Can artificial intelligence separate the wheat from the chaff in systematic reviews of health economic articles?

OBJECTIVES: Artificial intelligence-powered tools, such as ASReview, could reduce the burden of title and abstract screening. This study aimed to assess the accuracy and efficiency of using ASReview in a health economic context. METHODS: A sample from a previous systematic literature review containing 4,994 articles was used. Previous manual screening resulted in 134 articles included for full-text screening (FT) and 50 for data extraction (DE). Here, accuracy and efficiency was evaluated by comparing the number of identified relevant articles with ASReview versus manual screening. Pre-defined stopping rules using sampling criteria and heuristic criteria were tested. Robustness of the AI-tool's performance was determined using 1,000 simulations. RESULTS: Considering included stopping rules, median accuracy for FT articles remained below 85%, but reached 100% for DE articles. To identify all relevant articles, a median of 89.9% of FT articles needed to be screened, compared to 7.7% for DE articles. Potential time savings between 49 and 59 hours could be achieved, depending on the stopping rule. CONCLUSIONS: In our case study, all DE articles were identified after screening 7.7% of the sample, allowing for substantial time savings. ASReview likely has the potential to substantially reduce screening time in systematic reviews of health economic articles.

All circulating EpCAM+CK+CD45- objects predict overall survival in castration-resistant prostate cancer.

BACKGROUND: Presence of five or more circulating tumor cells (CTC) in patients with metastatic carcinomas is associated with poor survival. Although many objects positive for epithelial cell adhesion molecules and cytokeratin (EpCAM+CK+) are not counted as CTC, they may be an important predictor for survival. We evaluated the association between these objects and survival in patients with prostate cancer. PATIENTS AND METHODS: Included in this follow-up study were 179 patients with castration-resistant prostate cancer. CellSearch was used to isolate EpCAM+ objects and to stain DNA, cytokeratin and CD45. All EpCAM+CK+ objects were subdivided into seven classes on the basis of predefined morphological appearance in 63 independent samples. Association of each class with survival was studied using Kaplan-Meier and Cox regression analyses. RESULTS: Each EpCAM+CK+CD45- class showed a strong association with overall survival (P < 0.001). This included small tumor microparticles (S-TMP), which did not require a nucleus and thus are unable to metastasize. A higher number of objects in any class was associated with decreased survival. A good prediction model included large tumor cell fragments (L-TCF), age, hemoglobin and lactate dehydrogenase. Models with S-TMP or CTC instead of L-TCF performed similarly. CONCLUSION: EpCAM+CK+CD45- that do not meet strict definitions for CTC are strong prognostic markers for survival.

Experience with multiple control groups in a large population-based case-control study on genetic and environmental risk factors.

We discuss the analytic and practical considerations in a large case-control study that had two control groups; the first control group consisting of partners of patients and the second obtained by random digit dialling (RDD). As an example of the evaluation of a general lifestyle factor, we present body mass index (BMI). Both control groups had lower BMIs than the patients. The distribution in the partner controls was closer to that of the patients, likely due to similar lifestyles. A statistical approach was used to pool the results of both analyses, wherein partners were analyzed with a matched analysis, while RDDs were analyzed without matching. Even with a matched analysis, the odds ratio with partner controls remained closer to unity than with RDD controls, which is probably due to unmeasured confounders in the comparison with the random controls as well as intermediary factors. However, when studying injuries as a risk factor, the odds ratio remained higher with partner control subjects than with RRD control subjects, even after taking the matching into account. Finally we used factor V Leiden as an example of a genetic risk factor. The frequencies of factor V Leiden were identical in both control groups, indicating that for the analyses of this genetic risk factor the two control groups could be combined in a single unmatched analysis. In conclusion, the effect measures with the two control groups were in the same direction, and of the same order of magnitude. Moreover, it was not always the same control group that produced the higher or lower estimates, and a matched analysis did not remedy the differences. Our experience with the intricacies of dealing with two control groups may be useful to others when thinking about an optimal research design or the best statistical approach.

Recurrent thrombosis and survival after a first venous thrombosis of the upper extremity.

