramural Research Program Hjartavernd (the Icelandic Heart Association) Althingi (the Icelandic Parliament) Icelandic Osteoarthritis Fund University of Iceland Research Fun

Body size at birth and age-related macular degeneration in old age

Purpose To study associations between body size at birth and age-related macular degeneration (AMD) in old age. Methods The study sample consists of 1497 community-dwelling individuals (56.1% women) aged 67-89 years with birth data and retinal data collected twice in old age 5 years apart. Birth data (weight, length, birth order) were extracted from original birth records. Digital retinal photographs were graded to determine AMD status. Data on covariates were collected at the baseline physical examination in old age. Multivariable regression analyses were used to study the association between birth data and AMD adjusting for known confounding factors, including birth year cohort effects. Results The prevalence and 5-year incidence of any AMD were 33.1% and 17.0%, respectively. Men and women born in 1930-1936 were significantly leaner and slightly longer at birth compared to those in earlier birth cohorts. There were no consistent associations between weight, length or ponderal index (PI) at birth and AMD in old age even when stratified by birth cohort. Age-related macular degeneration (AMD) prevalence (39.8%) and 5-year incidence (28.6%) were highest in individuals who were in the highest quartile of PI at birth and who were obese in old age. Conclusion Body size at birth was not consistently associated with AMD in old age, suggesting that intrauterine growth might have little direct importance in the development of AMD in old age. It is possible that some yet unknown factors related to larger size at birth and obesity in old age may explain differences in the prevalence and incidence of AMD in the ageing population.Peer reviewe