Stillbirth and early neonatal mortality rates may be underestimated using recall information: A comparison of demographic surveillance methodologies.

OBJECTIVE: Child mortality and stillbirth rates (SBR) remain high in low-income countries but may be underestimated due to incomplete reporting of child deaths in retrospective pregnancy/birth histories. The aim of this study is to compare stillbirth and mortality estimates derived using two different methods: the method assuming full information and the prospective method. METHODS: Bandim Health Project's Health and Demographic Surveillance Systems (HDSS) follows women of reproductive age and children under five through routine home visits every 1, 2 or 6 months. Between 2012 and 2020, we estimated and compared early neonatal (ENMR, <7 days), neonatal (NMR, <28 days), and infant mortality (IMR, <1 year) per 1000 live births and SBR per 1000 births. Risk time for children born to registered women was calculated from birth (the method assuming full information) versus date of first observation in the HDSS (the prospective method), either at birth (for pregnancy registration) or registration. Rates were calculated using the Kaplan-Meier estimator and compared in generalised linear models allowing for within-child correlation obtaining relative risks (RR). RESULTS: We registered and followed 29,413 infants (1380 deaths; 1459 stillbirths) prospectively. An additional 164 infant deaths and 129 stillbirths were registered retrospectively and included in the method assuming full information. The ENMR was 24.5 (95%CI: 22.6-26.4) for the method assuming full information and 25.8 (23.7-27.8) for the prospective method, RR = 0.96 (0.93-0.99). Differences were smaller for the NMRs and IMRs. For SBRs, the estimates were 53.5 (50.9-56.0) and 58.6 (55.7-61.5); RR = 0.91 (0.90-0.93). The difference between methods became more pronounced when the analysis was limited to areas visited every 6 months: RR for ENMR: 0.91 (0.86-0.96) and RR for SBR: 0.85 (0.83-0.87). CONCLUSIONS: Assuming full information underestimates SBR and ENMR. Accounting for omissions of stillbirths and early neonatal deaths may lead to more accurate estimates and improved ability to monitor mortality.

Inherited and Acquired Determinants of Hepatic CYP3A Activity in Humans.

Human CYP3A enzymes (including CYP3A4 and CYP4A5) metabolize about 40% of all drugs and numerous other environmental and endogenous substances. CYP3A activity is highly variable within and between humans. As a consequence, therapy with standard doses often results in too low or too high blood and tissue concentrations resulting in therapeutic failure or dose-related adverse reactions. It is an unanswered question how much of the big interindividual variation in CYP3A activity is caused by genetic or by environmental factors. This question can be answered by the twin study approach. Using midazolam as CYP3A probe drug, we studied 43 monozygotic and 14 dizygotic twins and measured midazolam and its metabolite 1-OH-midazolam. In addition, endogenous biomarkers of CYP3A activity, 4ß-OH-cholesterol and 6ß-OH-cortisol, were analyzed. Additive genetic effects accounted for only 15% of the variation in midazolam AUC, whereas 48% was attributed to common environmental factors. In contrast, 73, 56, and 31% of 1-OH-midazolam, 4ß-OH-cholesterol and 6ß-OH-cortisol variation was due to genetic effects. There was a low phenotypic correlation between the four CYP3A biomarkers. Only between midazolam and its 1-OH-metabolite, and between midazolam and 6ß-OH-cortisol we found significant bivariate genetic correlations. Midazolam AUC differed depending on the CYP3A4∗22 variant (p = 0.001) whereas plasma 4ß-OH-cholesterol was significantly lower in homozygous carriers of CYP3A5∗3 (p = 0.02). Apparently, non-genomic factors played a dominant role in the inter-individual variation of the CYP3A probe drug midazolam. A small intra-individual pharmacokinetic variation after repeated administration of midazolam was rated earlier as indication of high heritability of CYP3A activity, but according to present data that could also largely be due to constant environmental factors and/or heritability of liver blood flow. The higher heritabilities of 4ß-OH-cholesterol and of 1-OH-midazolam may deserve further research on the underlying factors beyond CYP3A genes. Clinical Trial Registration: ClinicalTrials.gov: NCT01845194 and EUDRA-CT: 2008-006223-31.

Changes in Drug Use and Polypharmacy After the Age of 90: A Longitudinal Study of the Danish 1905 Cohort.