BACKGROUND: Little is known about the consequences of a first venous thrombosis in the upper extremity. We studied the incidence of, survival, and risk factors for recurrence in a follow-up study. METHODS AND RESULTS: We followed up 224 patients 18 to 70 years of age after a first venous thrombosis of the arm. Information was collected through anticoagulation clinics, the national death registry, discharge letters, and questionnaires. The median follow-up was 3 years, during which time 30 patients experienced a recurrent event, yielding an incidence rate of 43.2 per 1000 person-years. Survival was reduced: 55 of 224 patients died, which was 5.4-fold higher than age- and sex-adjusted population rates (standardized mortality ratio, 5.4; 95% CI, 4.2 to 7.0). The risk of recurrence was 2-fold higher in women than in men (hazard ratio, 1.8; 95% CI, 0.9 to 3.9). A central venous catheter at the time of first thrombosis was associated with a reduced risk of recurrence. A body mass index > or =25 kg/m(2) and a first nonsubclavian thrombosis appeared to increase the risk of a recurrent event. Prothrombotic mutation carriers did not appear to have an increased recurrence risk. CONCLUSIONS: The risk of recurrence was high, with women, patients with body mass index > or =25 kg/m(2), and patients with a first nonsubclavian vein thrombosis having a higher risk of recurrence. Patients with a first venous thrombosis of the arm have a poor vital prognosis.

Donor profiles: demographic factors and their influence on the donor career.

BACKGROUND AND OBJECTIVES: Studying the contribution of demographic factors to the donor career provides important knowledge to be used for donor management. The aim of this study is to gain insight into donor characteristics, more specifically into the demographic profile of active vs. resigned donors, and multi-gallon vs. occasional donors. MATERIALS AND METHODS: The study population consisted of all registered Dutch whole-blood donors between 1 January 2004 and 1 January 2005 (N = 370 470). The effect of several blood donor characteristics and demographic variables on (i) resigning donating and (ii) being a multi-gallon donor were assessed. Blood donor characteristics were extracted from the blood bank information system and included age, sex, blood group, number of donations and invitations. Demographic characteristics were constituted by population data on urbanization level, socio-economic status (income, housing value), and ethnicity. RESULTS: Men clearly resigned less often than women (odds ratio (OR) 0.73, 95% confidence interval (CI) 0.72-0.75). Being older than 24 years, having a high income, a high-priced house, living in less urbanized areas or areas with relatively few ethnically diverse people also reduced the stopping risk. With respect to multi-gallon donorship, men were five times more often multi-gallon donor than women (OR 5.27, 95% CI 5.15-5.39) irrespective of the number of donation invitations. Furthermore, multi-gallon donors appeared to live in urbanized areas and have a higher income than occasional donors. CONCLUSION: Our results show that different donor profiles can be distinguished. Differences between active and resigned donors include age, the number of donations, sex, socio-economic-status, ethnicity, and urbanization level. The factors highly associated with being a multi-gallon donor are sex, age, socio-economic status, and to a lesser extent urbanization level. Donor profiles do provide the blood bank with knowledge on their donor population, which may be used as valuable information for donor recruitment and retention policies.

Mechanisms of the factor V Leiden paradox.

OBJECTIVE: Carriers of the factor V Leiden mutation (FVL-carriers) have a substantially increased risk of deep venous thrombosis (DVT), whereas the risk of pulmonary embolism (PE) is only mildly increased compared with noncarriers. So far few studies have investigated possible mechanisms for this so-called FVL paradox. METHODS AND RESULTS: Consecutive patients with a first DVT or PE were included in a large population-based case-control study (MEGA study). Patients, aged 18 to 70 years, provided a questionnaire, DNA (n=3313), or plasma (n=1474). Surgery, injury, and travel were considered thrombosis-provocative. Of 2063 patients with isolated DVT, 20% were FVL-carrier, as were 8% of the 885 patients with isolated PE. Among DVT patients, FVL-carriers had their thrombi more often proximal and a higher number of affected veins than noncarriers. No differences were observed between FVL-carriers and noncarriers in time between provocation and diagnosis, in vitro coagulation time, and thrombus density. Compared with patients with both DVT and PE, isolated DVT patients more often had thrombi located distally and had a similar number of affected veins. Compared with isolated PE patients, isolated DVT patients had a similar time between provocation and diagnosis, and similar in vitro coagulation time and thrombus density. CONCLUSIONS: Although some effects were differential for FVL-carriers and noncarriers, and some were differential for PE and DVT patients, none of the potential mechanisms offered a clear explanation.

