Abstract Background Gestational exposure to toxic environmental chemicals and maternal social hardships are individually associated with impaired fetal growth, but it is unclear whether the effects ...of environmental chemical exposure on infant birth weight are modified by maternal hardships. Methods We used data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a pan-Canadian cohort of 1982 pregnant females enrolled between 2008 and 2011. We quantified eleven environmental chemical concentrations from two chemical classes – six organochlorine compounds (OCs) and five metals – that were detected in ≥ 70% of blood samples collected during the first trimester. We examined fetal growth using birth weight adjusted for gestational age and assessed nine maternal hardships by questionnaire. Each maternal hardship variable was dichotomized to indicate whether the females experienced the hardship. In our analysis, we used elastic net to select the environmental chemicals, maternal hardships, and 2-way interactions between maternal hardships and environmental chemicals that were most predictive of birth weight. Next, we obtained effect estimates using multiple linear regression, and plotted the relationships by hardship status for visual interpretation. Results Elastic net selected trans -nonachlor, lead, low educational status, racially minoritized background, and low supplemental folic acid intake. All were inversely associated with birth weight. Elastic net also selected interaction terms. Among those with increasing environmental chemical exposures and reported hardships, we observed stronger negative associations and a few positive associations. For example, every two-fold increase in lead concentrations was more strongly associated with reduced infant birth weight among participants with low educational status ( β = -100 g (g); 95% confidence interval (CI): -215, 16), than those with higher educational status ( β = -34 g; 95% CI: -63, -3). In contrast, every two-fold increase in mercury concentrations was associated with slightly higher birth weight among participants with low educational status ( β = 23 g; 95% CI: -25, 71) compared to those with higher educational status ( β = -9 g; 95% CI: -24, 6). Conclusions Our findings suggest that maternal hardships can modify the associations of gestational exposure to some OCs and metals with infant birth weight.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
To examine the relation between prenatal urinary phthalate metabolite concentrations and preterm birth (PTB).
Methods
The data were drawn from the Maternal-Infant Research on Environmental ...Chemicals (MIREC) Study, a pan-Canadian cohort of 1857 pregnant women enrolled between 2008 and 2011. We quantified urinary concentrations of 7 phthalate metabolites that were detected in > 70% of urine samples collected during the first trimester. Gestational age was obtained from either the last menstrual period or early ultrasound. We used Cox proportional hazard models to examine the associations of urinary phthalate metabolite concentrations, plus the molar sum of di-2-ethylhexyl phthalate metabolites (∑DEHP), with time to delivery before 37 weeks of gestation. We also examined PTB by clinical presentation. PTBs presented with either spontaneous labour or premature rupture of the membrane were considered spontaneous PTB (sPTB). Additionally, we used multiple linear regression to model changes in mean gestational age in relation to phthalate exposure.
Results
We found no evidence of an association between first trimester phthalate metabolite concentrations and PTB among the MIREC study participants. For example, each 2-fold increase in any of the 7 phthalate concentrations or ∑DEHP was associated with hazard ratios (HRs) for PTB ranging from 0.95 to 1.07 with 95% confidence intervals including the null. An assessment of non-linear trends showed some evidence of non-monotonic dose-response relationships between phthalates and PTB. Furthermore, male infants exposed to MCPP showed higher sPTB risk compared with female infants.
Conclusion
Phthalate exposure during early pregnancy is not clearly associated with the risk of PTB among this Canadian population.
Studying the effects of gestational exposures to chemical mixtures on infant birth weight is inconclusive due to several challenges. One of the challenges is which statistical methods to rely on. ...Bayesian factor analysis (BFA), which has not been utilized for chemical mixtures, has advantages in variance reduction and model interpretation.
We analyzed data from a cohort of 384 pregnant women and their newborns using urinary biomarkers of phthalates, phenols, and organophosphate pesticides (OPs) and serum biomarkers of polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), perfluoroalkyl substances (PFAS), and organochlorine pesticides (OCPs). We examined the association between exposure to chemical mixtures and birth weight using BFA and compared with multiple linear regression (MLR) and Bayesian kernel regression models (BKMR).
