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BACKGROUND: Data on the effectiveness and safety of dolutegravir-based antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection in pregnancy as compared with other ART regimens commonly used in the United States and Europe, particularly when initiated before conception, are limited. METHODS: We conducted a study involving pregnancies in persons with HIV-1 infection in the Pediatric HIV/AIDS Cohort Study whose initial ART in pregnancy included dolutegravir, atazanavir-ritonavir, darunavir-ritonavir, oral rilpivirine, raltegravir, or elvitegravir-cobicistat. Viral suppression at delivery and the risks of infants being born preterm, having low birth weight, and being small for gestational age were compared between each non-dolutegravir-based ART regimen and dolutegravir-based ART. Supplementary analyses that included participants in the Swiss Mother and Child HIV Cohort Study were conducted to improve the precision of our results. RESULTS: Of the pregnancies in the study, 120 were in participants who received dolutegravir, 464 in those who received atazanavir-ritonavir, 185 in those who received darunavir-ritonavir, 243 in those who received rilpivirine, 86 in those who received raltegravir, and 159 in those who received elvitegravir-cobicistat. The median age at conception was 29 years; 51% of the pregnancies were in participants who started ART before conception. Viral suppression was present at delivery in 96.7% of the pregnancies in participants who received dolutegravir; corresponding percentages were 84.0% for atazanavir-ritonavir, 89.2% for raltegravir, and 89.8% for elvitegravir-cobicistat (adjusted risk differences vs. dolutegravir, -13.0 percentage points [95% confidence interval {CI}, -17.0 to -6.1], -17.0 percentage points [95% CI, -27.0 to -2.4], and -7.0 percentage points [95% CI, -13.3 to -0.0], respectively). The observed risks of preterm birth were 13.6 to 17.6%. Adjusted risks of infants being born preterm, having low birth weight, or being small for gestational age did not differ substantially between non-dolutegravir-based ART and dolutegravir. Results of supplementary analyses were similar. CONCLUSIONS: Atazanavir-ritonavir and raltegravir were associated with less frequent viral suppression at delivery than dolutegravir. No clear differences in adverse birth outcomes were observed with dolutegravir-based ART as compared with non-dolutegravir-based ART, although samples were small. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).
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Fármacos Anti-VIH , Infecciones por VIH , Inhibidores de la Proteasa del VIH , VIH-1 , Compuestos Heterocíclicos con 3 Anillos , Oxazinas , Piperazinas , Nacimiento Prematuro , Piridonas , Adulto , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Sulfato de Atazanavir/efectos adversos , Sulfato de Atazanavir/uso terapéutico , Cobicistat/efectos adversos , Cobicistat/uso terapéutico , Estudios de Cohortes , Darunavir/efectos adversos , Darunavir/uso terapéutico , Femenino , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/efectos adversos , Inhibidores de la Proteasa del VIH/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Recién Nacido , Oxazinas/efectos adversos , Oxazinas/uso terapéutico , Piperazinas/efectos adversos , Piperazinas/uso terapéutico , Embarazo , Nacimiento Prematuro/inducido químicamente , Piridonas/efectos adversos , Piridonas/uso terapéutico , Quinolonas/efectos adversos , Quinolonas/uso terapéutico , Raltegravir Potásico/efectos adversos , Raltegravir Potásico/uso terapéutico , Rilpivirina/efectos adversos , Rilpivirina/uso terapéutico , Ritonavir/efectos adversos , Ritonavir/uso terapéutico , Estados UnidosRESUMEN
Perinatally acquired HIV infection (PHIV) currently affects approximately 1.7 million children worldwide. Youth with PHIV (YPHIV) are at increased risk for emotional and behavioral symptoms, yet few studies have examined relationships between these symptoms and brain structure. Previous neuroimaging studies in YPHIV report alterations within the salience network (SN), cognitive control network (CCN), and default mode network (DMN). These areas have been associated with social and emotional processing, emotion regulation, and executive function. We examined structural brain network integrity from MRI using morphometric similarity networks and graph theoretical measures of segregation (transitivity), resilience (assortativity), and integration (global efficiency). We examined brain network integrity of 40 YPHIV compared to 214 youths without HIV exposure or infection. Amongst YPHIV, we related structural brain network metrics to the Emotional Symptoms Index of the Behavioral Assessment System for Children, 2nd edition. We also examined the relationship of inflammatory biomarkers in YPHIV to brain network integrity. YPHIV had significantly lower global efficiency in the SN, DMN, and the whole brain network compared to controls. YPHIV also demonstrated lower assortativity or resilience (i.e., network robustness) compared to controls in the DMN and whole brain network. Further, higher emotional symptom score was associated with higher global efficiency in the SN and lower global efficiency in the DMN, signaling more emotional challenges. A significant association was also found between several inflammatory and cardiac markers with structural network integrity. These findings suggest an impact of HIV on developing brain networks, and potential dysfunction of the SN and DMN in relation to network efficiency.
