Models to Assess the Association of a Semiquantitative Exposure With Outcomes.
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ABSTRACT:
SUBMITTER: Lachin JM
PROVIDER: S-EPMC7705609 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Introduction: Human-induced pluripotent stem cells (iPSCs) represent a promising cell source for the construction of organotypic culture models for chemical toxicity screening and characterization. Materials and Methods: To characterize the effects of chemical exposure on the human neurovasculature, we constructed neurovascular unit (NVU) models consisting of endothelial cells (ECs) and astrocytes (ACs) derived from human-iPSCs, as well as human brain-derived pericytes (PCs). The cells were cocultured on synthetic poly(ethylene glycol) (PEG) hydrogels that guided the self-assembly of capillary-like vascular networks. High-content epifluorescence microscopy evaluated dose-dependent changes to multiple aspects of NVU morphology. Results: Cultured vascular networks underwent quantifiable morphological changes when incubated with vascular disrupting chemicals. The activity of predicted vascular disrupting chemicals from a panel of 38 compounds (U.S. Environmental Protection Agency) was ranked based on morphological features detected in the NVU model. In addition, unique morphological neurovascular disruption signatures were detected per chemical. A comparison of PEG-based NVU and Matrigel™-based NVU models found greater sensitivity and consistency in chemical detection by the PEG-based NVU models. Discussion: We suspect that specific morphological changes may be used for discerning adverse outcome pathways initiated by chemical exposure and rapid mechanistic characterization of chemical exposure to neurovascular function. Conclusion: The use of human stem cell-derived vascular tissue and PEG hydrogels in the construction of NVU models leads to rapid detection of adverse chemical effects on neurovascular stability. The use of multiple cell types in coculture elucidates potential mechanisms of action by chemicals applied to the model.
| S-EPMC6594538 | biostudies-literature
Project description:BackgroundThe Time in Therapeutic Range (TTR) is the gold-standard measure used to assess the quality of oral anticoagulation with vitamin K antagonists. However, TTR is a static measure, and International Normalized Ratio (INR) control is a dynamic process. Group-based Trajectory Models (GBTM) can address this dynamic nature by classifying patients into different trajectories of INR control over time.ObjectivesThe objective of this study was to assess the quality of INR control in a population-based cohort of new users of vitamin K antagonist with a diagnosis of atrial fibrillation using GBTM.MethodsWe classified patients into different trajectories according to their propensity for being adequately anticoagulated over their first year of treatment using GBTM, and we evaluated the association between trajectories and relevant clinical outcomes over the following year.ResultsWe included 8024 patients in the cohort who fulfilled the inclusion criteria; the mean number of INR determinations over the first year of treatment was 13.9. We identified 4 differential trajectories of INR control: Optimal (9.7% of patients, TTR: 83.8%), Improving (27.4% of patients, TTR: 61.2%), Worsening (28%; TTR: 69.1%), and Poor control (34.9%; TTR: 41.5%). In adjusted analysis, Poor and Worsening control patients had a higher risk of death than Optimal control patients (hazard ratio: 1.79; IC 95%, 1.36-2.36 and hazard ratio: 1.36; IC 95%, 1.02-1.81, respectively). Differences in other outcomes did not achieve statistical significance, except for a reduced risk of transient ischemic attack in the Improving Control group.ConclusionsGBTM may contribute to a better understanding and assessment of the quality of oral anticoagulation and may be used in addition to traditional, well-established measures such as TTR.
| S-EPMC7069412 | biostudies-literature
Project description:Much remains unknown concerning the mechanism by which the splicing machinery pinpoints short exons within intronic sequences and how splicing factors are directed to their pre-mRNA targets. Part of the explanation probably lies in differences in chromatin organization between exons and introns. Proteomic, co-immunoprecipitation, and sedimentation analyses described here indicated that SF3B1, an essential splicing component of the U2 snRNP complex, is strongly associated with nucleosomes. ChIP-seq and RNA-seq analyses revealed that SF3B1 is specifically bound to nucleosomes located at exonic positions. SF3B1 binding is enriched at nucleosomes positioned over short exons flanked by long introns that are also characterized by differential GC content between exons and introns. Disruption of SF3B1 binding to such nucleosomes affected the splicing of these exons similarly to inhibition of SF3B1 expression. Our findings suggest that the association of SF3B1 with nucleosomes is functionally important for splice site recognition and that SF3B1 conveys splicing-relevant information embedded in chromatin structure. MNase-seq on Input and SF3B1 pull-down, mRNA-seq on control and SF3B1 si-RNA treated cells as well as on TSA (Trichostatin A) treated and untreated cells.
