A genome-wide gene-based gene-environment interaction study of breast cancer in more than 90,000 women.

Background: Genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for breast cancer, but these variants explain less than a fifth of the disease risk. Although gene-environment interactions have been proposed to account for some of the remaining heritability, few studies have empirically assessed this. Methods: We obtained genotype and risk factor data from 46,060 cases and 47,929 controls of European ancestry from population-based studies within the Breast Cancer Association Consortium (BCAC). We built gene expression prediction models for 4,864 genes with a significant (P<0.01) heritable component using the transcriptome and genotype data from the Genotype-Tissue Expression (GTEx) project. We leveraged predicted gene expression information to investigate the interactions between gene-centric genetic variation and 14 established risk factors in association with breast cancer risk, using a mixed-effects score test. Results: After adjusting for number of tests using Bonferroni correction, no interaction remained statistically significant. The strongest interaction observed was between the predicted expression of the C13orf45 gene and age at first full-term pregnancy (PGXE=4.44×10-6). Conclusion: In this transcriptome-informed genome-wide gene-environment interaction study of breast cancer, we found no strong support for the role of gene expression in modifying the associations between established risk factors and breast cancer risk. Impact: Our study suggests a limited role of gene-environment interactions in breast cancer risk.

Distinct Reproductive Risk Profiles for Intrinsic-Like Breast Cancer Subtypes: Pooled Analysis of Population-Based Studies.

BACKGROUND: Reproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear. METHODS: Analyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2-like, HER2-enriched-like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided. RESULTS: Compared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2-like, and HER2-enriched-like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like. CONCLUSIONS: This large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared with other subtypes, with implications for the understanding of disease etiology and risk prediction.

Association Between the BNT162b2 Messenger RNA COVID-19 Vaccine and the Risk of Sudden Sensorineural Hearing Loss.

IMPORTANCE: Identification of adverse events after vaccination increases awareness of vaccine-associated complications, leading to early diagnosis and treatment. Evidence remains scarce on the association between the BNT162b2 messenger RNA (mRNA) COVID-19 vaccine (Pfizer-BioNTech) and sudden sensorineural hearing loss (SSNHL). OBJECTIVE: To assess the association between the BNT162b2 mRNA COVID-19 vaccine and SSNHL. DESIGN, SETTING, AND PARTICIPANTS: This retrospective, population-based cohort study was performed from December 20, 2020, to May 31, 2021, using data from the largest health care organization in Israel. Patients 16 years or older who received the first vaccine dose between December 20, 2020, and April 30, 2021, and the second vaccine dose between January 10, 2021, and April 30, 2021, were included. EXPOSURES: Receipt of first and second BNT162b2 mRNA COVID-19 vaccine doses. MAIN OUTCOMES AND MEASURES: The main outcome was SSNHL based on International Classification of Diseases, Ninth Revision (ICD-9) codes in conjunction with concurrent prednisone dispensing. Observed cases of SSNHL, occurring within 21 days after each of the first and second vaccine doses, were compared with the expected cases based on the experience of the population in 2018 and 2019. Standardized incidence ratios (SIRs) and attributable risks were computed. RESULTS: Overall, 2 602 557 patients (mean [SD] age, 46.8 [19.6] years; 51.5% female) received the first dose of BNT162b2 mRNA COVID-19 vaccine, with 91 cases of SSNHL reported. Of these patients, 2 441 719 (93.8%) received the second vaccine dose, with 79 cases of SSNHL reported. The age- and sex-weighted SIRs were 1.35 (95% CI, 1.09-1.65) after the first vaccine dose and 1.23 (95% CI, 0.98-1.53) after the second vaccine dose. After the first vaccine dose, the estimated SIRs were more pronounced in female patients aged 16 to 44 years (SIR, 1.92; 95% CI, 0.98-3.43) and female patients 65 years or older (SIR, 1.68; 95% CI, 1.15-2.37). After the second vaccine dose, the highest estimated SIR was observed in male patients 16 to 44 years (SIR, 2.45; 95% CI, 1.36-4.07). The attributable risks were generally small, and the results were similar when 2019 was used as a reference to estimate the expected number of SSNHL cases. CONCLUSIONS AND RELEVANCE: This study suggests that the BNT162b2 mRNA COVID-19 vaccine might be associated with increased risk of SSNHL; however, the effect size is very small. Further studies are warranted to establish this possible association.

