Does oral polio vaccine have non-specific effects on all-cause mortality? Natural experiments within a randomised controlled trial of early measles vaccine.

BACKGROUND: BCG and measles vaccine (MV) may have beneficial non-specific effects (NSEs). If an unplanned intervention with a vaccine (a natural experiment) modifies the estimated effect in a randomised controlled trial (RCT), this suggests NSEs. We used this approach to test NSEs of triple oral polio vaccine (OPV). METHODS: During an RCT of 2 doses of MV at 4.5 and 9 months versus 1 dose of MV at 9 months of age, we experienced 2 natural experiments with OPV. We assessed whether these OPV experiments modified the effect of 2-dose MV in the MV trial. SETTING: MV RCT conducted in urban Guinea-Bissau 2003-2009. INTERVENTIONS: Natural experiments with OPV due to missing vaccine and the implementation of OPV campaigns. MAIN OUTCOME MEASURE: Changes in the mortality rate ratio (MRR) for 2-dose MV versus 1-dose MV. RESULTS: First, the MRR (2-dose/1-dose MV) overall was 0.70 (0.52 to 0.94), but the MRR was 1.04 (0.53 to 2.04) when OPV at birth (OPV0) was not given, suggesting that early priming with OPV was important for the effect of 2-dose MV. The effect of OPV0 depended on age of administration; the MRR (2-dose/1-dose MV) was 0.45 (0.29 to 0.71) for children receiving OPV0 in the first week of life, but 3.63 (0.87 to 15.2) for those receiving OPV0 after the first month of life (p=0.007, test of no interaction). Second, campaign-OPV may have reduced the difference between the randomisation groups since the MRR (2-dose/1-dose MV) was 0.60 (0.42 to 0.85) for children who had not received campaign-OPV before RCT-enrolment versus 0.72 (0.23 to 2.31) and 1.42 (0.70 to 2.90) for children who had received 1 or 2 doses of campaign-OPV-before-enrolment, respectively. CONCLUSIONS: Bissau had no polio infection during this trial, so OPV0 and campaign-OPV may have NSEs since they modified the effect of 2-dose MV in an RCT. Different interventions may interact to a much larger effect than usually assumed

Measles vaccination in the presence or absence of maternal measles antibody: impact on child survival.

BACKGROUND: Measles vaccine (MV) has a greater effect on child survival when administered in early infancy, when maternal antibody may still be present. METHODS: To test whether MV has a greater effect on overall survival if given in the presence of maternal measles antibody, we reanalyzed data from 2 previously published randomized trials of a 2-dose schedule with MV given at 4-6 months and at 9 months of age. In both trials antibody levels had been measured before early measles vaccination. RESULTS: In trial I (1993-1995), the mortality rate was 0.0 per 1000 person-years among children vaccinated with MV in the presence of maternal antibody and 32.3 per 1000 person-years without maternal antibody (mortality rate ratio [MRR], 0.0; 95% confidence interval [CI], 0-.52). In trial II (2003-2007), the mortality rate was 4.2 per 1000 person-years among children vaccinated in presence of maternal measles antibody and 14.5 per 1000 person-years without measles antibody (MRR, 0.29; 95% CI, .09-.91). Possible confounding factors did not explain the difference. In a combined analysis, children who had measles antibody detected when they received their first dose of MV at 4-6 months of age had lower mortality than children with no maternal antibody, the MRR being 0.22 (95% CI, .07-.64) between 4-6 months and 5 years. CONCLUSIONS: Child mortality in low-income countries may be reduced by vaccinating against measles in the presence of maternal antibody, using a 2-dose schedule with the first dose at 4-6 months (earlier than currently recommended) and a booster dose at 9-12 months of age. CLINICAL TRIALS REGISTRATION: NCT00168558

Physical Activity, Heart Rate, Metabolic Profile, and Estradiol in Premenopausal Women