2015-04-22 | E-GEOD-65644 | biostudies-arrayexpress
Project description:BackgroundPrevious epidemiologic studies of dampness and mold relied on metrics that did not fully assess exposure-response relationships. Our objective was to examine quantitative metrics of dampness and mold during infancy and respiratory health outcomes during childhood.MethodsIn-home visits were conducted before age 1 for children in the Cincinnati Childhood Allergy and Air Pollution Study. Respiratory outcomes included age 3 wheeze and age 7 asthma and wheeze. The associations between home exposure and respiratory outcomes were evaluated for 779 children using logistic regression adjusting for household income, neighborhood socioeconomic status, and the presence of pests.ResultsChildren residing in homes with ≥0.29 m2 of moisture damage were significantly more likely to have wheezing at age 3 and persistent wheeze through age 7 (adjusted odds ratio [aOR] = 2.2; 95% confidence interval [CI] = 1.0, 4.3 and aOR = 3.2; CI = 1.3, 7.5, respectively). Additionally, homes having ≥0.19 m2 of mold damage were associated with wheezing at age 3 and early transient wheeze assessed at age 7 (aOR = 2.9; CI = 1.3, 6.4 and aOR = 3.5; CI = 1.5, 8.2, respectively). Mold damage <0.19 m2 and moisture damage <0.29 m2 were not associated with health outcomes. Mold and moisture damage were also not associated with asthma.ConclusionOur data indicate that only the highest categories analyzed for mold (≥0.19 m2) and moisture damage (≥0.29 m2) in homes at age 1 were significantly associated with wheeze at ages 3 and 7; however, data below these levels were too sparse to assess the shape of the relationship or explore potential health-relevant thresholds.
| S-EPMC7423528 | biostudies-literature
Project description:The study of effects associated with human exposure to repeated low-level blast during training or operations of select military occupational specialties (MOS) challenges medical science because acute negative effects that might follow such exposures cannot be expected to be clear or prevalent. Any gross effects from such occupational blast exposure on health or performance should be expected to have been already identified and addressed by affected military units through changes to their standard training protocols. Instead, effects, if any, should be expected to be incremental in nature and to vary among individuals of different susceptibilities and exposure histories. Despite the challenge, occupational blast-associated effects in humans are emerging in ongoing research. The purpose of the present study was to examine medical records for evidence of blast-associated effects that may have clinical significance in current standard of care. We hypothesized that populations exposed to blast by virtue of their military occupation would have poorer global medical outcomes than cohorts less likely to have been occupationally exposed. Records from a population of 50,254 service members in MOSs with a high likelihood of occupational blast exposure were compared to records from a matched cohort of 50,254 service members in MOSs with a lower likelihood of occupational blast exposure. These two groups were compared in hospitalizations, outpatient visits, pharmacy, and disability ratings. The clearest finding was higher risk among blast-exposed MOSs for ambulatory encounters for tinnitus, with adjusted risk ratios of 1.19 (CI 1.03-1.37), 1.21 (CI 1.16-1.26), and 1.31 (CI 1.18-1.45) across career time points. Other hypothesized effects (i.e., neurological outcomes) were smaller and were associated with acute exposure. This study documents that service members in occupations that likely include repeated exposure to blast are at some increased risk for neurosensory conditions that present in medical evaluations. Other hypothesized risks from occupational exposure may manifest as symptomology not visible in the medical system or current standard of care. Separate studies, observational and epidemiological, are underway to evaluate further the potential for occupational risk, but the evidence presented here may indicate near-term opportunities to guide efforts to reduce neurosensory risk among exposed service members.
| S-EPMC7413071 | biostudies-literature
Project description:ObjectiveTo investigate the extent to which antibiotic exposure in the first 2 years of life is associated with the risk of immunological, metabolic, and neurobehavioral health conditions with childhood onset.Patients and methodsIn this population-based cohort study, we identified all children born in Olmsted County, Minnesota, between January 1, 2003, and December 31, 2011, through the Rochester Epidemiology Project medical records-linkage system. Demographic characteristics, antibiotic prescriptions, and diagnostic codes through June 30, 2017, were retrieved using the Rochester Epidemiology Project infrastructure. Time-to-event analysis was performed to assess the impact of antibiotic exposure on the risk of several adverse health conditions.ResultsThis study included 14,572 children (7026 girls and 7546 boys), of whom 70% (10,220) received at least 1 antibiotic prescription during the first 2 years of life. Early antibiotic exposure was associated with an increased risk of childhood-onset asthma, allergic rhinitis, atopic dermatitis, celiac disease, overweight, obesity, and attention deficit hyperactivity disorder (hazard ratios ranging from 1.20 to 2.89; P<.05 for all). The associations were influenced by the number, type, and timing of antibiotic exposure. Moreover, children exposed to antibiotics had a higher probability of having combinations of conditions, particularly when given multiple prescriptions.ConclusionThe present study finds significant associations between early life antibiotic exposure and several distinct health conditions with childhood onset. Additional research is warranted to establish practical guidelines to optimize the benefit and minimize the risk of antibiotics in children.
| S-EPMC7796951 | biostudies-literature
Project description:Much remains unknown concerning the mechanism by which the splicing machinery pinpoints short exons within intronic sequences and how splicing factors are directed to their pre-mRNA targets. Part of the explanation probably lies in differences in chromatin organization between exons and introns. Proteomic, co-immunoprecipitation, and sedimentation analyses described here indicated that SF3B1, an essential splicing component of the U2 snRNP complex, is strongly associated with nucleosomes. ChIP-seq and RNA-seq analyses revealed that SF3B1 is specifically bound to nucleosomes located at exonic positions. SF3B1 binding is enriched at nucleosomes positioned over short exons flanked by long introns that are also characterized by differential GC content between exons and introns. Disruption of SF3B1 binding to such nucleosomes affected the splicing of these exons similarly to inhibition of SF3B1 expression. Our findings suggest that the association of SF3B1 with nucleosomes is functionally important for splice site recognition and that SF3B1 conveys splicing-relevant information embedded in chromatin structure.