Association between vaccination with the BNT162b2 mRNA COVID-19 vaccine and Bell's palsy: a population-based study.

BACKGROUND: An excess risk of Bell's palsy has been suggested after mRNA vaccines. We examined the association between the BNT162b2 mRNA COVID-19 vaccine and Bell's palsy. METHODS: Using the database of the largest healthcare provider in Israel, we retrieved data from different periods in 2018-2021. Observed cases of Bell's palsy occurring within 21-days after the first vaccine dose and within 30-days after the second vaccine dose were compared to the expected cases, based on the experience of the population in 2019. Standardized incidence ratios (SIRs) and attributable risks (ARs) were computed. FINDINGS: Overall, 132 cases of Bell's palsy were reported in 2,594,990 vaccinees with the first dose, and 152 cases in 2,434,674 vaccinees after the second dose. The age and sex weighted SIRs were 1.36(95% CI, 1.14-1.61) and 1.16(0.99-1.36) after the first and second vaccine dose, respectively. SIRs tended to be higher in older age groups after the first and second vaccine doses. The estimates were more pronounced in older females after the first vaccine dose; SIR=1.71(1.10-2.54) at age 45-64, and 2.51(1.65-3.68) at age ≥65 years. The highest AR was 4.46 per 100,000 vaccinees detected in females aged ≥65 years. In patients with previous history of Bell's palsy, only 4 cases of Bell's palsy were reported in 7,567 vaccinees and 10 cases in 7,045 vaccinees after the first and the second dose, respectively. The age and sex weighted SIRs were 1.15(0.36-2.76) and 2.15(1.09-3.83) after the first and second vaccine dose, respectively. INTERPRETATION: This study suggests that the BNT162b2 mRNA COVID-19 vaccine might be associated with increased risk of Bell's palsy. The small estimated attributable risks suggest that the impact on public health is relatively minor. The benefits of vaccinations explicitly outweigh the possible link to Bell's palsy that has high recovery rate if timely treated with corticosteroids. FUNDING: No external funding was available for this study.

The factors associated with maternal consent to human papillomavirus vaccination among adolescents in Israel.

Purpose: To evaluate the knowledge and attitudes toward the human papillomavirus (HPV) vaccine among mothers of 8th graders in Israel, and to determine the factors associated with maternal consent to the HPV vaccine.Methods: We conducted a cross-sectional study among mothers of 8th grade students in 27 schools in Haifa and Northern districts of Israel during the 2016-17 school year. Data were collected using a structured telephone questionnaire.Results: 313 mothers answered the questionnaire (response rate = 91.8%). The mean knowledge level score was low (3.96 points [out of 10] ±2.68). Knowledge level was positively associated with Jewish nationality, being secular in religious practice and higher education. The attitude mean score was low-moderate (11.22 points [out of 18] ± 5.01). Attitude score was positively associated with Arab nationality. No significant association was found between knowledge level and attitudes. According to multivariate analysis, mothers' consent to the HPV vaccine was associated with the knowledge level score (OR = 0.82; 95%CI 0.68-0.98), the attitude score (OR = 1.76; 95%CI 1.53-2.02) and nationality (OR = 27.86, 95%CI 3.41-227.56).Conclusions: The knowledge level and attitudes toward the HPV vaccine were found to be unsatisfactory with racial disparities between Arabs and Jews. Jewish mothers compared with Arab mothers, mothers with a higher knowledge level or less positive attitudes were less likely to consent to the vaccine. These findings could contribute toward adapting programs to the different Israeli sectors in order to improve the rates of HPV vaccine receipt among adolescents.

What affects pediatric healthcare providers to encourage receipt of routine childhood vaccinations? Results from the Northern District of Israel, 2016.