For BFA, a 10-fold increase in the concentrations of PCB and PFAS mixtures was associated with an 81 g (95% confidence intervals CI = -132 to -31 g) and 57 g (95% CI = -105 to -10 g) reduction in birth weight, respectively. BKMR results confirmed the direction of effect. However, the 95% credible intervals all contained the null. For single-pollutant MLR, a 10-fold increases in the concentrations of multiple chemicals were associated with reduced birth weight, yet the 95% CI all contained the null. Variance inflation from MLR was apparent for models that adjusted for copollutants, resulting in less precise confidence intervals.
We demonstrated the merits of BFA on mixture analysis in terms of precision and interpretation compared with MLR and BKMR. We also identified the association between exposure to PCBs and PFAS and lower birth weight.
Purpose of Review
Biomarkers are widely used in perinatal epidemiology to examine the health effects of environmental chemical exposures during pregnancy. These measurements take the form of chemical ...concentrations measured in blood, urine, or other biospecimens. Biomarkers have the advantage of providing objective estimates of chemical exposures from multiple sources. However, they are difficult to handle at the data analysis stage. We review recent trends and developments in the statistical analysis of biomarkers with particular emphasis on exposure assessment and multivariable modeling.
Recent Findings
Six statistical challenges are presented in the recent literature: (1) the analysis of biomarkers that fall below the limit of detection, (2) adjustment for dilution-dependent sample variation, (3) handling repeated biomarker measurements within a single pregnancy, (4) accounting for heterogeneity in biomarker levels between chemicals within the same chemical class, (5) variable selection and shrinkage for biomarkers in the same class, and finally, (6) dimension reduction strategies including the sum-of-chemical approach.
Summary
The analysis of biomarkers of environmental chemical exposures remains immensely difficult, and the proper application of emerging statistical techniques requires input from experts in diverse disciplines. We highlight specific gaps in the literature where innovation in statistical methods is required.
Purpose
We evaluated clinical features and survival outcomes among patients with signet ring and mucinous histologies of colorectal adenocarcinoma by using data from the National Cancer Data Base ...(NCDB).
Methods
Patients aged 18–90 years with colorectal adenocarcinoma diagnosed between 1998 and 2002 were identified from the NCDB. Site-stratified (colon vs. rectum) survival analysis was performed by multivariate relative survival adjusted for multiple clinicopathologic and treatment variables.
Results
The study included 244,794 patients: 25,546 (10%) with mucinous, 2,260 (1%) with signet ring, and 216,988 (89%) with nonmucinous, non–signet ring adenocarcinoma. Mucinous and signet ring cancers were more frequently right-sided (60% and 62%, respectively) than were nonmucinous, non–signet ring adenocarcinomas (42%,
P
< 0.001). Signet ring histology was associated with a higher stage (
P
< 0.001), and 77.2% of signet ring tumors were high-grade lesions, compared with 20% of mucinous and 17% of non–signet ring, nonmucinous adenocarcinomas (
P
< 0.001). After adjustment for covariates, signet ring histology was independently associated with higher risk of death hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33–1.51, and HR 1.57, CI 1.38–1.77, for tumors located in the colon and rectum, respectively. Mucinous tumors of the rectum (HR 1.22, CI 1.16–1.29), but not the colon (HR 1.03, CI 1.00–1.06), were associated with increased risk of death.
Conclusions
Signet ring cell adenocarcinomas of the colon and rectum and mucinous adenocarcinomas of the rectum are associated with poorer survival. These aggressive histologic variants of colorectal adenocarcinoma should be targeted for research initiatives to improve outcomes.