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Infecciones por VIH , Niño , Humanos , Adolescente , Infecciones por VIH/psicología , Encéfalo , Imagen por Resonancia Magnética , Función Ejecutiva/fisiología , EmocionesRESUMEN
OBJECTIVE: To evaluate the associations of plasma polybrominated diphenyl ether (PBDE) concentrations in early pregnancy with gestational weight gain (GWG). DESIGN: Prospective cohort study. SETTING: US-based, multicentre cohort of pregnant women. POPULATION: We used data from 2052 women without obesity and 397 women with obesity participating in the NICHD Fetal Growth Studies - Singleton Cohort, with first-trimester plasma PBDE concentrations and weight measurements throughout pregnancy. METHODS: We applied generalised linear models and Bayesian kernel machine regression (BKMR) to evaluate both the individual and joint associations of PBDEs with measures of GWG, adjusting for potential confounders. MAIN OUTCOME MEASURES: Total GWG (kg), total and trimester-specific GWG velocities (kg/week), and GWG categories and trajectory groups. RESULTS: Mean pre-pregnancy BMIs were 23.6 and 34.5 kg/m2 for women without and with obesity, respectively. Among women without obesity, there were no associations of PBDEs with any GWG measure. Among women with obesity, one standard deviation increase in log-transformed PBDE 47 was associated with a 1.87 kg higher total GWG (95% CI 0.39-3.35) and a 0.05 kg/week higher total GWG velocity (95% CI 0.01-0.09). Similar associations were found for PBDE 47 in BKMR among women with obesity, and PBDE 47, 99 and 100 were associated with lower odds of being in the low GWG trajectory group. CONCLUSIONS: PBDEs were not associated with GWG among individuals without obesity. Among those with obesity, only PBDE 47 showed consistent positive associations with GWG measures across multiple statistical methods. Further research is needed to validate this association and explore potential mechanisms.
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BACKGROUND: Little is known about inflammation/immune activation during pregnancy in people with HIV (PWH) and growth in their children who are HIV-exposed and uninfected (CHEU). METHODS: Using data from the Pediatric HIV/AIDS Cohort Study and an HIV-seronegative comparison group, we assessed associations of (1) HIV status, mode of HIV acquisition (perinatally vs nonperinatally acquired), and type of antiretroviral therapy (ART) with inflammation/immune activation in pregnancy; and (2) inflammation/immune activation in pregnancy with growth of CHEU at 12 months. Interleukin 6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), soluble(s) TNF-α receptor 1 and 2 (sTNFR1, sTNFR2), sCD14, and sCD163 were measured between 13 and 27 weeks' gestation. Linear regression models were fit to estimate differences between groups for each log-transformed biomarker, adjusted for confounders. RESULTS: Pregnant PWH (188 total, 39 perinatally acquired, 149 nonperinatally acquired) and 76 HIV-seronegative persons were included. PWH had higher IL-6, sTNFR1, sCD14, and sCD163 and lower sTNFR2 compared to HIV-seronegative persons in adjusted models. Among PWH, sCD163 was higher in those with perinatally versus nonperinatally acquired HIV and on PI-based versus INSTI-based ART. Higher maternal concentrations of IL-6, sTNFR2, and hs-CRP were associated with poorer growth at 12 months. CONCLUSIONS: Maternal HIV status is associated with a distinct profile of inflammation/immune activation during pregnancy, which may influence child growth.
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Síndrome de Inmunodeficiencia Adquirida , Infecciones por VIH , Embarazo , Femenino , Humanos , Niño , Estados Unidos , Proteína C-Reactiva , Interleucina-6 , Estudios de Cohortes , Receptores de Lipopolisacáridos , Inflamación , Biomarcadores , Infecciones por VIH/complicaciones , Síndrome de Inmunodeficiencia Adquirida/complicacionesRESUMEN
STUDY QUESTION: Are occupational factors associated with markers of testicular function among men attending a fertility center? SUMMARY ANSWER: Men working non-daytime/rotating shifts and those with physically demanding jobs have higher sperm concentration and total sperm count as well as higher estradiol and total testosterone concentrations. WHAT IS KNOWN ALREADY: Semen quality has declined during recent decades and has been negatively correlated with higher risks of common chronic diseases and mortality, highlighting its public health importance beyond fertility and reproduction. While most of the previous epidemiology literature on male fertility has focused on environmental exposures, dietary factors, and other related variables, little attention has been paid to occupational factors. STUDY DESIGN, SIZE, DURATION: This observational study included 377 men who were male partners in couples seeking infertility treatment at a fertility center, who enrolled in the Environment and Reproductive Health (EARTH) study between 2005 and 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Self-reported information on lifting/moving heavy objects, typical shift, and physical level of exertion at work was collected from a take-home questionnaire. Semen samples were analyzed following World Health Organization guidelines. Enzyme immunoassays were used to assess reproductive hormone concentrations. Linear regression models were used to evaluate the association between occupational factors and measures of testicular function, while adjusting for covariates such as age, BMI, education, race, smoking, and abstinence time, and accounting for multiple semen samples (mean = 2, min-max = 1-9) in analyses for semen parameters. MAIN RESULTS AND THE ROLE OF CHANCE: Men had a median (interquartile range) age of 36 (33, 39) years and were predominantly Caucasian (87%). Of the men who completed the