Venous thrombosis in the elderly.

While the overall incidence of venous thrombosis is 1-2 per 1000 per year, it is close to 1% per year in the very old. The case-fatality rate of thrombosis is high in the elderly, particularly among those with cancer. The risk of major hemorrhage during anticoagulant treatment is also strongly age-dependent, contributing to the vulnerability of the old patient with thrombosis. From this perspective it is surprising that far fewer studies into the etiology and treatment of venous thrombosis have focused on the elderly than on young and middle-aged patients. In this review we discuss that, while environmental risk factors, such as immobilization and cancer, are important causes of thrombosis in the elderly, abnormalities of the coagulation system are equally, or even more, important than in young individuals. In addition to a review of the literature, new data are presented from the MEGA-study. Thrombosis in the elderly should be a focus of future studies.

Regular sports activities decrease the risk of venous thrombosis.

BACKGROUND: Stasis of the blood has been postulated as a major cause of venous thrombosis. However, little is known about the effect of stimulating the blood flow in order to prevent venous thrombosis through, for example, sports activities. OBJECTIVES: In a large population-based case-control study (MEGA study), we studied whether participating in sports activities on a regular basis was associated with venous thrombosis risk. PATIENTS/METHODS: Consecutive patients with a first venous thrombosis of the leg or a pulmonary embolism, and control subjects, consisting of partners of the patients and randomly selected control subjects from the general population, were asked to participate. Sports activities and other risk factors for venous thrombosis were reported in a standardized mailed questionnaire. Participants with malignancy were excluded. RESULTS: Out of 3608 patients, 1136 (31.5%), and of our 4252 control subjects 1686 (39.7%), participated in sports activities. Participating in sports activities reduced the risk of venous thrombosis compared with not participating in sports activities [odds ratio (OR) 0.64; 95% CI 0.58-0.71]. Risk reductions were similar after adjustment for sex, age and body mass index (OR(adj) 0.71; 95% CI 0.64-0.78) and when the analysis was restricted to healthy individuals (OR(adj) 0.67; 95% CI 0.58-0.78). No differences in risk were found for various frequencies, intensities and types of sport. CONCLUSION: Regular sports activities reduce the risk of venous thrombosis.

The association of prothrombin A19911G polymorphism with plasma prothrombin activity and venous thrombosis: results of the MEGA study, a large population-based case-control study.

BACKGROUND: Prothrombin (FII) G20210A mutation and elevated plasma prothrombin activity are known risk factors for venous thrombosis. The risk of venous thrombosis among 19911G carriers of the prothrombin A19911G polymorphism has not been extensively investigated. OBJECTIVES AND METHODS: We assessed prothrombin activity, FIIG20210A, and FIIA19911G polymorphisms in a large population-based case-control study, the Multiple Environmental and Genetic Assessment (MEGA) study of risk factors for venous thrombosis. Four thousand three hundred and sixty-five consecutive patients with a first episode of deep vein thrombosis of the leg or pulmonary embolism were included. The control group (n = 4779) consisted of partners of patients or persons gathered using a random-digit dialing method. We studied the effect of FIIA19911G polymorphism on prothrombin activity and thrombosis risk, also in combination with factor V Leiden. RESULTS: Among FII20210-GG control subjects, FII19911-GG carriers had 7.1% [95% confidence interval (CI): 5.7-8.5] higher mean prothrombin activity than FII19911-AA carriers and the risk for GG carriers was 1.43-fold increased compared to AA carriers [odds ratio (OR) 1.43; 95% CI: 1.27-1.61]. Among FII20210-GA control carriers, the mean prothrombin activity in both FII19911-AA and -AG carriers was nearly equivalent [131.7% and 133.4%; mean difference (95% CI) = 1.7% (-7.2-10.7)]. Because of genetic linkage, FII19911-GG carriers were very rare on a FII20210-GA background, as only one FII20210A carrier had FII19911-GG. In FII20210-GA carriers, the OR increased from 3.05 (95% CI: 2.17-4.27) in subjects with FII19911-AA to 3.33 (2.28-4.85) in subjects with FII19911-AG, compared to those with FII20210-GG and FII19911-AA. CONCLUSIONS: The FIIA19911G polymorphism is associated with mildly elevated prothrombin activity and is a risk factor for venous thrombosis.