OBJECTIVES: To determine the longitudinal development of drug use in very old adults. DESIGN: Longitudinal cohort study with waves in 1998, 2000, 2002, and 2005. SETTING: Nationwide study in Denmark. PARTICIPANTS: All living Danes born in 1905 were approached in 1998; 2,262 responded at baseline. MEASUREMENTS: Self-reported use of regularly taken drugs. Mean and median number of drugs and growth curve models were used to identify the change in number of drugs as the cohort aged from 92 to 100. RESULTS: The within-person use of drugs increased with age for women (0.19 per year; 95% confidence interval (CI) = 0.15-0.24) and men (0.15 per year; 95% CI = 0.06-0.24). Persons leaving the study prematurely had higher baseline values and a steeper increase in their annual use of drugs. The population-level mean number of drugs increased from baseline (3.6 drugs) to the first follow-up (4.1 drugs) but thereafter remained stable at approximately 4 drugs. Women used more drugs than men at all waves. CONCLUSION: In this first longitudinal study of drug use in nonagenarians, individuals used an increasing number of drugs as they aged. This increase is difficult to detect in cross-sectional analyses of the population-level mean. More efforts to understand what is reasonable prescribing at these older ages are needed.

Twin methodology in epigenetic studies.

Since the final decades of the last century, twin studies have made a remarkable contribution to the genetics of human complex traits and diseases. With the recent rapid development in modern biotechnology of high-throughput genetic and genomic analyses, twin modelling is expanding from analysis of diseases to molecular phenotypes in functional genomics especially in epigenetics, a thriving field of research that concerns the environmental regulation of gene expression through DNA methylation, histone modification, microRNA and long non-coding RNA expression, etc. The application of the twin method to molecular phenotypes offers new opportunities to study the genetic (nature) and environmental (nurture) contributions to epigenetic regulation of gene activity during developmental, ageing and disease processes. Besides the classical twin model, the case co-twin design using identical twins discordant for a trait or disease is becoming a popular and powerful design for epigenome-wide association study in linking environmental exposure to differential epigenetic regulation and to disease status while controlling for individual genetic make-up. It can be expected that novel uses of twin methods in epigenetic studies are going to help with efficiently unravelling the genetic and environmental basis of epigenomics in human complex diseases.

Multivariate modeling of body mass index, pulse pressure, systolic and diastolic blood pressure in Chinese twins.

Systolic and diastolic blood pressure, pulse pressure (PP), and body mass index (BMI) are heritable traits in human metabolic health but their common genetic and environmental backgrounds are not well investigated. The aim of this article was to explore the phenotypic and genetic associations among PP, systolic blood pressure (SBP), diastolic blood pressure (DBP), and BMI. The studied sample contained 615 twin pairs (17-84 years) collected in the Qingdao municipality. Univariate and multivariate structural equation models were fitted for assessing the genetic and environmental contributions. The AE model combining additive genetic (A) and unique environmental (E) factors produced the best fit for each four phenotypes. Heritability estimated in univariate analysis ranged from 0.42 to 0.74 with the highest for BMI (95% CI 0.70-0.78), and the lowest for PP (95% CI 0.34-0.49). The multivariate model estimated (1) high genetic correlations for DBP with SBP (0.87), PP with SBP (0.75); (2) low-moderate genetic correlations between PP and DBP (0.32), each BP component and BMI (0.24-0.37); (3) moderate unique environmental correlation for PP with SBP (0.68) and SBP with DBP (0.63); (4) there was no significant unique environmental correlation between PP and BMI. Overall, our multivariate analyses revealed common genetic and environmental backgrounds for PP, BP, and BMI in Chinese twins.

Epigenetic signature of birth weight discordance in adult twins.

BACKGROUND: A low birth weight has been extensively related to poor adult health outcomes. Birth weight can be seen as a proxy for environmental conditions during prenatal development. Identical twin pairs discordant for birth weight provide an extraordinary model for investigating the association between birth weight and adult life health while controlling for not only genetics but also postnatal rearing environment. We performed an epigenome-wide profiling on blood samples from 150 pairs of adult monozygotic twins discordant for birth weight to look for molecular evidence of epigenetic signatures in association with birth weight discordance. RESULTS: Our association analysis revealed no CpG site with genome-wide statistical significance (FDR < 0.05) for either qualitative (larger or smaller) or quantitative discordance in birth weight. Even with selected samples of extremely birth weight discordant twin pairs, no significant site was found except for 3 CpGs that displayed age-dependent intra-pair differential methylation with FDRs 0.014 (cg26856578, p = 3.42e-08), 0.0256 (cg15122603, p = 1.25e-07) and 0.0258 (cg16636641, p = 2.05e-07). Among the three sites, intra-pair differential methylation increased with age for cg26856578 but decreased with age for cg15122603 and cg16636641. There was no genome-wide statistical significance for sex-dependent effects on intra-pair differential methylation in either the whole samples or the extremely discordant twins. CONCLUSIONS: Genome-wide DNA methylation profiling did not reveal epigenetic signatures of birth weight discordance although some sites displayed age-dependent intra-pair differential methylation in the extremely discordant twin pairs.

