Meta-Analysis on the Health Effects Resulting from Evacuation or Relocation.

OBJECTIVE: Evacuation and relocation are key actions used to protect the public in response to natural or technological disasters, but there are inherent risks to both. Unfortunately, these risks have not been fully quantified, which limits the ability of emergency managers and the public to effectively balance the risks and benefits of evacuation or relocation. This work provides quantitative data on the risks of health effects from displacement following evacuation or relocation. METHODS: Researchers performed a literature review and meta-analysis of published studies and quantified risks of 14 different health effects, including both physical and socio-behavioral outcomes, from studies of 9 different disaster types. RESULTS: The findings show statistically significant increases in 9 of the 14 health effects in displaced populations, indicating an increased likelihood of experiencing detrimental health effects compared with nondisplaced populations. A pooled analysis of all negative health effects found an odds ratio of 1.49 (95% confidence interval: 1.24-1.79), which shows a significant relationship between displacement and negative health outcomes. CONCLUSIONS: These findings demonstrate that evacuated or relocated populations have an increased risk of experiencing negative health effects associated with displacement. The broad number of disaster types included mean that findings are applicable to any emergency evacuation or relocation.

Microarray analysis of hub genes, non-coding RNAs and pathways in lung after whole body irradiation in a mouse model.

PURPOSE: Previous research has highlighted the impact of radiation damage, with cancer patients developing acute disorders including radiation induced pneumonitis or chronic disorders including pulmonary fibrosis months after radiation therapy ends. We sought to discover biomarkers that predict these injuries and develop treatments that mitigate this damage and improve quality of life. MATERIALS AND METHODS: Six- to eight-week-old female C57BL/6 mice received 1, 2, 4, 8, 12 Gy or sham whole body irradiation. Animals were euthanized 48 h post exposure and lungs removed, snap frozen and underwent RNA isolation. Microarray analysis was performed to determine dysregulation of messenger RNA (mRNA), microRNA (miRNA), and long non-coding RNA (lncRNA) after radiation injury. RESULTS: We observed sustained dysregulation of specific RNA markers including: mRNAs, lncRNAs, and miRNAs across all doses. We also identified significantly upregulated genes that can indicate high dose exposure, including Cpt1c, Pdk4, Gdf15, and Eda2r, which are markers of senescence and fibrosis. Only three miRNAs were significantly dysregulated across all radiation doses: miRNA-142-3p and miRNA-142-5p were downregulated and miRNA-34a-5p was upregulated. IPA analysis predicted inhibition of several molecular pathways with increasing doses of radiation, including: T cell development, Quantity of leukocytes, Quantity of lymphocytes, and Cell viability. CONCLUSIONS: These RNA biomarkers might be highly relevant in the development of treatments and in predicting normal tissue injury in patients undergoing radiation treatment. We are conducting further experiments in our laboratory, which includes a human lung-on-a-chip model, to develop a decision tree model using RNA biomarkers.

Microarray analysis identifies coding and non-coding RNA markers of liver injury in whole body irradiated mice.

Radiation injury from medical, accidental, or intentional sources can induce acute and long-term hepatic dysregulation, fibrosis, and cancer. This long-term hepatic dysregulation decreases quality of life and may lead to death. Our goal in this study is to determine acute changes in biological pathways and discover potential RNA biomarkers predictive of radiation injury. We performed whole transcriptome microarray analysis of mouse liver tissue (C57BL/6 J) 48 h after whole-body irradiation with 1, 2, 4, 8, and 12 Gray to identify significant expression changes in mRNAs, lncRNAs, and miRNAs, We also validated changes in specific RNAs through qRT-PCR. We used Ingenuity Pathway Analysis (IPA) to identify pathways associated with gene expression changes. We observed significant dysregulation of multiple mRNAs across all doses. In contrast, miRNA dysregulation was observed upwards of 2 Gray. The most significantly upregulated mRNAs function as tumor suppressors: Cdkn1a, Phlda3, and Eda2r. The most significantly downregulated mRNAs were involved in hemoglobin synthesis, inflammation, and mitochondrial function including multiple members of Hbb and Hba. The most significantly upregulated miRNA included: miR-34a-5p, miR-3102-5p, and miR-3960, while miR-342-3p, miR-142a-3p, and miR-223-3p were most significantly downregulated. IPA predicted activation of cell cycle checkpoint control pathways and inhibition of pathways relevant to inflammation and erythropoietin. Clarifying expression of mRNA, miRNA and lncRNA at a short time point (48 h) offers insight into potential biomarkers, including radiation markers shared across organs and animal models. This information, once validated in human models, can aid in development of bio-dosimetry biomarkers, and furthers our understanding of acute pathway dysregulation.

Childhood Physical Health and Attention Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis of Modifiable Factors.