survey, 12% reported often lifting or moving heavy objects at work, 6% reported heavy physical exertion at work, and 9% reported evening or rotating shifts. Men who reported often lifting or moving heavy objects at work had 46% higher sperm concentrations (P = 0.01) and 44% higher total counts (P = 0.01) compared with men who reported never lifting or moving heavy objects at work. Similar results were found for men working in rotating shifts compared to those in day shifts, as well as for men involved in heavy levels of physical exertion compared to those with light levels at work. We also found that men involved in heavy/moderate levels of physical exertion at work had higher circulating testosterone concentrations compared to those with lighter exertion (adjusted means of 515 and 427 ng/dl, respectively, P = 0.08), and men who often moved/lifted heavy objects at work had higher estradiol concentrations, compared to those who never did (adjusted means of 36.8 and 27.1 pg/ml, respectively, P = 0.07). Men working evening/rotating shifts had 24% higher testosterone (P = 0.04) and 45% higher estradiol concentrations (P = 0.01), compared to men working day shifts. No associations were observed for ejaculated volume, total motility, morphologically normal sperm, or serum FSH and LH concentrations. LIMITATIONS, REASONS FOR CAUTION: Due to our study design which recruited men from couples seeking fertility treatment, it may not be possible to generalize our findings to men from the general population. Also, as is the case of all studies based on self-reported questionnaires, measurement error and misclassification of the exposure are potential concerns. WIDER IMPLICATIONS OF THE FINDINGS: Physically demanding jobs and rotating or evening shift occupations may be associated with higher testicular function in men measured as higher sperm concentrations and counts as well as higher serum testosterone and estradiol levels. Confirmation of these findings in other non-fertility clinic study populations is warranted. STUDY FUNDING/COMPETING INTEREST(S): NIH grants R01ES022955, R01ES009718, R01ES033651, and R01ES000002 from the National Institute of Environmental Health Sciences (NIEHS) and Legacy, Inc. R.A.G. works part time for Legacy, Inc., which provided funds to perform this analysis. There are no other conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.
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Análisis de Semen , Semen , Humanos , Masculino , Femenino , Motilidad Espermática , Hormona Folículo Estimulante , Recuento de Espermatozoides , Testosterona , EstradiolRESUMEN
RESEARCH QUESTION: Is self-reported psychological stress associated with markers of ovarian reserve among subfertile women? DESIGN: Observational study of women (nâ¯=â¯520) seeking fertility care at the Massachusetts General Hospital who enrolled in the Environment and Reproductive Health study between 2005 and 2019. Women completed the short version of the validated PSS4, which assesses psychological stress. Ovarian reserve markers included AFC and circulating serum levels of day-3 FSH, with AMH assessed in a subset of participants (nâ¯=â¯185). RESULTS: Higher total PSS4 scores were negatively associated with AFC and serum AMH levels. Analyses adjusted for age, BMI, race, smoking, education, physical activity and type of infertility diagnosis. Women in the second and third tertiles of stress had lower AFC (13.3, 95% CI 12.7 to 13.8; and 13.5, 95% CI 13.0 to 14.1) compared with women in the lowest tertile of psychological stress score (14.3, 95% CI 13.8 to 14.9, both P < 0.05). Women in the second and third tertiles of total PSS4 scores also had lower mean serum AMH compared with women in the lowest tertile (2.99, 95% CI 2.24 to 3.74), and (2.99 95% CI 2.22 to 3.76) versus (3.94 95% CI 3.23 to 4.64). These associations varied by several socioeconomic factors, and were observed among women who were younger, belonging to minority races, with a college degree or with annual household income less than $100,000. CONCLUSIONS: Higher perceived stress was negatively associated with AFC and serum AMH levels. These associations varied by several socioeconomic factors.
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Infertilidad Femenina , Reserva Ovárica , Femenino , Humanos , Folículo Ovárico , Infertilidad Femenina/diagnóstico , Hormona AntimüllerianaRESUMEN
There has been heightened interest in identifying critical windows of exposure for adverse health outcomes; that is, time points during which exposures have the greatest impact on a person's health. Multiple informant models implemented using generalized estimating equations (MIM GEEs) have been applied to address this research question because they enable statistical comparisons of differences in associations across exposure windows. As interest rises in using MIMs, the feasibility and appropriateness of their application under settings of correlated exposures and partially missing exposure measurements requires further examination. We evaluated the impact of correlation between exposure measurements and missing exposure data on the power and differences in association estimated by the MIM GEE and an inverse probability weighted extension to account for informatively missing exposures. We assessed these operating characteristics under a variety of correlation structures, sample sizes, and missing data mechanisms considering various exposure-outcome scenarios. We showed that applying MIM GEEs maintains higher power when there is a single critical window of exposure and exposure measures are not highly correlated, but may result in low power and bias under other settings. We applied these methods to a study of pregnant women living with HIV to explore differences in association between trimester-specific viral load and infant neurodevelopment.