The differential association of conjugated equine estrogen and esterified estrogen with activated protein C resistance in postmenopausal women.

OBJECTIVES: Clinical trials have demonstrated that oral conjugated equine estrogen (CEE) therapy with or without medroxyprogesterone (MPA) increases venous thrombotic risk but this safety issue has not been investigated for other oral estrogens. Based on observational study findings that esterified estrogen (EE) was not associated with venous thrombotic risk whereas CEE was, we hypothesized that CEE users would be more resistant to activated protein C (APC), a prothrombotic phenotype, than EE users. METHODS: We conducted an observational, cross-sectional study of postmenopausal women 30-89 years old who were controls in a case-control study of venous thrombosis. Use of CEE, EE, and MPA at the time of phlebotomy was determined using computerized pharmacy records. APC resistance was measured in plasma by the endogenous thrombin potential normalized APC sensitivity ratio. Adjusted mean APC resistance values were compared across estrogen type and CEE:EE ratios are presented. RESULTS: There were 119 CEE and 92 EE users at the time of phlebotomy. Compared with EE users, CEE users had APC resistance measures that were 52% higher (1.52; 95% confidence intervals: 1.07-2.17) in adjusted analyses. Restricting to modal dose users (0.625 mg) and stratifying by MPA use did not materially change associations. CONCLUSIONS: CEE use was associated with higher levels of APC resistance when compared with EE use in postmenopausal women. These findings might provide an explanation for the higher risk of venous thromboembolism previously observed with CEE compared with EE use and, if replicated, may have safety implications for women when choosing an estrogen for symptom relief.

Incidence and prognostic factors of chronic pain after isolated musculoskeletal extremity injury.

BACKGROUND: Chronic pain in patients is usually related to an episode of pain following acute injury, emphasizing the need to prevent progression from acute to chronic pain. Multiple factors in the acute phase might be responsible for perpetuating the pain. The presentation of patients at the emergency department (ED) presents a prime opportunity to identify patients at high risk for chronic pain and to start appropriate treatment. METHODS: The PROTACT study is a prospective follow-up study aiming to estimate the incidence and prognostic factors responsible for the development of chronic pain after musculoskeletal injury. Data including sociodemographic, pain, clinical, injury- or treatment-related and psychological factors of 435 patients were collected from registries and questionnaires at ED visit, 6-week, 3- and 6-month follow-up. RESULTS: At 6 months post-injury, 43.9% of the patients had some degree of pain (Numeric Rating Scale (NRS) ≥1) and 10.1% had chronic pain (NRS ≥4). Patients aged over 40 years, in poor physical health, with pre-injury chronic pain, pain catastrophizing, high urgency level and severe pain at discharge were found to be at high risk for chronic pain. CONCLUSIONS: Two prognostic factors, severe pain at discharge and pain catastrophizing, are potentially modifiable. The implementation of a pain protocol in the ED and the use of cognitive-behavioural techniques involving reducing catastrophizing might be useful.

Old and new risk factors for upper extremity deep venous thrombosis.