Probing genetic overlap in the regulation of systolic and diastolic blood pressure in Danish and Chinese twins.

Although the phenotypic correlation between systolic blood pressure (SBP) and diastolic blood pressure (DBP) is well known, the genetic basis for the correlation has rarely been investigated. The aim of this paper is to examine the genetic overlap between SBP and DBP by fitting bivariate models to Danish and Chinese twins and comparing ethnic differences between the two samples. Our estimates revealed a high proportion of additive genetic components shared by both SBP and DBP in Danish (0.71, 95% confidence interval (CI): 0.65-0.75) and Chinese (0.62, 95% CI: 0.50-0.71) twins with no statistically significant ethnic differences. The estimated genetic component in phenotypic correlation could serve to guide molecular genetic studies searching for genetic variants that affect both SBP and DBP. The bivariate model also estimated genetic and environmental contributions to SBP and DBP separately, with an overall pattern of higher genetic regulation or heritability in Danish (0.72, 95% CI: 0.67-0.76 for SBP; 0.70, 95% CI: 0.65-0.75 for DBP) than in Chinese (0.54, 95% CI: 0.44-0.63 for SBP; 0.57, 95% CI: 0.47-0.65 for DBP) twins and a higher contribution from unique environmental factors in Chinese compared with Danish twins. The estimated contribution from unique environmental factors suggests that promoting healthy lifestyles may provide an efficient way of controlling high blood pressure, particularly in the Chinese population.

Tracking and fixed ranking of leukocyte telomere length across the adult life course.

Short leukocyte telomere length (LTL) is associated with atherosclerosis in adults and diminished survival in the elderly. LTL dynamics are defined by LTL at birth, which is highly variable, and its age-dependent attrition thereafter, which is rapid during the first 20 years of life. We examined whether age-dependent LTL attrition during adulthood can substantially affect individuals' LTL ranking (e.g., longer or shorter LTL) in relation to their peers. We measured LTL in samples donated 12 years apart on average by 1156 participants in four longitudinal studies. We observed correlations of 0.91-0.96 between baseline and follow-up LTLs. Ranking individuals by deciles revealed that 94.1% (95% confidence interval of 92.6-95.4%) showed no rank change or a 1 decile change over time. We conclude that in adults, LTL is virtually anchored to a given rank with the passage of time. Accordingly, the links of LTL with atherosclerosis and longevity appear to be established early in life. It is unlikely that lifestyle and its modification during adulthood exert a major impact on LTL ranking.

Prevalence in the use of complementary medicine among cancer patients in Tuscany, Italy.

AIMS AND BACKGROUND: A previous survey by Molassiotis et al. (Ann Oncol, 16: 655-663, 2005) on the use of complementary and alternative medicines (CAM) among cancer patients in Europe reported that 73% of the Italian cancer patients had used CAM, a number well above the European average of 36%. Some national variation in preference of CAM was reported, and Italian cancer patients were reported to have high use of homeopathy, herbal medicine, and spiritual therapies. The difference between CAM use in Italy and other European countries intrigued a further investigation of CAM use among Italian cancer patients. METHODS: A survey using the same questionnaire as Molassiotis et al. was conducted at two oncology day hospitals in Tuscany and included 132 patients (55% male, 45% female, with various forms of cancer) on chemotherapy. The response rate was 71%. RESULTS: The incidence of CAM use after cancer diagnosis among Tuscan cancer patients was 17%. The most widely used forms were herbal medicine (52%), homeopathy (30%) and acupuncture (13%). Use was higher in the urban area and among women, breast cancer patients, and persons with a higher education. These results agree with results of other studies on the use of CAM among Italians and Europeans in general, as well as among cancer patients in Italy. CONCLUSIONS: The high prevalence of CAM use among Italians reported by Molassiotis et al. cannot be regarded a national estimate on the use of CAM for cancer in Italy. Rather it may reflect a relatively high use of CAM in palliative care, in Northern Italy and in urban areas. CAM use among Italians in general as well as among Tuscan cancer patients in chemotherapy is modest compared with the overall European use and reflects a general high use of CAM among urbanites, women and those with a higher education. Most commonly used forms of CAM are herbal medicine and homeopathy.

Methylenetetrahydrofolate reductase 677C>T and methionine synthase 2756A>G mutations: no impact on survival, cognitive functioning, or cognitive decline in nonagenarians.