Purpose: To study whether physical inactive women with a tendency to develop metabolic syndrome have high levels of 17[beta]-estradiol (E2) of importance for breast cancer risk. Methods: Two hundred and four healthy women of reproductive age were assessed for self-reported leisure-time physical activity (LPA), resting heart rate (HR), blood pressure (BP), anthropometry, and serum glucose, lipids, and insulin [Norwegian Energy Balance and Breast Cancer Aspect (EBBA) study]. E2 was measured in daily saliva samples throughout an entire menstrual cycle. A clustered metabolic risk score [z metabolic syndrome (zMS); total cholesterol-high-density lipoprotein-cholesterol (HDL-C) ratio, insulin resistance, total fat tissue, BP, and triglycerides] was defined. Linear regression and linear mixed models were used, and confounding factors were tested. Results: Physically active women had lower fat percentage (Ptrend = 0.003) and HRs (Ptrend = 0.003) than sedentary women. We estimated an increase in E2 of 1.27 pmol[middle dot]L-1 [95% confidence interval (CI), 0.06-2.47] for each 11.7 beats[middle dot]min-1 (1 SD) increase in HR, and this corresponds to the 7% change in mean concentration of E2 for the total group. Associations with E2 were also found for fat tissue, total cholesterol-HDL-C ratio, insulin resistance, and triglycerides. A dose-response relationship was observed among the three levels of LPA and HR and zMS (Ptrend = 0.03 for LPA; Ptrend = 0.004 for HR). Women in the highest tertile of the clustered metabolic risk score had average salivary E2profiles that were markedly higher, throughout the cycle, than those of the other groups, with a cycle peak-day difference in E2 of 22-28%. Conclusion: LPA and HR were associated with metabolic risk score, and this score was associated with daily level of E2, pointing to important biologic mechanisms operating between a sedentary lifestyle and an increased breast cancer risk.AnthropologyHuman Evolutionary Biolog

Paraoxonase 1 Polymorphism and Prenatal Pesticide Exposure Associated with Adverse Cardiovascular Risk Profiles at School Age

Background: Prenatal environmental factors might influence the risk of developing cardiovascular disease later in life. The HDL-associated enzyme paraoxonase 1 (PON1) has anti-oxidative functions that may protect against atherosclerosis. It also hydrolyzes many substrates, including organophosphate pesticides. A common polymorphism, PON1 Q192R, affects both properties, but a potential interaction between PON1 genotype and pesticide exposure on cardiovascular risk factors has not been investigated. We explored if the PON1 Q192R genotype affects cardiovascular risk factors in school-age children prenatally exposed to pesticides. Methods: Pregnant greenhouse-workers were categorized as high, medium, or not exposed to pesticides. Their children underwent a standardized examination at age 6-to-11 years, where blood pressure, skin folds, and other anthropometric parameters were measured. PON1-genotype was determined for 141 children (88 pesticide exposed and 53 unexposed). Serum was analyzed for insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGFBP3), insulin and leptin. Body fat percentage was calculated from skin fold thicknesses. BMI results were converted to age and sex specific Z-scores. Results: Prenatally pesticide exposed children carrying the PON1 192R-allele had higher abdominal circumference, body fat content, BMI Z-scores, blood pressure, and serum concentrations of leptin and IGF-I at school age than unexposed children. The effects were related to the prenatal exposure level. For children with the PON1 192QQ genotype, none of the variables was affected by prenatal pesticide exposure. Conclusion: Our results indicate a gene-environment interaction between prenatal pesticide exposure and the PON1 gene. Only exposed children with the R-allele developed adverse cardiovascular risk profiles thought to be associated with the R-allele

A comparison of sexual behaviour and attitudes of healthy adolescents in a Danish high school in 1982, 1996, and 2001