IMPORTANCE: Colon cancer is increasing among adults younger than 50 years. However, the prognosis of young-onset colon cancer remains poorly defined given significant age-related demographic, ...disease, and treatment differences. OBJECTIVE: To define stage-specific treatments and prognosis of colon cancer diagnosed in young adults (ages 18-49 years) vs older adults (ages 65-75 years) outside of the clinical trial setting while accounting for real-world age-related variations in patient, tumor, and treatment factors. DESIGN, SETTING, AND PARTICIPANTS: A nationwide cohort study was conducted among US hospitals accredited by the American College of Surgeons Commission on Cancer. Participants were 13 102 patients diagnosed as having young-onset colon adenocarcinoma aged 18 to 49 years and 37 007 patients diagnosed as having later-onset colon adenocarcinoma aged 65 to 75 years treated between January 1, 2003, and December 31, 2005, and reported to the National Cancer Data Base. EXPOSURES: Patients who underwent surgical resection and postoperative systemic chemotherapy of curative intent. MAIN OUTCOMES AND MEASURES: The primary end point was stage-specific relative survival, an objective measure of survival among patients with cancer, adjusting for baseline mortality rates and independent of the data on cause of death. The secondary end point was stage-specific likelihood of receiving postoperative systemic chemotherapy. RESULTS: Most young-onset colon cancer was initially seen at advanced stages (61.8% had stage III or IV). After adjusting for patient-related and tumor-related factors, young patients were more likely to receive systemic chemotherapy, particularly multiagent regimens, at all stages relative to those with later-onset disease. These odds ratios were 2.88 (95% CI, 2.21-3.77) for stage I, 3.93 (95% CI, 3.58-4.31) for stage II, 2.42 (95% CI, 2.18-2.68) for stage III, and 2.74 (95% CI, 2.44-3.07) for stage IV. The significantly more intense treatments received by younger patients were unmatched by any survival gain, which was nil for stage II (relative risk, 0.90; 95% CI, 0.69-1.17) and marginal for stage III (relative risk, 0.89; 95% CI, 0.81-0.97) and stage IV (relative risk, 0.84; 95% CI, 0.79-0.90). CONCLUSIONS AND RELEVANCE: Young adults with colon cancer received significantly more postoperative systemic chemotherapy at all stages, but they experienced only minimal gain in adjusted survival compared with their older counterparts who received less treatment. This mismatch suggests that attention should be given to long-term cancer survivorship in young adults with colon cancer because they likely face survivorship needs that are distinct from those of their older counterparts.
The ubiquitin-proteasome pathway plays an important role in the pathogenesis of neurodegeneration, but mechanisms controlling expression of components in this pathway remain poorly understood. ...Nuclear factor E2-related factor 1 (Nrf1) transcription factor has been shown to regulate expression of antioxidant and cytoprotective genes. To determine the function of Nrf1 in the brain, mice with a late-stage deletion of Nrf1 in neuronal cells were generated. Loss of Nrf1 leads to impaired proteasome function and neurodegeneration. Gene expression profiling and RT-PCR analysis revealed a coordinate down-regulation of various proteasomal genes including PsmB6, which encodes a catalytic subunit of the proteasome. Transcriptional analysis and chromatin immunoprecipitation experiments demonstrated that PsmB6 is an Nrf1 target gene. These findings reveal Nrf1 as a key transcriptional regulator required for the expression of proteasomal genes in neurons and suggest that perturbations of Nrf1 function may contribute to the pathogenesis of neurodegenerative diseases.