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Modelos Estadísticos , Lactante , Humanos , Embarazo , Femenino , Probabilidad , Sesgo , Trimestres del Embarazo , Tamaño de la MuestraRESUMEN
Midlife in women is an understudied time for environmental chemical exposures and menopausal outcomes. Recent cross-sectional research links phthalates with hot flashes, but little is known regarding such associations over time. Our objective was to estimate longitudinal associations between repeated measures of urinary phthalate metabolite concentrations and hot flash outcomes in midlife women. Using data from the Midlife Women's Health Study (MWHS), a prospective longitudinal study, we fit generalized linear mixed-effects models (GLMMs) and Cox proportional hazards regression models to repeated measures over a 4-year period. Recruitment occurred in Baltimore and surrounding counties, Maryland, USA between 2006 and 2015. Participants were premenopausal/perimenopausal women (n = 744) aged 45-54 years, who were not pregnant, not taking menopausal symptom medication or oral contraceptives, did not have hysterectomy/oophorectomy, and irrespective of hot flash experience. Baseline mean (SD) age was 48.4 (2.45), and 65% were premenopausal. Main outcome measures included adjusted odds ratios (ORs) for 4 self-reported hot flash outcomes (ever experienced, past 30 days experience, weekly/daily, and moderate/severe), and hazard ratios (HRs) for incident hot flashes. We observed mostly increased odds of certain hot flash outcomes with higher concentrations of metabolites of di (2-ethylhexyl) phthalate (DEHP), monoisobutyl phthalate (MiBP), and a molar summary measure of plasticizer phthalate metabolites (DEHP metabolites, mono-(3-carboxypropyl) phthalate (MCPP), monobenzyl phthalate (MBzP)). Some associations between exposures and outcomes indicated decreased odds. In conclusion, phthalate metabolites were associated with certain hot flash outcomes in midlife women. Midlife may be a sensitive period for higher phthalate metabolite concentrations with respect to menopausal symptoms.
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Dietilhexil Ftalato , Contaminantes Ambientales , Ácidos Ftálicos , Femenino , Humanos , Embarazo , Sofocos/epidemiología , Contaminantes Ambientales/orina , Estudios Prospectivos , Estudios Transversales , Estudios Longitudinales , Ácidos Ftálicos/orina , Exposición a Riesgos Ambientales , Salud de la MujerRESUMEN
Prenatal exposure to endocrine disrupting chemicals (EDCs) from personal care products may be associated with birth outcomes including preterm birth and low birth weight. There is limited research examining the role of personal care product use during pregnancy on birth outcomes. Our pilot study consisted of 164 participants in the Environmental Reproductive and Glucose Outcomes (ERGO) study (Boston, MA), with data on self-reported personal care product use at four study visits throughout pregnancy (product use in the 48 h before a study visit and hair product use in the month before a study visit). We used covariate-adjusted linear regression models to estimate differences in mean gestational age at delivery, birth length, and sex-specific birth weight-for-gestational age (BW-for-GA) Z-score based on personal care product use. Hair product use in the past month prior to certain study visits was associated with decreased mean sex-specific BW-for-GA Z-scores. Notably, hair oil use in the month prior to study visit 1 was associated with a lower mean BW-for-GA Z-score (V1: -0.71, 95% confidence interval: -1.12, -0.29) compared to non-use. Across all study visits (V1-V4), increased mean birth length was observed among nail polish users vs. non-users. In comparison, decreased mean birth length was observed among shave cream users vs. non-users. Liquid soap, shampoo, and conditioner use at certain study visits were significantly associated with higher mean birth length. Suggestive associations were observed across study visits for other products including hair gel/spray with BW-for-GA Z-score and liquid/bar soap with gestational age. Overall, use of a variety of personal care products throughout pregnancy was observed to be associated with our birth outcomes of interest, notably hair oil use during early pregnancy. These findings may help inform future interventions/clinical recommendations to reduce exposures linked to adverse pregnancy outcomes.
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Cosméticos , Nacimiento Prematuro , Embarazo , Masculino , Femenino , Humanos , Recién Nacido , Proyectos Piloto , Jabones , Nacimiento Prematuro/inducido químicamente , Nacimiento Prematuro/epidemiología , Recién Nacido de Bajo Peso , Peso al NacerRESUMEN
BACKGROUND: Combination antiretroviral therapy (cART) initiation during pregnancy reduces the risk of perinatal human immunodeficiency virus (HIV) transmission; however, studies have suggested that there may be unintended adverse consequences on birth outcomes for selected cART regimens. METHODS: We analyzed adverse birth outcomes among a prospective cohort of 1307 pregnant women with HIV in Dar es Salaam who initiated cART during the first or second trimester of a singleton pregnancy. Our primary analysis compared birth outcomes by gestational age at cART initiation among these women initiating cART in pregnancy. RESULTS: Among women who initiated cART in pregnancy, there was no relationship of gestational age at cART initiation with the risk of fetal death or stillbirth. However, women who initiated cART before 20 weeks of gestation compared with after 20 weeks had increased risk of preterm birth (risk ratio [RR], 1.30; 95% confidence interval [CI], 1.03-1.67) but decreased risk of small-for-gestational age birth (RR, 0.71; 95% CI, .55-.93). CONCLUSIONS: With increasing use of cART preconception and early in pregnancy, clinicians should be aware of the benefits and potential risks of cART regimens to optimize birth outcomes.