BACKGROUND: Well known risk factors for upper extremity deep venous thrombosis are the presence of a central venous catheter (CVC) and malignancy, but other potential risk factors, such as surgery, injury and hormone replacement therapy (HRT), have not yet been explored. METHODS: We performed a population-based case-control study including 179 consecutive patients, aged 18-70 years with upper extremity deep venous thrombosis and 2399 control subjects. Participants reported on acquired risk factors in a questionnaire and factor V Leiden and prothrombin 20210A mutation were ascertained. Information on CVC was obtained from discharge letters. RESULTS: Forty-two patients (23%) and one control subject (0.04%) had a CVC (ORadj: 1136, 95% CI: 153-8448, adjusted for age and sex). Cancer patients without a CVC had an eightfold increased risk of venous thrombosis of the arm (ORcrude: 7.7, 95% CI: 4.6-13.0). Other evident risk factors were prothrombotic mutations, surgery, immobilization of the arm (plaster cast), oral contraceptive use and family history, with odds ratios varying from 2.0 up to 13.1. The risk in the presence of injury and during puerperium was twofold or more increased, although not significantly. In contrast HRT, unusual exercise, travel and obesity did not increase the risk. Hormone users had an increased risk in the presence of prothrombotic mutations or surgery. Obese persons (BMI > 30 kg m(-2)) undergoing surgery had a 23-fold increased risk of arm thrombosis compared with non-obese persons not undergoing surgery. CONCLUSION: A CVC is a very strong risk factor for arm thrombosis. Most risk factors for thrombosis in the leg are also risk factors for arm thrombosis.

Pain management in trauma patients in (pre)hospital based emergency care: current practice versus new guideline.

INTRODUCTION: Acute pain in trauma patients in emergency care is still undertreated. Early pain treatment is assumed to effectively reduce pain in patients and improve long-term outcomes. In order to improve pain management in the chain of emergency care, a national evidence-based guideline was developed. The aim of this study was to assess whether current practice is in compliance with the guideline 'Pain management for trauma patients in the chain of emergency care' from the Netherlands Association for Emergency Nurses (in Dutch NVSHV), and to evaluate early and initial pain management for adult trauma patients in emergency care. METHODS: Chart reviews were conducted in three regions of the Netherlands using electronic patient files of trauma patients from the chain of emergency care. We included one after-hours General Practitioner Co-operation (GPC), one ambulance Emergency Medical Services (EMS), two Helicopter Emergency Medical Services (HEMS), and three Emergency Departments (EDs). Organisation of pain management, pain assessment, and pain treatment was examined and compared with national guideline recommendations, including quality indicators. RESULTS: We assessed a random sample of 1066 electronic patient files. The use of standardised tools to assess pain was registered in zero to 52% of the electronic patient files per organisation. Registration of (non-)pharmacological pain treatment was found in less than half of the files. According to the files, pharmacological pain treatment deviated from the guideline in 73-99% of the files. Time of administration of medication was missing in 73-100%. Reassessment of pain following pain medication was recorded in half of the files by the HEMS, but not in files of the other organisations. CONCLUSIONS: The (registration of) current pain management in trauma patients in the chain of emergency care varies widely between healthcare organisation, and deviates from national guideline recommendations. Although guideline compliance differs across groups of healthcare professionals, maximum compliance rate with indicators registered is 52%. In order to improve pain management and evaluate its effectiveness, we recommend to improve pain registration in patient files. Furthermore, we advise to identify barriers and facilitators related to the implementation of the national guideline in all emergency care organisations.

The 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene is not associated with myocardial infarction.

Several studies have found an association between high plasminogen activator inhibitor-1 (PAI-1) levels and myocardial infarction. Whether this is causal or a consequence of atherosclerosis or tissue damage, remains unclear. Homozygous carriers of the 4G allele of the 4G/5G polymorphism in the PAI-1 gene have higher PAI-1 levels compared to carriers of the 5G allele in healthy persons in some studies, but not all. If PAI-1 levels are causally related to myocardial infarction, one would expect more homozygous carriers of the 4G allele among patients, provided that these carriers have high PAI-1 levels among healthy persons in that population. We investigated the distribution of this polymorphism in the "Study of Myocardial Infarctions Leiden" (SMILE), including 331 men with a myocardial infarction and 302 control subjects and measured PAI-1 antigen levels among the latter. Secondly, we looked into the association of cardiovascular risk factors with PAI-1 levels. We did not find an increase in risk of myocardial infarction in carriers of the 4G allele. Neither did we find an association, nor a trend, between the 4G/5G polymorphism and PAI-1 antigen levels in control subjects. Controls with obesity, hypertension, or who smoked had significant higher PAI-1 antigen levels compared with persons without these factors. High cholesterol and triglyceride levels were also associated with high PAI-1 antigen levels, and HDL-cholesterol levels showed an inverse association. We conclude that the 4G/5G polymorphism in the PAI-1 gene is not associated with the risk of myocardial infarction. As we did not find any association between this polymorphism and PAI-1 antigen levels in healthy persons, we cannot draw any conclusions about the causality of PAI-1 itself for myocardial infarction.