BACKGROUND: Pediatric healthcare providers (HCPs) are a major resource which helps parents make decisions about their children's vaccinations. It is important to assess their behavior to encourage the receipt of routine vaccines. OBJECTIVES: (1) To evaluate the knowledge level of and attitudes towards routine childhood vaccinations among pediatric HCPs; (2) To assess their behavior to encourage the receipt of routine vaccinations and associated predictors; (3) To examine their willingness to receive immunization training and to improve their skills to cope with vaccine-hesitant parents. STUDY DESIGN AND SETTINGS: This is a cross-sectional study among pediatric physicians and nurses working at primary clinics (curative service) and mother-child health clinics (preventive service) in Jewish localities in the Northern District of Israel. METHODS: A structured, anonymous, self-administered questionnaire was used. RESULTS: The study included 271 HCPs (response rate = 72.2%). An insufficient knowledge level about vaccines was demonstrated among participants (mean score: 5.2 ±â€¯0.91 and 4.71 ±â€¯1.21 points out of 6 in the preventive and curative services, respectively; p = 0.000). The overall attitude towards vaccinations was positive (mean score: 45.40 ±â€¯5.98 and 42.95 ±â€¯6.84 points out of 56 in the preventive and curative services, respectively; p = 0.002). The two predictors that were associated with the behavior of HCPs to encourage childhood vaccinations were workplace (preventive vs. curative service) and the number of parents encountered by the HCP who opposed or feared vaccines. No association was found between the behavior and the knowledge level and the attitudes. Of the HCPs, 79.3% were interested in immunization training and 66.1% in participating in workshops to improve their communication skills to cope with vaccine-hesitant parents. CONCLUSIONS: There is a need to increase the commitment of HCPs to encourage parents to vaccinate their children with routine vaccines, to improve their knowledge about vaccines, and to provide them with communication tools to deal with vaccine-hesitant parents.

Knowledge and recommendation regarding routine childhood vaccinations among pediatric healthcare providers in Israel.

BACKGROUND: A recommendation by pediatric healthcare providers (HCPs) is a major factor influencing parents' decision to vaccinate their children. Consequently, it is important to understand the motives behind the HCPs' recommendations to vaccinate children according to the routine immunization program. OBJECTIVES: To study the association of pediatric HCPs' knowledge about and attitudes towards childhood vaccinations and of their professional and demographic characteristics, with two variables: 1. Their recommendations to parents regarding adherence to the routine immunization program. 2. Their choices concerning routine immunization of their own children. STUDY DESIGN AND SETTINGS: We conducted a cross-sectional study of pediatric nurses and physicians working at Mother-Child Health Clinics (MCHCs) in Haifa and Tel-Aviv districts and at a hospital in Hadera City, Israel. METHODS: A structured, anonymous self-administered questionnaire was used. RESULTS: The overall response rate was 60%, totaling 218 participants. 92% of whom were nurses. Misconceptions related to vaccine safety were found among a high percentage of the participants. The HCPs knowledge level was associated with the HCPs vaccinating their own children according to the recommended immunization program (OR=1.32; CI95% 1.06-1.64), but not with their recommendation to parents to adhere to the program. No association was found between attitudes and these variables. Workplace (MCHCs versus hospital) correlated with the above mentioned two dependent variables (OR=1.89; CI95% 1.21-2.97 and OR=2.42; CI95% 1.73-3.4, respectively). CONCLUSIONS: Amplifying the knowledge of HCPs and addressing their concern about vaccinations can improve their adherence to the routine immunization program regarding their own children. This may lead to better adherence of other parents who are frequently interested in the HCPs' behavior and consider them as a role model. In general, there is a need to emphasize the HCP's responsibility for the successful implementation of the immunization program in the community and at hospitals.

Morbidity of overweight (>or=85th percentile) in the first 2 years of life.

OBJECTIVES: Our hypothesis was that morbidity related to overweight/obesity is already evident in infants and young toddlers. The major objectives of this study were (1) to assess the prevalence of overweight in a sample of hospitalized infants and (2) to assess the prevalence of morbidity in overweight infants in a community-based sample. METHODS: The hospital admission study population included 2139 infants, or=85th weight-for-height percentile in >or=2 measurements, >or=3 months apart), or=95th percentile had more admissions than expected, as well as a larger number of repeated admissions. In the second part of the study, we found that rates of developmental delays (mainly delayed gross motor skills) and snoring were significantly higher in infants of >or=85th percentile. In addition, although the results were not statistically significant, infants with overweight suffered more frequently from breathing problems, such as asthma and stridor. When the mothers were asked to assess whether their child was overweight, only 31.6% of mothers of overweight children thought that the child was overweight. CONCLUSIONS: The high admission rates for infants of >or=95th percentile and the high incidence rates of respiratory morbidity, snoring, and delayed gross motor skills in overweight infants support our hypothesis regarding early morbidity associated with overweight.