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Infecciones por VIH , Complicaciones Infecciosas del Embarazo , Nacimiento Prematuro , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Recién Nacido , Embarazo , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Resultado del Embarazo , Estudios Prospectivos , TanzaníaRESUMEN
In countries with high human immunodeficiency virus (HIV) prevalence, up to 30% of pregnant women are living with HIV, with fetal exposure to both HIV and antiretroviral therapy during pregnancy. In addition, pregnant women without HIV but at high risk of HIV acquisition are increasingly receiving HIV preexposure antiretroviral prophylaxis (PrEP). Investments are being made to establish and follow cohorts of children to evaluate the long-term effects of in utero HIV and antiretroviral exposure. Agreement on a key set of definitions for relevant exposures and outcomes is important both for interpreting individual study results and for comparisons across cohorts. Harmonized definitions of in utero HIV and antiretroviral drug (maternal treatment or PrEP) exposure will also facilitate improved classification of these exposures in future observational studies and clinical trials. The proposed definitions offer a uniform approach to facilitate the consistent description and estimation of effects of HIV and antiretroviral exposures on key child health outcomes.
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Fármacos Anti-VIH , Infecciones por VIH , Profilaxis Pre-Exposición , Complicaciones Infecciosas del Embarazo , Fármacos Anti-VIH/efectos adversos , Antirretrovirales/uso terapéutico , Niño , Femenino , VIH , Infecciones por VIH/prevención & control , Humanos , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Embarazo , Complicaciones Infecciosas del Embarazo/tratamiento farmacológicoRESUMEN
Human immunodeficiency virus (HIV) viral load (VL) is an important quantitative marker of disease progression and treatment response in people living with HIV infection, including children with perinatally acquired HIV. Measures of VL are often used to predict different outcomes of interest in this population, such as HIV-associated neurocognitive disorder. One popular approach to summarizing historical viral burden is the area under a time-VL curve (AUC). However, alternative historical VL summaries (HVS) may better answer the research question of interest. In this article, we discuss and contrast the AUC with alternative HVS, including the time-averaged AUC, duration of viremia, percentage of time with suppressed VL, peak VL, and age at peak VL. Using data on youth with perinatally acquired HIV infection from the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol, we show that HVS and their associations with full-scale intelligence quotient depend on when the VLs were measured. When VL measurements are incomplete, as can be the case in observational studies, analysis results may be subject to selection bias. To alleviate bias, we detail an imputation strategy, and we present a simulation study demonstrating that unbiased estimation of a historical VL summary is possible with a correctly specified imputation model.
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Infecciones por VIH , Adolescente , Niño , Estudios de Cohortes , Humanos , Pruebas Serológicas , Carga Viral , ViremiaRESUMEN
STUDY QUESTION: Are peripubertal blood lead levels (BLLs) associated with semen parameters and serum reproductive hormones among young Russian men? SUMMARY ANSWER: We observed a suggestion of lower ejaculate volume with higher peripubertal BLL but no associations of BLLs with reproductive hormones measured throughout adolescence or with other sperm parameters measured at adulthood. WHAT IS KNOWN ALREADY: Lead is a known reproductive toxicant and endocrine disruptor. Previous literature has shown associations between high lead exposure and poorer semen quality both in occupationally and environmentally exposed men. However, to our knowledge, no longitudinal studies have explored the association of childhood lead exposure with semen parameters and reproductive hormones in young men. STUDY DESIGN, SIZE, DURATION: The Russian Children's Study is a prospective cohort study that enrolled 516 boys at age 8-9 years in 2003-2005 and followed them annually for 10 years. BLLs were measured at entry and lifestyle and health questionnaires were completed. Reproductive hormones were measured in blood samples collected every 2 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Among the 516 boys enrolled, 481 had BLLs measured at entry. Of these, 453 had at least one measurement of serum testosterone, follicle stimulating hormone (FSH) or luteinizing hormone (LH) (median = 5 samples per boy) and 223 had semen samples collected â¼10 years after enrolment. Semen assessment included ejaculated volume, sperm concentration, progressive motility and total sperm count, and parameters were categorized using published andrology standards for low semen quality based on sperm count and motility. Linear mixed models were used to examine the associations of log-transformed BLLs (and BLL categories) with reproductive hormones and semen parameters, adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 223 young men with peripubertal BLLs and at least one semen sample (total samples = 438), the median (interquartile range) BLL was 3 (2, 5) µg/dl and 27% had BLL ≥5 µg/dl. Overall, 49% of the semen samples fell below reference levels for sperm count and/or motility. Men with peripubertal BLL ≥5 µg/dl had significantly lower ejaculated volume than those with BLL <5 µg/dl (mean = 2.42 vs 2.89 ml, P = 0.02), but this difference was attenuated in adjusted models (mean = 2.60 vs 2.83 ml, P = 0.25). No associations were observed between BLL measured at age 8-9 years and reproductive hormone levels or sperm parameters, including sperm concentration, total count, progressive motility and total progressive motile sperm count, or with the probability of having low semen quality based on sperm count/motility. LIMITATIONS, REASONS FOR CAUTION: Only a subset of the original cohort participated in the semen quality portion of the study, although inverse probability weighting was used to account for possible selection bias. BLLs were only measured at a single time in peripuberty, and other exposure time periods, including later or longer-term childhood exposure, may be more predictive of semen quality. The young men were also exposed to other chemical contaminants before and during pubertal development. WIDER IMPLICATIONS OF THE FINDINGS: While semen volume often receives less attention than other sperm parameters, it is an important component of male fertility. Additional prospective studies covering different exposure windows and including other seminal plasma biomarkers are warranted to explore our finding of potentially lower ejaculated volume with higher BLLs and to confirm the lack of associations for other semen parameters among youth exposed to environmental BLLs. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided through grants R01ES0014370 and P30ES000002 from the National Institute of Environmental Health Sciences, grant R82943701 from the U.S. Environmental Protection Agency, and grant 18-15-00202 from the Russian Science Foundation (O.S and Y.D.). All authors report no competing interests. TRIAL REGISTRATION NUMBER: N/A.