AIM: To assess changes in sexual behaviour among students at a high school in Denmark from 1982 to 2001. METHODS: An anonymous self-administered questionnaire was used to compare data from three identical cross-sectional surveys performed in 1982, 1996, and 2001. RESULTS: Girls: More girls reported their first sexual intercourse before their 16th birthday in 2001 (42%) than in 1996 (29%) In 1982 it was also 42% (Chi-square for trend: p = 0.003). Fewer girls with no regular partner used condoms for their personal protection in 2001 (2%) than in 1996 (9%) and 1982 (0%) (Chi-square for trend p = 0.016). The proportion of girls with no regular partner who considered protection from sexually transmitted disease important for their choice of contraception was 39% in 2001 compared with 71% in 1996 and only 10% in 1982 (Chi-square for trend: p < 0.0001). Boys: More boys reported sexual debut before their 16th birthday in 2001 (40%) than in 1996 (37%) and 1982 (24%) (Chi-square for trend: p = 0.023). For boys with no regular partner, condom was preferred for personal protection by 85% in 2001, 91% in 1996 and 61% in 1982 (Chi-square for trend p = 0.007). Protection against sexually transmitted infection declined, especially among boys with no regular partner, from 51% in 2001 to 72% in 1996 and 21% in 1982 Chi-square for trend: p < 0.0001). The tendency towards earlier sexual debut and less use of safe sex practices to protect against sexually transmitted infections (STI) was accompanied by a rise in the number of detected STIs during this period. CONCLUSIONS: The period from 1982 to 1996 during which sexual attitudes were directed toward safer sex seems to have given way to a reverse trend in the period from 1996 to 2001. These findings may have significant implications for health care authorities organising preventive strategies for healthy adolescents

Lower birth weight and increased body fat at school age in children prenatally exposed to modern pesticides: a prospective study

Background: Endocrine disrupting chemicals have been hypothesized to play a role in the obesity epidemic. Long-term effects of prenatal exposure to non-persistent pesticides on body composition have so far not been investigated. The purpose of this study was to assess possible effects of prenatal exposure to currently used pesticides on children's growth, endocrine and reproductive function. Methods: In a prospective study of 247 children born by women working in greenhouses in early pregnancy, 168 were categorized as prenatally exposed to pesticides. At three months (n = 203) and at 6 to11 years of age (n = 177) the children underwent a clinical examination and blood sampling for analysis of IGF-I, IGFBP3 and thyroid hormones. Body fat percentage at age 6 to11 years was calculated from skin fold measurements. Pesticide related associations were tested by linear multiple regression analysis, adjusting for relevant confounders. Results: Compared to unexposed children birth weight and weight for gestational age were lower in the highly exposed children: -173 g (-322; -23), -4.8% (-9.0; -0.7) and medium exposed children: -139 g (-272; -6), -3.6% (-7.2; -0.0). Exposed (medium and highly together) children had significantly larger increase in BMI Z-score (0.55 SD (95% CI: 0.1; 1.0) from birth to school age) and highly exposed children had 15.8% (0.2; 34.6) larger skin folds and higher body fat percentage compared to unexposed. If prenatally exposed to both pesticides and maternal smoking (any amount), the sum of four skin folds was 46.9% (95% CI: 8.1; 99.5) and body fat percentage 29.1% (95% CI: 3.0; 61.4) higher. There were subtle associations between exposure and TSH Z-score -0.66(-1.287; -0.022) and IGF-I Z-score (girls: -0.62(-1.0; -0.22), boys: 0.38(-0.03; 0.79)), but not IGFBP3. Conclusions: Occupational exposure to currently used pesticides may have adverse effects in spite of the added protection offered to pregnant women. Maternal exposure to combinations of modern, non-persistent pesticides during early pregnancy was associated with affected growth, both prenatally and postnatally. We found a biphasic association with lower weight at birth followed by increased body fat accumulation from birth to school age. We cannot rule out some residual confounding due to differences in social class, although this was adjusted for. Associations were stronger in highly exposed than in medium exposed children, and effects on body fat content at school age was potentiated by maternal smoking in pregnancy