Sean S. Brummel

OBJECTIVE: There is limited information on the public health impact of wildfires. The relationship of cardiorespiratory hospital admissions (n = 40 856) to wildfire-related particulate matter (PM(2.5)) during catastrophic wildfires in southern California in October 2003 was evaluated. METHODS: Zip code level PM(2.5) concentrations were estimated using spatial interpolations from measured PM(2.5), light extinction, meteorological conditions, and smoke information from MODIS satellite images at 250 m resolution. Generalised estimating equations for Poisson data were used to assess the relationship between daily admissions and PM(2.5), adjusted for weather, fungal spores (associated with asthma), weekend, zip code-level population and sociodemographics. RESULTS: Associations of 2-day average PM(2.5) with respiratory admissions were stronger during than before or after the fires. Average increases of 70 microg/m(3) PM(2.5) during heavy smoke conditions compared with PM(2.5) in the pre-wildfire period were associated with 34% increases in asthma admissions. The strongest wildfire-related PM(2.5) associations were for people ages 65-99 years (10.1% increase per 10 microg/m(3) PM(2.5), 95% CI 3.0% to 17.8%) and ages 0-4 years (8.3%, 95% CI 2.2% to 14.9%) followed by ages 20-64 years (4.1%, 95% CI -0.5% to 9.0%). There were no PM(2.5)-asthma associations in children ages 5-18 years, although their admission rates significantly increased after the fires. Per 10 microg/m(3) wildfire-related PM(2.5), acute bronchitis admissions across all ages increased by 9.6% (95% CI 1.8% to 17.9%), chronic obstructive pulmonary disease admissions for ages 20-64 years by 6.9% (95% CI 0.9% to 13.1%), and pneumonia admissions for ages 5-18 years by 6.4% (95% CI -1.0% to 14.2%). Acute bronchitis and pneumonia admissions also increased after the fires. There was limited evidence of a small impact of wildfire-related PM(2.5) on cardiovascular admissions. CONCLUSIONS: Wildfire-related PM(2.5) led to increased respiratory hospital admissions, especially asthma, suggesting that better preventive measures are required to reduce morbidity among vulnerable populations.

BACKGROUND: A preliminary safety signal for neural-tube defects was previously reported in association with dolutegravir exposure from the time of conception, which has affected choices of antiretroviral treatment (ART) for human immunodeficiency virus (HIV)-infected women of reproductive potential. The signal can now be evaluated with data from follow-up of additional pregnancies. METHODS: We conducted birth-outcomes surveillance at hospitals throughout Botswana, expanding from 8 to 18 sites in 2018. Trained midwives performed surface examinations of all live-born and stillborn infants. Research assistants photographed abnormalities after maternal consent was obtained. The prevalence of neural-tube defects and major external structural defects according to maternal HIV infection and ART exposure status was determined. In the primary analyses, we used the Newcombe method to evaluate differences in prevalence with 95% confidence intervals. RESULTS: From August 2014 through March 2019, surveillance captured 119,477 deliveries; 119,033 (99.6%) had an infant surface examination that could be evaluated, and 98 neural-tube defects were identified (0.08% of deliveries). Among 1683 deliveries in which the mother was taking dolutegravir at conception, 5 neural-tube defects were found (0.30% of deliveries); the defects included two instances of myelomeningocele, one of anencephaly, one of encephalocele, and one of iniencephaly. In comparison, 15 neural-tube defects were found among 14,792 deliveries (0.10%) in which the mother was taking any non-dolutegravir ART at conception, 3 among 7959 (0.04%) in which the mother was taking efavirenz at conception, 1 among 3840 (0.03%) in which the mother started dolutegravir treatment during pregnancy, and 70 among 89,372 (0.08%) in HIV-uninfected mothers. The prevalence of neural-tube defects was higher in association with dolutegravir treatment at conception than with non-dolutegravir ART at conception (difference, 0.20 percentage points; 95% confidence interval [CI], 0.01 to 0.59) or with other types of ART exposure. Major external structural defects were found in 0.95% of deliveries among women exposed to dolutegravir at conception and 0.68% of those among women exposed to non-dolutegravir ART at conception (difference, 0.27 percentage points; 95% CI, -0.13 to 0.87). CONCLUSIONS: The prevalence of neural-tube defects was slightly higher in association with dolutegravir exposure at conception than with other types of ART exposure at conception (3 per 1000 deliveries vs. 1 per 1000 deliveries). (Funded by the National Institutes of Health.).