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Plomo , Semen , Adolescente , Adulto , Niño , Estudios de Cohortes , Humanos , Hormona Luteinizante , Masculino , Estudios Prospectivos , Análisis de Semen , Recuento de Espermatozoides , Motilidad EspermáticaRESUMEN
Greater understanding of the pathways through which an environmental mixture operates is important to design effective interventions. We present new methodology to estimate natural direct and indirect effects and controlled direct effects of a complex mixture exposure on an outcome through a mediator variable. We implement Bayesian Kernel Machine Regression (BKMR) to allow for all possible interactions and nonlinear effects of (1) the co-exposures on the mediator, (2) the co-exposures and mediator on the outcome, and (3) selected covariates on the mediator and/or outcome. From the posterior predictive distributions of the mediator and outcome, we simulate counterfactuals to obtain posterior samples, estimates, and credible intervals of the mediation effects. Our simulation study demonstrates that when the exposure-mediator and exposure-mediator-outcome relationships are complex, BKMR-Causal Mediation Analysis performs better than current mediation methods. We applied our methodology to quantify the contribution of birth length as a mediator between in utero co-exposure to arsenic, manganese, and lead, and children's neurodevelopmental scores, in a prospective birth cohort in Bangladesh. Among younger children, we found a negative (adverse) association between the metal mixture and neurodevelopment. We also found evidence that birth length mediates the effect of exposure to the metal mixture on neurodevelopment for younger children. If birth length were fixed to its 75th percentile value, the harmful effect of the metal mixture on neurodevelopment is attenuated, suggesting nutritional interventions to help increase fetal growth, and thus birth length, could potentially block the harmful effect of the metal mixture on neurodevelopment.
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Análisis de Mediación , Metales , Teorema de Bayes , Causalidad , Niño , Humanos , Metales/análisis , Estudios ProspectivosRESUMEN
BACKGROUND: Although phthalate exposures have been associated with adverse effects on male reproductive health, few studies have explored longitudinal associations with male pubertal development. OBJECTIVES: We examined the association of prepubertal urinary concentrations of phthalate metabolites with age at pubertal onset in a prospective cohort of Russian boys. METHODS: At enrollment at ages 8-9 years, medical history, dietary, and demographic information was collected. At entry and annually, physical examinations and pubertal staging [Genitalia (G), Pubarche (P), and testicular volume (TV, in ml)] were conducted and spot urines were collected. Prepubertal urine samples (defined as either TV = 1, 2 and G = 1, 2 or TV = 3 and G = 1) were pooled for each boy and phthalate metabolite concentrations were quantified using isotope dilution LC-MS/MS at Moscow State University. We measured 15 metabolites including those from anti-androgenic parent phthalates (AAPs) such as di (2-ethylhexyl) (DEHP) and di-isononyl (DiNP) phthalates as well as monobenzyl (MBzP), mono-n-butyl (MnBP), and mono-isobutyl (MiBP) metabolites. We calculated the molar sums of DEHP (∑DEHP), DiNP (∑DiNP), and AAP (∑AAP) metabolites. Separate interval-censored models were used to assess associations of quartiles of prepubertal phthalate metabolites with each pubertal onset indicator, G2+, P2+ and TV > 3 mL, adjusted for covariates and urine specific gravity. RESULTS: 304 boys had 752 prepubertal urine samples (median 2, range: 1-6) for pooling. In adjusted models, higher urinary AAPs were consistently associated with later pubertal onset (P2) with mean shifts ranging from 8.4 to 14.2 months for the highest versus lowest quartiles. Significantly later onset for G2 and TV > 3 mL was observed for higher versus lower quartiles of MiBP, MBzP, ∑DEHP and ∑DiNP. CONCLUSIONS: On average, boys with higher concentrations of prepubertal urinary AAPs had later pubertal onset by six months to over a year. The impact of AAPs on timing of male puberty may be attributable to disruption of androgen-dependent biological pathways.
