Objective: To evaluate quantitatively articles that compared effects of second and third generation oral contraceptives on risk of venous thrombosis. Design: Meta-analysis. Studies: Cohort and case-control studies assessing risk of venous thromboembolism among women using oral contraceptives before October 1995. Main outcome measures: Pooled adjusted odds ratios calculated by a general variance based random effects method. When possible, two by two tables were extracted and combined by the Mantel-Haenszel method. Results: The overall adjusted odds ratio for third versus second generation oral contraceptives was 1.7 (95% confidence interval 1.4 to 2.0; seven studies). Similar risks were found when oral contraceptives containing desogestrel or gestodene were compared with those containing levonorgestrel. Among first time users, the odds ratio for third versus second generation preparations was 3.1 (2.0 to 4.6; four studies). The odds ratio was 2.5 (1.6 to 4.1; five studies) for short term users compared with 2.0 (1.4 to 2.7; five studies) for longer term users. The odds ratio was 1.3 (1.0 to 1.7) in studies funded by the pharmaceutical industry and 2.3 (1.7 to 3.2) in other studies. Differences in age and certainty of diagnosis of venous thrombosis did not affect the results. Conclusions: This meta-analysis supports the view that third generation oral contraceptives are associated with an increased risk of venous thrombosis compared with second generation oral contraceptives. The increase cannot be explained by several potential biases. What is already known on this topic: Third generation oral contraceptives have been reported to increase the risk of venous thrombosis compared with second generation oral contraceptives The findings have been vigorously debated, with suggestions that the results can be explained by confounding or bias, or both. What this study adds: Women taking third generation oral contraceptives have a 1.7-fold increased risk of venous thrombosis compared with those taking second generation oral contraceptives Risk is highest in first time users The biases were not large enough to account for the observed results

Journal of Medical Internet Research - International Scientific Journal for Medical Research, Information and Communication on the Internet

We investigated whether a polymorphism at nucleotide position 1220, resulting in an asparagine-to-serine change at codon 363 in the glucocorticoid receptor (GR) gene is associated with an altered sensitivity to glucocorticoids. In a group of 216 elderly persons, 13 heterozygotes for the N363S polymorphism were identified by PCR/single strand conformation polymorphism analysis. In 2 dexamethasone (DEX) suppression tests (DSTs), using 1 and 0.25 mg DEX, the circulating cortisol and insulin concentrations were compared between N363S carriers and controls. In the 1-mg DST, there were no differences between N363S carriers and controls, with respect to adrenal suppression, but there was a significantly higher (P < 0.05) insulin response in N363S carriers. In the 0.25-mg DST, a significantly larger (P < 0.05) cortisol suppression and higher (P < 0.05) insulin response were seen in N363S carriers. Comparison of blood pressure, body mass index (BMI), and bone mineral density (BMD) between the N363S carriers and controls showed that N363S carriers had a higher (P < 0.05) BMI but normal blood pressure. There was an obvious trend towards lower age-, BMI-, and sex-adjusted BMD in the lumbar spine in N363S carriers. GR characteristics measured in 41 controls and 9 N363S carriers in peripheral mononuclear leucocytes showed no differences between N363S carriers and controls, with respect to GR number and ligand binding affinity. However, there was a trend towards greater sensitivity to DEX in the carriers’ lymfocytes, in a mitogen-induced cell proliferation assay. In transfection assays, the capacity of the codon 363 variant to activate mouse mammary tumor virus promotor-mediated transcription in COS-1 cells was unaltered, when compared with the wild-type GR. We conclude that in 6.0% of our study population, a polymorphism in codon 363 of the GR gene was found. Individuals carrying this polymorphism seemed healthy at clinical examination but had a higher sensitivity to exogenously administered glucocorticoids, with respect to both cortisol suppression and insulin response. Life-long exposure to the mutated allele may be accompanied by an increased BMI and a lowered BMD in the lumbar spine but does not affect blood pressure.

