Toward a Better Understanding of Prostate Cancer Statistics

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The Role of Genotypes That Modify the Toxicity of Chemical Mutagens in the Risk for Myeloproliferative Neoplasms

Background: The etiology of myeloproliferative neoplasms (MPN) (polycythemia vera; essential thrombocythemia; primary myelofibrosis) is unknown, however they are associated with a somatic mutation—JAK2 V617F—suggesting a potential role for environmental mutagens. Methods: We conducted a population-based case-control study in three rural Pennsylvania counties of persons born 1921–1968 and residing in the area between 2000–2008. Twenty seven MPN cases and 292 controls were recruited through random digit dialing. Subjects were genotyped and odds ratios estimated for a select set of polymorphisms in environmentally sensitive genes that might implicate specific environmental mutagens if found to be associated with a disease. Results: The presence of NAT2 slow acetylator genotype, and CYP1A2, GSTA1, and GSTM3 variants were associated with an average 3–5 fold increased risk. Conclusions: Exposures, such as to aromatic compounds, whose toxicity is modified by genotypes associated with outcome in our analysis may play a role in the environmental etiology of MPNs

Polymorphisms in estrogen-metabolizing and estrogen receptor genes and the risk of developing breast cancer among a cohort of women with benign breast disease

BACKGROUND: A cohort study was conducted to examine the role of genetic polymorphisms in three estrogen metabolizing enzymes (COMT, CYP1A1, CYP1B1) and the two estrogen receptors (ESR1, ESR2) in the progression of benign breast disease (BBD) to breast cancer. METHODS: Among participants in an ongoing cohort study, 1438 Caucasian women had a breast biopsy for BBD and were successfully genotyped for at least one of the polymorphisms examined in this study. Genotypes were determined using DNA extracted from blood specimens collected in 1989. Incident cases of breast cancer occurring subsequent to BBD diagnosis up to 2003 were identified through cancer registries. RESULTS: Among all participants, the ESR2 *5772G allele was associated with a significant decrease in the risk of breast cancer among women with BBD (Odds Ratio (OR) 0.38; 95% Confidence Interval (CI) 0.15, 0.96). Compared to the reference wild-type genotypes, marginally significant associations with the development of breast cancer were observed between carriers of the variant ESR1 – 104062T allele (OR 0.70, 95% CI 0.45, 1.09), the variant ESR2 *38A allele (OR 1.40; 95% CI 0.88, 2.25), and the variant CYP1B1 453Ser allele (OR 1.48, 95% CI 0.95, 2.32). CONCLUSION: The results indicate that specific polymorphisms in the CYP1B1, ESR1, and ESR2 genes may play a role in progression of BBD to breast cancer among Caucasian women. Although additional studies are needed to confirm or refute our findings, these results suggest that genetic markers may aid in the identification of women who are at risk for progression of BBD to cancer

Predictors of language acquisition in preschool children with autism spectrum disorders

Journal of Autism and Developmental DisordersIn 118 children followed from age 2 to 5 (59 with autism, 24 with PDD-NOS and 35 with nonspectrum developmental disabilities), age 2 and age 3 scores of non-verbal ability, receptive communication, expressive communication and socialization were compared as predictors of receptive and expressive language at age 5. Non-verbal cognitive ability at age 2 was generally the strongest predictor of age 5 language, while at age 3 communication scores were a stronger predictor of age 5 language for children with autism. Early joint attention as well as vocal and motor imitation skills were more impaired in children who did not develop language by age 5 (but had relatively strong non-verbal cognitive skills) than in children who did develop language by 5

Advanced Parental Age and the Risk of Autism Spectrum Disorder

This study evaluated independent effects of maternal and paternal age on risk of autism spectrum disorder. A case-cohort design was implemented using data from 10 US study sites participating in the Centers for Disease Control and Prevention's Autism and Developmental Disabilities Monitoring Network. The 1994 birth cohort included 253,347 study-site births with complete parental age information. Cases included 1,251 children aged 8 years with complete parental age information from the same birth cohort and identified as having an autism spectrum disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. After adjustment for the other parent's age, birth order, maternal education, and other covariates, both maternal and paternal age were independently associated with autism (adjusted odds ratio for maternal age ≥35 vs. 25–29 years = 1.3, 95% confidence interval: 1.1, 1.6; adjusted odds ratio for paternal age ≥40 years vs. 25–29 years = 1.4, 95% confidence interval: 1.1, 1.8). Firstborn offspring of 2 older parents were 3 times more likely to develop autism than were third- or later-born offspring of mothers aged 20–34 years and fathers aged <40 years (odds ratio = 3.1, 95% confidence interval: 2.0, 4.7). The increase in autism risk with both maternal and paternal age has potential implications for public health planning and investigations of autism etiology