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Dietilhexil Ftalato , Contaminantes Ambientales , Ácidos Ftálicos , Antagonistas de Andrógenos , Niño , Cromatografía Liquida , Exposición a Riesgos Ambientales/análisis , Contaminantes Ambientales/orina , Humanos , Masculino , Ácidos Ftálicos/orina , Estudios Prospectivos , Espectrometría de Masas en TándemRESUMEN
Phthalate exposure has been associated with adverse reproductive outcomes and oxidative stress is a potential mechanism by which they act. However, few human studies have explored co-exposure confounding or joint effects. Furthermore, most studies examine associations between biomarkers of exposure and oxidative stress from the same urine sample. We investigated single-exposure, co-exposure-adjusted, and joint associations between phthalate metabolites and oxidative stress in the Environment and Reproductive Health (EARTH) study among couples undergoing fertility treatment. We examined cross-sectional associations in both women and men, and longitudinal associations in women. Urine was collected in the follicular phase (women only) and at the time of fertility procedure (women and men), and analyzed for 11 phthalate metabolites. Urine from the time of fertility procedure was analyzed for oxidative stress biomarkers, including free 8-iso-prostaglandin F2α (8-iso-PGF2α), its primary metabolite (2,3-dinor-5,6-dihydro-15-F2t-isoprostane [F2-IsoP-M]), and prostaglandin F2α (PGF2α). Linear mixed effects models were used to estimate single-exposure associations. Bayesian Kernel Machine Regression (BKMR) was used to adjust for co-exposures and to estimate joint effects. Among women, we observed positive associations between all phthalate metabolites and oxidative stress biomarkers in single-exposure models, but there was clear co-exposure confounding. For instance, in a single-exposure model, we estimated a 63% (95% confidence interval: 51, 77) increase in the 8-iso-PGF2α metabolite per interquartile range (IQR) difference in mono-n-butyl phthalate (MBP) versus a 34% (95% credible interval: 12, 60) increase in co-adjusted models. However, several phthalate metabolites remained associated with oxidative stress in co-exposure models, and the joint effects of all exposures were high (e.g., an 114% increase in the 8-iso-PGF2α metabolite per IQR difference in all exposures). Longitudinal results were also attenuated compared to cross-sectional results in women; however, the joint effect of all exposures and the 8-iso-PGF2α metabolite remained positive and statistically significant (11% increase per IQR difference in all exposures, 95% credible interval: 0.2, 23). In men, associations were generally less pronounced, although the joint effect of the mixture on 8-iso-PGF2α was above the null. Because oxidative stress is related to reproductive success among couples seeking fertility treatment, mitigating phthalate exposure should be considered as a potentially beneficial measure.
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Contaminantes Ambientales , Ácidos Ftálicos , Teorema de Bayes , Biomarcadores/orina , Estudios Transversales , Contaminantes Ambientales/orina , Femenino , Humanos , Masculino , Estrés Oxidativo , Ácidos Ftálicos/orina , ProstaglandinasRESUMEN
PURPOSE: To investigate whether history of comorbidities is associated with markers of ovarian reserve among subfertile women. METHODS: This observational study includes 645 women seeking fertility care at the Massachusetts General Hospital who enrolled in the Environment and Reproductive Health (EARTH) study (2005-2019). Women completed a comprehensive questionnaire including medical diagnosis of comorbidities. Ovarian reserve markers including antral follicle count (AFC), assessed by transvaginal ultrasound, and circulating serum levels of day 3 FSH and AMH, are assessed by immunoassays. We fit linear regression models to evaluate the association between history of comorbidities and markers of ovarian reserve while adjusting for confounders. RESULTS: Self-reported history of hypertension, cancer, and neurological disorders was negatively associated with AFC in unadjusted models and in adjusted models for age, smoking, physical activity, comorbidity count, and BMI. Adjusted mean AFC (95% CI) was lower among women with history of hypertension, compared to women with no self-reported history of hypertension (11.5 vs 15.6, p value 0.0001). In contrast, day 3 FSH levels were positively related to history of eating disorders in both unadjusted and adjusted models (10.8 vs. 7.43 IU/L, p value ≤ 0.0001). Self-reported history of other comorbidities was unrelated to AFC, day 3 FSH, and AMH levels. CONCLUSIONS: History of hypertension, cancer, and neurological disorders was negatively associated with AFC, and eating disorders were positively related to day 3 FSH levels. The prevention of common comorbidities among women in reproductive age may help increase women's fertility given the declining birth rates and increasing use of assisted reproductive technologies in the past years.
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Hipertensión , Infertilidad , Reserva Ovárica , Femenino , Humanos , Folículo Ovárico , Hormona Folículo Estimulante , Comorbilidad , Hormona AntimüllerianaRESUMEN
BACKGROUND: We identified host single-nucleotide variants (SNVs) associated with neurocognitive impairment (NCI) in perinatally HIV-infected (PHIV) children. METHODS: Whole-exome sequencing (WES) was performed on 217 PHIV with cognitive score for age (CSA)â <â 70 and 247 CSAâ ≥â 70 (discovery cohort [DC]). SNVs identified in DC were evaluated in 2 validation cohorts (VC). Logistic regression was used to estimate adjusted odds ratios (ORs) for NCI. A human microglia NLRP3 inflammasome assay characterized the role of identified genes. RESULTS: Twenty-nine SNVs in 24 genes reaching Pâ ≤â .002 and OR ≥ 1.5 comparing CSAâ <â 70 to CSA ≥ 70 were identified in the DC, of which 3 SNVs were identified in VCs for further study. Combining the 3 cohorts, SNV in CCRL2 (rs3204849) was associated with decreased odds of NCI (Pâ <â .0001); RETREG1/FAM134B (rs61733811) and YWHAH (rs73884247) were associated with increased risk of NCI (Pâ <â .0001 and Pâ <â .001, respectively). Knockdown of CCRL2 led to decreased microglial release of IL-1ß following exposure to ssRNA40 while knockdown of RETREG1 and YWHAH resulted in increased IL-1ß release. CONCLUSIONS: Using WES and 2 VCs, and gene silencing of microglia we identified 3 genetic variants associated with NCI and inflammation in HIV-infected children.