The HR2 haplotype of factor V is not associated with the risk of myocardial infarction.

The HR2 haplotype of the factor V gene, which contains the histidine to arginine substitution at position 1299, has been reported to be associated with reduced factor V levels. Because high factor V levels have been found to be associated with an increased risk of myocardial infarction, we examined how the presence of the R2 allele affected the risk of myocardial infarction in the case-control "Study of Myocardial Infarctions Leiden". Among 560 men with a first myocardial infarction before the age of 70 years, 9.5% were heterozygous carriers of the R2 allele. The control group consisted of 646 men, in which 9.9% were heterozygous and 0.2% homozygous carriers of the R2 allele. The risk of myocardial infarction in the presence of the R2 allele was not increased (odds ratio, 0.9; 95% confidence interval 0.6 to 1.4). Exclusion of factor V Leiden carriers did not change this result. The risk was 4.4-fold increased for smokers who carried the R2 allele compared to non-smoking noncarriers. No synergy was found between metabolic risk factors and the presence of the R2 allele. We conclude that the risk of myocardial infarction for men in the presence of the R2 allele of the His1299Arg polymorphism is neither increased nor decreased.

A mutation in the thrombomodulin gene, 127G to A coding for Ala25Thr, and the risk of myocardial infarction in men.

Thrombomodulin is an endothelial cell surface receptor that transforms the procoagulant thrombin into an anticoagulant. A mutation in the thrombomodulin gene is a potential risk factor for venous and arterial thrombosis. We screened a region within the coding sequence of the thrombomodulin gene by single-strand conformation polymorphism analysis (SSCP) in a pilot study of 104 patients with myocardial infarction and 104 age, sex and race matched controls. We identified a 127G to A mutation in the gene, which predicts an Ala25Thr substitution, in 2 out of 104 patients (1 man and 1 woman) with myocardial infarction but in no controls. We assessed the risk of myocardial infarction associated with the mutation in a larger "Study of Myocardial Infarctions Leiden" (SMILE). Among 560 men with a first myocardial infarction before the age of 70, 12 were carriers of the Ala25Thr substitution. In a control group of 646 men, frequency-matched for age, seven were carriers of the Ala25Thr substitution. The allelic frequencies were 1.07% among patients and 0.54% among controls suggesting risk associated with the mutation [odds ratio (OR) 2.0, 95% confidence interval (CI) 0.8-5.1]. In patients aged below 50, the predicted risk was almost seven times increased (OR 6.5, CI 0.8-54.2). In the presence of additional risk factors, such as smoking and a metabolic risk factor, the predicted risk increased to 9-fold (OR 8.8. CI 1.8-42.2) and 4-fold (OR 4.4, CI 0.9-21.3), respectively. While not conclusive, these results strongly suggest that the Ala25Thr substitution is a risk factor for myocardial infarction, especially in young men, and when in the presence of additional risk factors.

A genetic propensity to high factor VII is not associated with the risk of myocardial infarction in men.

Several studies have examined the relation between factor VII and coronary artery disease by measuring factor VII levels in plasma and some found an association between high levels and disease. This suffers problems of interpretation concerning the causality of high factor VII levels, because factor VII levels may be affected by atherogenic risk factors and may become elevated as a consequence of atherosclerosis. We investigated the association between a genetic variant (353Arg-->Gln), shown to be related to factor VII levels, and myocardial infarction in a large case-control study, including 560 cases and 644 controls. Individuals carrying the 353Arg-Arg genotype seemed to have a lower risk of myocardial infarction (odds ratio 0.80 [95% confidence interval 0.60-1.061). In this study, we confirmed higher factor VII antigen and activity level in 529 men homozygous for the 353Arg allele compared with 115 men carriers of the 353Gln allele (around 20% higher). Our results indicate that a genetic propensity to high factor VII levels is not associated with the risk of myocardial infarction. Since we confirmed the association of the 353Arg-Arg genotype with higher factor VII levels, we conclude that high levels of factor VII are not a causal determinant of myocardial infarction.

