Thrombotic variables and risk of idiopathic venous thromboembolism in women aged 45-64 years - Relationships to hormone replacement therapy

Hormone replacement therapy (HRT) has been shown to increase the relative risk of idiopathic venous thromboembolism (VTE) about threefold in several observational studies and one randomised controlled trial. Whether or not this relative risk is higher in women with underlying thrombophilia phenotypes, such as activated protein C (APC) resistance, is unknown. We therefore restudied the participants in a case-control study of the relationship between the use of HRT and the occurrence of idiopathic VTE in women aged 45-64 years. After protocol exclusions, 66 of the cases in the original study and 163 of the controls were studied. Twenty haematological variables relevant to risk of VTE were analysed, including thrombotic states defined from the literature. The relative risk of VTE showed significant associations with APC resistance (OR 4.06; 95% CI 1.62, 10.21); low antithrombin (3.33; 1.15, 9.65) or protein C (2.93; 1.06, 8.14); and high coagulation factor IX (2.34: 1.26, 1.35), or fibrin D-dimer (3.84; 1.99, 7.32). HRT use increased the risk of VTE in women without any of these thrombotic static; (OR 4.09; 95% CI 1.26, 13.30). A similar effect of HRT use on the relative risk of VTE was also found in women with prothrombotic states. Thus for example, the combination of HRT use and APC resistance increased the risk of VTE about 13-fold compared with women of similar age without either APC resistance or HRT use (OR 13.27; 95%, CI 4.30, 40.97). We conclude that the combination of HRT use and thrombophilias (especially if multiple) increases the relative risk of VTE substantially; hence women known to have thrombophilias (especially if multiple) should be counselled about this increased risk prior to prescription of HRT. However. HRT increases the risk of VTE about fourfold even in women without any thrombotic abnormalities: possible causes are discussed

Hormonal replacement therapy, prothrombotic mutations and the risk of venous thrombosis

Hormone replacement therapy (HRT) increases the risk of venous thrombosis. We investigated whether this risk is affected by carriership of hereditary prothrombotic abnormalities. Therefore, we determined the two most common prothrombotic mutations, factor V Leiden and prothrombin 20210A in women who participated in a case-control study on venous thrombosis. Relative risks were expressed as odds ratios (OR) with 95% confidence intervals (CI95). Among 7 7 women aged 45-64 years with a first venous thrombosis, 51% were receiving HRT at the time of thrombosis, compared with 24% of control women (OR = 3.3, CI95 1.8-5.8). Among the patients, 23% had a prothrombotic defect, versus 7% among the control women (OR = 3.8, CI95 1.7- 8.5). Women who had factor V Leiden and used HRT had a 15-fold increased risk (OR = 15.5, CI95 3.1-77), which exceeded the expected joint odds ratio of 6.1 (under an additive model). We conclude that the thrombotic risk of HRT may particularly affect women with prothrombotic mutations. Efforts to avoid HRT in women with increased risk of thrombosis are advisable

MintHint: Automated Synthesis of Repair Hints

Being able to automatically repair programs is an extremely challenging task. In this paper, we present MintHint, a novel technique for program repair that is a departure from most of today's approaches. Instead of trying to fully automate program repair, which is often an unachievable goal, MintHint performs statistical correlation analysis to identify expressions that are likely to occur in the repaired code and generates, using pattern-matching based synthesis, repair hints from these expressions. Intuitively, these hints suggest how to rectify a faulty statement and help developers find a complete, actual repair. MintHint can address a variety of common faults, including incorrect, spurious, and missing expressions. We present a user study that shows that developers' productivity can improve manyfold with the use of repair hints generated by MintHint -- compared to having only traditional fault localization information. We also apply MintHint to several faults of a widely used Unix utility program to further assess the effectiveness of the approach. Our results show that MintHint performs well even in situations where (1) the repair space searched does not contain the exact repair, and (2) the operational specification obtained from the test cases for repair is incomplete or even imprecise

Fertility in relation to the risk of breast cancer.

All studies reported here, like our own, support the view that the higher risk of breast cancer in women having a late first birth is attributable to early pregnancy itself having a direct protective effect against the disease, a benefit which they have not experienced. One study, however, has directly examined breast cancer risk in two groups of infertile women - those presumed to have 'progesterone deficiency' and those presumed to have infertility of non hormonal origin. The results suggested that breast cancer risk was increased in premenopausal women (but not in postmenopausal women) with 'progesterone deficiency'. The number of cases of premenopausal breast cancer included in the analysis (11) was, however, very small. In our view, the findings in this study do not weigh heavily against our results and those of others

Oral contraceptives and cervical cancer--further findings from the Oxford Family Planning Association contraceptive study.

In 1983, we reported results from the Oxford Family Planning Association contraceptive study regarding the association between oral contraceptives (OCs) and cervical neoplasia, after a 10 year follow-up of a cohort of 17,000 women. Further findings from this study are reported here after an additional 12 years of follow-up. A nested case--control design was used in which cases were all women diagnosed under 45 years of age with invasive carcinoma (n = 33), carcinoma in situ (n = 121) or dysplasia (n = 159). Controls were randomly selected from among cohort members and matched to cases on exact year of birth and clinic attended at recruitment to study. Conditional logistic regression analysis was used to determine odds ratios (ORs) and 95% confidence intervals (CIs) associated with various aspects of OC use relative to never users adjusted for social class, smoking, age at first birth and ever use of diaphragm or condom. Ever users of OCs had a slightly elevated OR for all types of cervical neoplasia combined (OR = 1.40, 95% CI 1.00-1.96). Odds ratios were highest for invasive carcinoma (OR = 4.44, 95% CI 1.04-31.6), intermediate for carcinoma in situ (OR = 1.73, 95% CI 1.00-3.00) and lowest for dysplasia (OR = 1.07, 95% CI 0.69-1.66). The elevated risk associated with OC use appeared to be largely confined to current or recent (last use in the past 2 years) long-term users of OCs. Among current or recent users, ORs for all types of cervical neoplasia combined were 3.34 (95% CI 1.96-5.67) for 49-72 months of use, 1.69 (95% CI 0.97-2.95) for 73-96 months and 2.04 (95% CI 1.34-3.11) for 97 or more months. These results suggest a possible effect of OC use on later stages of cervical carcinogenesis, although residual confounding due to sexual factors or human papillomavirus (HPV) infection cannot be ruled out