Asian Americans (AsA), Native Hawaiians, and Pacific Islanders (NHPI) comprise 7.7% of the U.S. population, and AsA have had the fastest growth rate since 2010. Yet the National Institutes of Health ...(NIH) has invested only 0.17% of its budget on AsA and NHPI research between 1992 and 2018. More than 40 ethnic subgroups are included within AsA and NHPI (with no majority subpopulation), which are highly diverse culturally, demographically, linguistically, and socioeconomically. However, data for these groups are often aggregated, masking critical health disparities and their drivers. To address these issues, in March 2021, the National Heart, Lung, and Blood Institute, in partnership with 8 other NIH institutes, convened a multidisciplinary workshop to review current research, knowledge gaps, opportunities, barriers, and approaches for prevention research for AsA and NHPI populations. The workshop covered 5 domains: 1) sociocultural, environmental, psychological health, and lifestyle dimensions; 2) metabolic disorders; 3) cardiovascular and lung diseases; 4) cancer; and 5) cognitive function and healthy aging. Two recurring themes emerged: Very limited data on the epidemiology, risk factors, and outcomes for most conditions are available, and most existing data are not disaggregated by subgroup, masking variation in risk factors, disease occurrence, and trajectories. Leveraging the vast phenotypic differences among AsA and NHPI groups was identified as a key opportunity to yield novel clues into etiologic and prognostic factors to inform prevention efforts and intervention strategies. Promising approaches for future research include developing collaborations with community partners, investing in infrastructure support for cohort studies, enhancing existing data sources to enable data disaggregation, and incorporating novel technology for objective measurement. Research on AsA and NHPI subgroups is urgently needed to eliminate disparities and promote health equity in these populations.
The genetic basis of variation in the progression of primary tauopathies has not been determined. We aimed to identify genetic determinants of survival in progressive supranuclear palsy (PSP).
In ...stage one of this two stage genome-wide association study (GWAS), we included individuals with PSP, diagnosed according to pathological and clinical criteria, from two separate cohorts: the 2011 PSP GWAS cohort, from brain banks based at the Mayo Clinic (Jacksonville, FL, USA) and in Munich (Germany), and the University College London PSP cohort, from brain banks and the PROSPECT study, a UK-wide longitudinal study of patients with atypical parkinsonian syndromes. Individuals were included if they had clinical data available on sex, age at motor symptom onset, disease duration (from motor symptom onset to death or to the date of censoring, Dec 1, 2019, if individuals were alive), and PSP phenotype (with reference to the 2017 Movement Disorder Society criteria). Genotype data were used to do a survival GWAS using a Cox proportional hazards model. In stage two, data from additional individuals from the Mayo Clinic brain bank, which were obtained after the 2011 PSP GWAS, were used for a pooled analysis. We assessed the expression quantitative trait loci (eQTL) profile of variants that passed genome-wide significance in our GWAS using the Functional Mapping and Annotation of GWAS platform, and did colocalisation analyses using the eQTLGen and PsychENCODE datasets.
Data were collected and analysed between Aug 1, 2016, and Feb 1, 2020. Data were available for 1001 individuals of white European ancestry with PSP in stage one. We found a genome-wide significant association with survival at chromosome 12 (lead single nucleotide polymorphism rs2242367, p=7·5 × 10−10, hazard ratio 1·42 95% CI 1·22–1·67). rs2242367 was associated with survival in the individuals added in stage two (n=238; p=0·049, 1·22 1·00–1·48) and in the pooled analysis of both stages (n=1239; p=1·3 × 10−10, 1·37 1·25–1·51). An eQTL database screen revealed that rs2242367 is associated with increased expression of LRRK2 and two long intergenic non-coding RNAs (lncRNAs), LINC02555 and AC079630.4, in whole blood. Although we did not detect a colocalisation signal for LRRK2, analysis of the PSP survival signal and eQTLs for LINC02555 in the eQTLGen blood dataset revealed a posterior probability of hypothesis 4 of 0·77, suggesting colocalisation due to a single shared causal variant.
Genetic variation at the LRRK2 locus was associated with survival in PSP. The mechanism of this association might be through a lncRNA-regulated effect on LRRK2 expression because LINC02555 has previously been shown to regulate LRRK2 expression. LRRK2 has been associated with sporadic and familial forms of Parkinson's disease, and our finding suggests a genetic overlap with PSP. Further functional studies will be important to assess the potential of LRRK2 modulation as a disease-modifying therapy for PSP and related tauopathies.
PSP Association, CBD Solutions, Medical Research Council (UK).
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