2015-04-22 | GSE65644 | GEO
Project description:Maternofoetal physiologically-based pharmacokinetic models integrating multi-compartmental maternal and foetal units were developed using Simbiology® to estimate prenatal drug exposure. Processes governing drug disposition were described using differential equations with key system and drug-specific parameters. Transplacental drug transfer was modelled as bidirectional passive diffusion and benchmarked against those for thalidomide as a control. Model-predictions for pharmacokinetic parameters during pregnancy were within acceptable ranges for qualification (two-fold difference of clinically-observed values). Predicted foetal exposure to thalidomide was higher than efavirenz, with median (range) foetal-to-maternal plasma ratios of 4.55 (3.06-9.57) for 400?mg thalidomide versus 0.89 (0.73-1.05) for 400?mg efavirenz at third trimester. Model-predictions indicated foetal exposure consistently above 300% of maternal plasma concentration for thalidomide throughout pregnancy, while exposure to efavirenz increased from under 20% at second trimester to above 100% at third trimester. Further qualification of this approach as a tool in evaluating drug exposure and safety during pregnancy is warranted.
| S-EPMC6853277 | biostudies-literature
Project description:BackgroundEcological studies support the hypothesis that suicide may be "contagious" (i.e., exposure to suicide may increase the risk of suicide and related outcomes). However, this association has not been adequately assessed in prospective studies. We sought to determine the association between exposure to suicide and suicidality outcomes in Canadian youth.MethodsWe used baseline information from the Canadian National Longitudinal Survey of Children and Youth between 1998/99 and 2006/07 with follow-up assessments 2 years later. We included all respondents aged 12-17 years in cycles 3-7 with reported measures of exposure to suicide.ResultsWe included 8766 youth aged 12-13 years, 7802 aged 14-15 years and 5496 aged 16-17 years. Exposure to a schoolmate's suicide was associated with ideation at baseline among respondents aged 12-13 years (odds ratio [OR] 5.06, 95% confidence interval [CI] 3.04-8.40), 14-15 years (OR 2.93, 95% CI 2.02-4.24) and 16-17 years (OR 2.23, 95% CI 1.43-3.48). Such exposure was associated with attempts among respondents aged 12-13 years (OR 4.57, 95% CI 2.39-8.71), 14-15 years (OR 3.99, 95% CI 2.46-6.45) and 16-17 years (OR 3.22, 95% CI 1.62-6.41). Personally knowing someone who died by suicide was associated with suicidality outcomes for all age groups. We also assessed 2-year outcomes among respondents aged 12-15 years: a schoolmate's suicide predicted suicide attempts among participants aged 12-13 years (OR 3.07, 95% CI 1.05-8.96) and 14-15 years (OR 2.72, 95% CI 1.47-5.04). Among those who reported a schoolmate's suicide, personally knowing the decedent did not alter the risk of suicidality.InterpretationWe found that exposure to suicide predicts suicide ideation and attempts. Our results support school-wide interventions over current targeted interventions, particularly over strategies that target interventions toward children closest to the decedent.
| S-EPMC3707992 | biostudies-literature
Project description:BackgroundStyrene is one of the aromatic compounds used in acetonitrile-butadiene-styrene (ABS) producing petrochemicals, which has an impact on health of workers. Therefore, this study aimed to investigate the health risks of styrene emitted from the petrochemical industry in Iran.MethodsAir samples were collected based on NIOSH 1501 method. The samples were analyzed by the Varian-cp3800 gas chromatograph. Finally, risk levels of styrene's health effects on employees were assessed by the quantitative method of the U.S. Environmental Protection Agency (U.S. EPA) and the semiquantitative way by the Singapore Occupational Safety and Health Association.ResultsBased on the results, the employees had the highest average exposure to styrene vapors (4.06 ×10-1mg.(kg-day)-1 ) in the polybutadiene latex (PBL) unit. Therefore, the most top predictors of cancer and non-cancer risk were 2.3 ×10-4 and 7.26 ×10-1 , respectively. Given that the lowest average exposure (1.5 ×10-2mg.(kg-day)-1 ) was in the dryer unit, the prediction showed a moderate risk of cancer (0.8 ×10-6 ) and non-cancer (2.3 ×10-3 ) for the employees. The EPA method also predicted that there would be a definite cancer risk in 16% and a probable risk in 76% of exposures. However, according to the semiquantitative approach, the rate of risk was at the "low" level for all staff. The results showed that there was a significant difference (p < 0.05) between the units in exposure and health risk of styrene (p < 0.05).ConclusionGiven the high risk of styrene's health effects, appropriate control measures are required to reduce the exposure level.
| S-EPMC8430436 | biostudies-literature