Geographic distribution of the 20210 G to A prothrombin variant.

A variant in prothrombin (clotting factor II), a G to A transition at nucleotide position 20210, has recently been shown to be associated with the prothrombin plasma levels and the risk of both venous and arterial thrombosis. The purpose of this study was to investigate the prevalence of carriership of this mutation in various populations. We combined data from 11 centres in nine countries, where tests for this mutation had been performed in groups representing the general population. We calculated an overall prevalence estimate, by a precision-weighted method, and, since the distribution of the prevalences did not appear homogeneous, by an unweighted average of the prevalences. We examined differences in the prevalences by geographical location and ethnic background as a possible explanation for the heterogeneity. Among a total of 5527 individuals who had been tested, 111 heterozygous carriers of the 20210A mutation were found. The prevalence estimates varied from 0.7 to 4.0 between the centres. The overall prevalence estimate was 2.0 percent (CI95 1.4-2.6%). The variation around the summary estimate appeared more than was expected by chance alone, and this heterogeneity could be explained by geographic differences. In southern Europe, the prevalence was 3.0 percent (CI95 2.3 to 3.7%), nearly twice as high as the prevalence in northern Europe (1.7%, CI95 1.3 to 2.2%). The prothrombin variant appeared very rare in individuals from Asian and African descent. The 20210A prothrombin variant is a common abnormality, with a prevalence of carriership between one and four percent. It is more common in southern than in northern Europe. Since this distribution within Europe is very different to that of another prothrombotic mutation (factor V Leiden or factor V R506Q), founder effects are the most likely explanation for the geographical distribution of both mutations.

Trends in medical management of acute myocardial infarction, Auckland 1983-90.

AIMS: To examine changes in the medical management of acute myocardial infarction in the Auckland region between 1983 and 1990. METHODS: 6190 patients aged 25-64 years with myocardial infarction were identified utilising a population based register, the ARCOS study. Data were collected on resuscitation attempts, transportation to hospital, coronary care unit (CCU) stay and medication use before and during the CCU stay. RESULTS: The median time delay between onset of symptoms and arrival at the CCU decreased by approximately 7 minutes per year. The average length of CCU stay decreased from 2.9 to 2.7 days and there were between hospital variations in length of CCU stay. The most striking change in drug therapy before the event was the increase in the use of antiplatelet agents from 5% in 1983 to 18.3% in 1990. There was also a big increase in the proportion of patients using antiplatelets (3.5 fold) and thrombolytic drugs (5.5 fold) during the CCU stay, in 1990, 50% of patients received thrombolytic agents and 56% received antiplatelet agents. CONCLUSION: The use of drugs of proven benefit could be further increased although it appears that major improvements in mortality rates will come primarily from primary prevention.

Variation in the time and day of onset of myocardial infarction and sudden death.

AIM: To examine circadian and weekly variation in the onset of acute myocardial infarction and sudden cardiac death. METHOD: A large population based coronary heart disease register, the ARCOS Study, which is collaborating in the WHO MONICA Project carried out in Auckland, New Zealand, 1983-90. There were 4983 patients aged 25-64 with definite myocardial infarction or coronary death. Main outcome measures--circadian and weekly variation in onset of symptoms of definite myocardial infarction and sudden cardiac death. RESULTS: Surviving patients showed a circadian pattern with a single morning peak in symptom onset (30.0%) while sudden death patients exhibited an afternoon peak (32.5%) and a secondary morning peak (27.6%). Within these two subgroups the circadian pattern was analysed by various risk factors and medications. A weekly variation was found with an increased incidence of onset of symptoms during the weekend and on Monday for surviving patients and a Saturday high (18.6%) for sudden death patients. CONCLUSIONS: Further investigation of physiological changes within subgroups during the key periods may provide insight into triggering mechanisms and lead to better means for prevention.