BACKGROUND: Several reports have shown an association between homocysteine, cognitive functioning, and survival among the oldest-old. Two common polymorphisms in the genes coding for methylenetetrahydrofolate reductase (MTHFR 677C>T) and methionine synthase (MTR 2756A>G) have an impact on plasma homocysteine level. METHODS: We examined the effect of the MTHFR 677C>T and MTR 2756A>G genotypes on baseline cognitive functioning, cognitive decline over 5 years measured in three assessments, and survival in a population-based cohort of 1581 nonagenarians. Cognitive functioning was assessed by using the Mini-Mental State Examination (MMSE) and five brief cognitive tests (cognitive composite). RESULTS: There are no differences in MMSE score (p =.83) or in cognitive composite (p =.56) at intake as a function of genotype tested by analysis of variance, whereas sex and social group have a impact on MMSE (p < or =.03), and social group on the cognitive composite (p <.01). The mean MMSE was lower for women than for men. However, considering the group participating in all three assessments, there were no sex-related differences in MMSE (p =.34). The cognitive decline in the group participating in all three assessments was investigated using regression models for the relationship between cognitive performance and genotype, age, sex, and social group and revealed no significant difference. Furthermore, the MTHFR 677T and MTR 2756A heterozygous and homozygous genotype had no significant impact on survival, with hazard ratios of 1.05 (95% confidence interval [CI], 0.93-1.17), 0.93 (95% CI, 0.77-1.14), 1.05 (95% CI, 0.94-1.18), and 0.97 (95% CI, 0.74-1.28). CONCLUSIONS: MTHFR and MTR genotypes are not associated with cognitive functioning, cognitive decline, or survival among nonagenarians.

Genetic and environmental contributions to hay fever among young adult twins.

BACKGROUND: The susceptibility to develop hay fever is putatively the result both of genetic and environmental causes. We estimated the significance and magnitude of genetic and environmental contributions to hay fever among young adult twins. METHODS: From the birth cohorts 1953-82 of The Danish Twin Registry 11,750 twin pairs were identified through a nationwide questionnaire survey. Subjects were regarded hay fever cases when responding affirmatively to the question 'Do you have, or have you ever had hay fever?' Latent factor models of genetic and environmental effects were fitted to the observed data using maximum likelihood methods. RESULTS: The overall cumulative prevalence of hay fever was 12.6%. Identical twins were significantly more likely to be concordant for hay fever than were fraternal twins (P<0.001). Additive genetic effects accounted for 71% and non-shared environmental effects accounted for 29% of the individual susceptibility to hay fever. The same genes contributed to the susceptibility to hay fever both in males and in females. In families with asthma, the susceptibility to develop hay fever was, in addition to genes, to a great extent ascribable to family environment, whereas the aetiology of 'sporadic' hay fever was mainly genetic. CONCLUSIONS: The susceptibility to develop hay fever is attributable to major genetic influences. However, effects of family environment and upbringing are also of importance in families where asthma is present. These results indicate that different sub-forms of hay fever may have different aetiologies.

Evidence for an association of methylene tetrahydrofolate reductase polymorphism C677T and an increased risk of fractures: results from a population-based Danish twin study.

Osteoporotic fractures are some of the major causes of morbidity and health care expenditure among the elderly. Identifying subjects at risk could be of major importance since several preventive treatments are now available. A large genetic component in the development of osteoporosis has been established. Previous studies concerning association of the common point mutation C677T in methylentetrahydrofolate reductase (MTHFR) and osteoporosis have revealed contradictory results. The aim of this study was to test the association between the MTHFR polymorphism, homocysteine, and fractures in a population-based sample of Danish twins aged 73+. In total, 689 subjects, with a mean age of 78 years, participated. Genotype and data of fractures are available from 687 subjects--144 with a previously diagnosed fracture. The genotype distribution is as follows: CC, CT, and TT genotypes, 317 (46.1%), 298 (43.3%), and 73 (10.6%), respectively. Using the proportional odds-ratio model adjusted for age, gender, and body mass Index, the odds-ratio of fracture was 1.5 per number of T alleles--meaning that fracture risk is 1.5 times higher in the CT group compared with the CC group and again 1.5 times higher in the TT group compared with the CT group. Homocysteine, smoking, and self-reported hormone use provided no significant contribution to fracture risk. Using biometrical modelling, the heritability of the liability to fractures was found to be approximately 0.10, when the effect of the MTHFR locus was included, and 0.07 when it was omitted. But both confidence intervals include zero and the estimates are therefore not significant. In conclusion, we here provide evidence for a significant impact of the MTHFR genotype on the occurrence of fractures in an elderly Danish population.