The prevalence and severity of metabolic dysfunction–associated steatotic liver disease (MASLD) are increasing. Physicians who treat patients with MASLD may acknowledge the strong coincidence with cardiometabolic disease, including atherosclerotic cardiovascular disease (asCVD). This raises questions on co-occurrence, causality, and the need for screening and multidisciplinary care for MASLD in patients with asCVD, and vice versa. Here, we review the interrelations of MASLD and heart disease and formulate answers to these matters. Epidemiological studies scoring proxies for atherosclerosis and actual cardiovascular events indicate increased atherosclerosis in patients with MASLD, yet no increased risk of asCVD mortality. MASLD and asCVD share common drivers: obesity, insulin resistance and type 2 diabetes mellitus (T2DM), smoking, hypertension, and sleep apnea syndrome. In addition, Mendelian randomization studies support that MASLD may cause atherosclerosis through mixed hyperlipidemia, while such evidence is lacking for liver-derived procoagulant factors. In the more advanced fibrotic stages, MASLD may contribute to heart failure with preserved ejection fraction by reduced filling of the right ventricle, which may induce fatigue upon exertion, often mentioned by patients with MASLD. Some evidence points to an association between MASLD and cardiac arrhythmias. Regarding treatment and given the strong co-occurrence of MASLD and asCVD, pharmacotherapy in development for advanced stages of MASLD would ideally also reduce cardiovascular events, as has been demonstrated for T2DM treatments. Given the common drivers, potential causal factors and especially given the increased rate of cardiovascular events, comprehensive cardiometabolic risk management is warranted in patients with MASLD, preferably in a multidisciplinary approach.

Background: Despite its benefits, it is uncommon to apply the nested case-control design in diagnostic research. We aim to show advantages of this design for diagnostic accuracy studies. Methods: We used data from a full cross-sectional diagnostic study comprising a cohort of 1295 consecutive patients who were selected on their suspicion of having deep vein thrombosis (DVT). We draw nested case-control samples from the full study population with case:control ratios of 1:1, 1:2, 1:3 and 1:4 (per ratio 100 samples were taken). We calculated diagnostic accuracy estimates for two tests that are used to detect DVT in clinical practice. Results: Estimates of diagnostic accuracy in the nested case-control samples were very similar to those in the full study population. For example, for each case:control ratio, the positive predictive value of the D-dimer test was 0.30 in the full study population and 0.30 in the nested case-control samples (median of the 100 samples). As expected, variability of the estimates decreased with increasing sample size. Conclusion: Our findings support the view that the nested case-control study is a valid and efficient design for diagnostic studies and should also be (re)appraised in current guidelines on diagnostic accuracy research.

Neonatal mortality is a global challenge; identification of individual and community determinants associated with it are important for targeted interventions. However in most low and middle income countries (LMICs) including Ghana this problem has not been adequately investigated as the impact of contextual factors remains undetermined despite their significant influence on under-five mortality and morbidity. Based on a modified conceptual framework for child survival, hierarchical modelling was deployed to examine about 6,900 women, aged 15 – 49 years (level 1), nested within 412 communities (level 2) in Ghana by analysing combined data of the 2003 and 2008 Ghana Demographic and Health Survey. The aim was to identify individual (maternal, paternal, neonatal, antenatal, delivery and postnatal) and community (socioeconomic disadvantage communities) determinants associated with neonatal mortality. The results showed both individual and community characteristics to be associated with neonatal mortality. Infants of multiple-gestation [OR 5.30; P-value < 0.001; 95% CI 2.81 – 10.00], neonates with inadequate birth spacing [OR 3.47; P-value < 0.01; 95% CI 1.60 – 7.57] and low birth weight [OR 2.01; P-value < 0.01; 95% CI 1.23 – 3.30] had a lower chance of surviving the neonatal period. Similarly, infants of grand multiparous mothers [OR 2.59; P-value < 0.05; 95% CI 1.03 – 6.49] and non-breastfed infants [OR 142.31; P-value < 0.001; 95% CI 80.19 – 252.54] were more likely to die during neonatal life, whereas adequate utilization of antenatal, delivery and postnatal health services [OR 0.25; P-value < 0.001; 95% CI 0.13 – 0.46] reduced the likelihood of neonatal mortality. Dwelling in a neighbourhood with high socioeconomic deprivation was associated with increased neonatal mortality [OR 3.38; P-value < 0.01; 95% CI 1.42 – 8.04]. Both individual and community characteristics show a marked impact on neonatal survival. Implementation of community-based interventions addressing basic education, poverty alleviation, women empowerment and infrastructural development and an increased focus on the continuum-of-care approach in healthcare service will improve neonatal survival.