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Infecciones por VIH/complicaciones , VIH-1 , Transmisión Vertical de Enfermedad Infecciosa , Inflamación/genética , Trastornos Neurocognitivos/genética , Proteínas 14-3-3 , Niño , Preescolar , Femenino , Estudio de Asociación del Genoma Completo , Genómica , Infecciones por VIH/psicología , Infecciones por VIH/transmisión , Humanos , Lactante , Inflamasomas , Péptidos y Proteínas de Señalización Intracelular , Masculino , Proteínas de la Membrana , Microglía , Trastornos Neurocognitivos/diagnóstico , Trastornos Neurocognitivos/virología , Receptores CCRRESUMEN
BACKGROUND: In a previous trial of antiretroviral therapy (ART) involving pregnant women with human immunodeficiency virus (HIV) infection, those randomly assigned to receive tenofovir, emtricitabine, and ritonavir-boosted lopinavir (TDF-FTC-LPV/r) had infants at greater risk for very premature birth and death within 14 days after delivery than those assigned to receive zidovudine, lamivudine, and ritonavir-boosted lopinavir (ZDV-3TC-LPV/r). METHODS: Using data from two U.S.-based cohort studies, we compared the risk of adverse birth outcomes among infants with in utero exposure to ZDV-3TC-LPV/r, TDF-FTC-LPV/r, or TDF-FTC with ritonavir-boosted atazanavir (ATV/r). We evaluated the risk of preterm birth (<37 completed weeks of gestation), very preterm birth (<34 completed weeks), low birth weight (<2500 g), and very low birth weight (<1500 g). Risk ratios with 95% confidence intervals were estimated with the use of modified Poisson models to adjust for confounding. RESULTS: There were 4646 birth outcomes. Few infants or fetuses were exposed to TDF-FTC-LPV/r (128 [2.8%]) as the initial ART regimen during gestation, in contrast with TDF-FTC-ATV/r (539 [11.6%]) and ZDV-3TC-LPV/r (954 [20.5%]). As compared with women receiving ZDV-3TC-LPV/r, women receiving TDF-FTC-LPV/r had a similar risk of preterm birth (risk ratio, 0.90; 95% confidence interval [CI], 0.60 to 1.33) and low birth weight (risk ratio, 1.13; 95% CI, 0.78 to 1.64). As compared to women receiving TDF-FTC-ATV/r, women receiving TDF-FTC-LPV/r had a similar or slightly higher risk of preterm birth (risk ratio, 1.14; 95% CI, 0.75 to 1.72) and low birth weight (risk ratio, 1.45; 95% CI, 0.96 to 2.17). There were no significant differences between regimens in the risk of very preterm birth or very low birth weight. CONCLUSIONS: The risk of adverse birth outcomes was not higher with TDF-FTC-LPV/r than with ZDV-3TC-LPV/r or TDF-FTC-ATV/r among HIV-infected women and their infants in the United States, although power was limited for some comparisons. (Funded by the National Institutes of Health and others.).
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Fármacos Anti-VIH/uso terapéutico , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Recién Nacido de Bajo Peso , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Resultado del Embarazo , Nacimiento Prematuro/epidemiología , Tenofovir/uso terapéutico , Adulto , Fármacos Anti-VIH/efectos adversos , Estudios de Cohortes , Transmisión de Enfermedad Infecciosa/prevención & control , Esquema de Medicación , Quimioterapia Combinada/efectos adversos , Emtricitabina/efectos adversos , Femenino , Humanos , Recién Nacido , Lamivudine/uso terapéutico , Lopinavir/efectos adversos , Lopinavir/uso terapéutico , Embarazo , Riesgo , Ritonavir/uso terapéutico , Tenofovir/efectos adversos , Zidovudina/uso terapéuticoRESUMEN
BACKGROUND: Uterine leiomyomata, or fibroids, are hormone-dependent neoplasms of the myometrium that can cause severe gynecologic morbidity. In previous studies, incidence of these lesions has been positively associated with exposure to polychlorinated biphenyls (PCBs), a class of persistent endocrine-disrupting chemicals. However, previous studies have been retrospective in design and none has used ultrasound to reduce disease misclassification. METHODS: The Study of Environment, Lifestyle, and Fibroids is a prospective cohort of 1,693 reproductive-aged Black women residing in Detroit, Michigan (enrolled during 2010-2012). At baseline and every 20 months for 5 years, women completed questionnaires, provided blood samples, and underwent transvaginal ultrasound to detect incident fibroids. We analyzed 754 baseline plasma samples for concentrations of 24 PCB congeners using a case-cohort study design. We used multivariable Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals for the association between plasma PCB concentrations and ultrasound-detected fibroid incidence over a 5-year period. RESULTS: We observed little association between PCB congener concentrations and fibroid incidence. The HR for a one-standard deviation increase in log-transformed total PCBs was 0.94 (95% CI = 0.78, 1.1). The PCB congener with the largest effect estimate was PCB 187 (HR for a one-standard deviation increase in log-transformed exposure = 0.88, 95% CI = 0.73, 1.1). Associations did not seem to vary strongly across PCB groupings based on hormonal activity. CONCLUSIONS: In this cohort of reproductive-aged Black women, plasma PCB concentrations typical of the contemporary general population were not appreciably associated with higher risk of fibroids.