Trends and patterns of antiseizure medication prescribing during pregnancy between 1995 and 2018 in the United Kingdom: A cohort study

OBJECTIVE: To examine antiseizure medication (ASM) prescription during pregnancy. DESIGN: Population-based drug utilisation study. SETTING: UK primary and secondary care data, 1995-2018, from the Clinical Practice Research Datalink GOLD version. POPULATION OR SAMPLE: 752 112 completed pregnancies among women registered for a minimum of 12 months with an 'up to standard' general practice prior to the estimated start of pregnancy and for the duration of their pregnancy. METHODS: We described ASM prescription across the study period, overall and by ASM indication, examined patterns of prescription during pregnancy including continuous prescription and discontinuation, and used logistic regression to investigate factors associated with those ASM prescription patterns. MAIN OUTCOME MEASURES: Prescription of ASMs during pregnancy and discontinuation of ASMs before and during pregnancy. RESULTS: ASM prescription during pregnancy increased from 0.6% of pregnancies in 1995 to 1.6% in 2018, driven largely by an increase in women with indications other than epilepsy. Epilepsy was an indication for 62.5% of pregnancies with an ASM prescription and non-epilepsy indications were present for 66.6%. Continuous prescription of ASMs during pregnancy was more common in women with epilepsy (64.3%) than in women with other indications (25.3%). Switching ASMs was infrequent (0.8% of ASM users). Factors associated with discontinuation included age ≥35, higher social deprivation, more frequent contact with the GP and being prescribed antidepressants or antipsychotics. CONCLUSIONS: ASM prescription during pregnancy increased between 1995 and 2018 in the UK. Patterns of prescription around the pregnancy period vary by indication and are associated with several maternal characteristics

Antidepressants during pregnancy and autism in offspring:population based cohort study

OBJECTIVES: To study the association between maternal use of antidepressants during pregnancy and autism spectrum disorder (ASD) in offspring. DESIGN: Observational prospective cohort study with regression methods, propensity score matching, sibling controls, and negative control comparison. SETTING: Stockholm County, Sweden. PARTICIPANTS: 254 610 individuals aged 4-17, including 5378 with autism, living in Stockholm County in 2001-11 who were born to mothers who did not take antidepressants and did not have any psychiatric disorder, mothers who took antidepressants during pregnancy, or mothers with psychiatric disorders who did not take antidepressants during pregnancy. Maternal antidepressant use was recorded during first antenatal interview or determined from prescription records. MAIN OUTCOME MEASURE: Offspring diagnosis of autism spectrum disorder, with and without intellectual disability. RESULTS: Of the 3342 children exposed to antidepressants during pregnancy, 4.1% (n=136) had a diagnosis of autism compared with a 2.9% prevalence (n=353) in 12 325 children not exposed to antidepressants whose mothers had a history of a psychiatric disorder (adjusted odds ratio 1.45, 95% confidence interval 1.13 to 1.85). Propensity score analysis led to similar results. The results of a sibling control analysis were in the same direction, although with wider confidence intervals. In a negative control comparison, there was no evidence of any increased risk of autism in children whose fathers were prescribed antidepressants during the mothers’ pregnancy (1.13, 0.68 to 1.88). In all analyses, the risk increase concerned only autism without intellectual disability. CONCLUSIONS: The association between antidepressant use during pregnancy and autism, particularly autism without intellectual disability, might not solely be a byproduct of confounding. Study of the potential underlying biological mechanisms could help the understanding of modifiable mechanisms in the aetiology of autism. Importantly, the absolute risk of autism was small, and, hypothetically, if no pregnant women took antidepressants, the number of cases that could potentially be prevented would be small