INTRODUCTION: Women who carry mutations in BRCA1 and BRCA2 have a substantially increased risk of developing breast cancer as compared with the general population. However, risk estimates range from 20 to 80%, suggesting the presence of genetic and/or environmental risk modifiers. Based on extensive in vivo and in vitro studies, one important pathway for breast cancer pathogenesis may be the insulin-like growth factor (IGF) signaling pathway, which regulates both cellular proliferation and apoptosis. BRCA1 has been shown to directly interact with IGF signaling such that variants in this pathway may modify risk of cancer in women carrying BRCA mutations. In this study, we investigate the association of variants in genes involved in IGF signaling and risk of breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations. METHODS: A cohort of 1,665 adult, female mutation carriers, including 1,122 BRCA1 carriers (433 cases) and 543 BRCA2 carriers (238 cases) were genotyped for SNPs in IGF1, IGF1 receptor (IGF1R), IGF1 binding protein (IGFBP1, IGFBP2, IGFBP5), and IGF receptor substrate 1 (IRS1). Cox proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was assumed; and for single SNP analyses, no additivity assumptions were made. RESULTS: Among BRCA1 carriers, significant associations were found between risk of breast cancer and LD blocks in IGF1R (global P = 0.011 for LD block 2 and global P = 0.012 for LD block 11). Among BRCA2 carriers, an LD block in IGFBP2 (global P = 0.0145) was found to be associated with the time to breast cancer diagnosis. No significant LD block associations were found for the other investigated genes among BRCA1 and BRCA2 carriers. CONCLUSIONS: This is the first study to investigate the role of genetic variation in IGF signaling and breast cancer risk in women carrying deleterious mutations in BRCA1 and BRCA2. We identified significant associations in variants in IGF1R and IRS1 in BRCA1 carriers and in IGFBP2 in BRCA2 carriers. Although there is known to be interaction of BRCA1 and IGF signaling, further replication and identification of causal mechanisms are needed to better understand these associations.

BACKGROUND.: Early antiretroviral therapy (ART) limits proviral reservoirs, a goal for human immunodeficiency virus type 1 (HIV-1) remission strategies. Whether this is an immediate or long-term effect of virologic suppression (VS) in perinatal infection is unknown. METHODS.: We quantified HIV-1 DNA longitudinally for up to 14 years in peripheral blood mononuclear cells (PBMCs) among 61 perinatally HIV-1-infected youths in the Pediatric HIV/AIDS Cohort Study who achieved VS at different ages. Participants in group 1 (n = 13) were <1 year of age and in group 2 (n = 48) from 1 through 5 years of age at VS. Piecewise linear mixed-effects regression models assessed the effect of age at VS on HIV-1 DNA trajectories during VS. RESULTS.: In the first 2 years following VS, HIV-1 DNA levels decreased by -0.25 (95% confidence interval [CI], -.36 to -.13) log10 copies/million PBMCs per year and was faster with early VS by age 1 year compared with after age 1 (-0.50 and -0.15 log10 copies/million PBMCs per year, respectively). Between years 2 and 14 from VS, HIV-1 DNA decayed by -0.05 (95% CI, -.06 to -.03) log10 copies/million PBMCs per year and was no longer significantly different between groups. The estimated mean half-life of HIV-1 DNA from VS was 15.9 years and was shorter for group 1 compared to group 2 at 5.9 years and 18.8 years, respectively (P = .09). Adjusting for CD4 cell counts had no effect on decay estimates. CONCLUSIONS.: Early effective, long-term ART initiated from infancy leads to decay of HIV-1-infected cells to exceedingly low concentrations desired for HIV-1 remission strategies.