Although neurobiologic and genetic factors figure prominently in the development of attention deficit/hyperactivity disorder (ADHD), adverse physical health experiences and conditions encountered during childhood may also play a role. Poor health is known to impact the developing brain with potential lifelong implications for behavioral issues. In attempt to better understand the relationship between childhood physical health and the onset and presence of ADHD symptoms, we summarized international peer-reviewed articles documenting relationships between a select group of childhood diseases or health events (e.g., illnesses, injuries, syndromes) and subsequent ADHD outcomes among children ages 0-17 years. Drawing on a larger two-phase systematic review, 57 longitudinal or retrospective observational studies (1978-2021) of childhood allergies, asthma, eczema, head injury, infection, or sleep problems and later ADHD diagnosis or symptomatology were identified and subjected to meta-analysis. Significant associations were documented between childhood head injuries, infections, and sleep problems with both dichotomous and continuous measures of ADHD, and between allergies with dichotomous measures of ADHD. We did not observe significant associations between asthma or eczema with ADHD outcomes. Heterogeneity detected for multiple associations, primarily among continuously measured outcomes, underscores the potential value of future subgroup analyses and individual studies. Collectively, these findings shed light on the importance of physical health in understanding childhood ADHD. Possible etiologic links between physical health factors and ADHD are discussed, as are implications for prevention efforts by providers, systems, and communities.

A Systematic Review and Meta-analysis of Parental Depression, Antidepressant Usage, Antisocial Personality Disorder, and Stress and Anxiety as Risk Factors for Attention-Deficit/Hyperactivity Disorder (ADHD) in Children.

Poor parental mental health and stress have been associated with children's mental disorders, including attention-deficit/hyperactivity disorder (ADHD), through social, genetic, and neurobiological pathways. To determine the strength of the associations between parental mental health and child ADHD, we conducted a set of meta-analyses to examine the association of parent mental health indicators (e.g., parental depression, antidepressant usage, antisocial personality disorder, and stress and anxiety) with subsequent ADHD outcomes in children. Eligible ADHD outcomes included diagnosis or symptoms. Fifty-eight articles published from 1980 to 2019 were included. We calculated pooled effect sizes, accounting for each study's conditional variance, separately for test statistics based on ADHD as a dichotomous (e.g., diagnosis or clinical cutoffs) or continuous measurement (e.g., symptoms of ADHD subtypes of inattentiveness and hyperactivity/impulsivity). Parental stress and parental depression were significantly associated with increased risk for ADHD overall and both symptoms and diagnosis. Specifically, maternal stress and anxiety, maternal prenatal stress, maternal depression, maternal post-partum depression, and paternal depression were positively associated with ADHD. In addition, parental depression was associated with symptoms of ADHD inattentive and hyperactive/impulsive subtypes. Parental antisocial personality disorder was also positively associated with ADHD overall and specifically ADHD diagnosis. Prenatal antidepressant usage was associated with ADHD when measured dichotomously only. These findings raise the possibility that prevention strategies promoting parental mental health and addressing parental stress could have the potential for positive long-term impacts on child health, well-being, and behavioral outcomes.

A Systematic Review and Meta-analysis of Prenatal, Birth, and Postnatal Factors Associated with Attention-Deficit/Hyperactivity Disorder in Children.

Previous studies have shown mixed results on the relationship between prenatal, birth, and postnatal ("pregnancy-related") risk factors and attention-deficit/hyperactivity disorder (ADHD). We conducted meta-analyses to identify potentially modifiable pregnancy-related factors associated with ADHD. A comprehensive search of PubMed, Web of Science, and EMBASE in 2014, followed by an updated search in January 2021, identified 69 articles published in English on pregnancy-related risk factors and ADHD for inclusion. Risk factors were included in the meta-analysis if at least three effect sizes with clear pregnancy-related risk factor exposure were identified. Pooled effect sizes were calculated for ADHD overall, ADHD diagnosis, inattention, and hyperactivity/impulsivity. Odds ratios (OR) were calculated for dichotomous measures and correlation coefficients (CC) for continuous measures. Prenatal factors (pre-pregnancy weight, preeclampsia, pregnancy complications, elevated testosterone exposure), and postnatal factors (Apgar score, neonatal illness, no breastfeeding) were positively associated with ADHD overall; the findings for ADHD diagnosis were similar with the exception that there were too few effect sizes available to examine pre-pregnancy weight and lack of breastfeeding. Prenatal testosterone was significantly associated with inattention and hyperactivity/impulsivity. Effect sizes were generally small (range 1.1-1.6 ORs, -0.16-0.11 CCs). Risk factors occurring at the time of birth (perinatal asphyxia, labor complications, mode of delivery) were not significantly associated with ADHD. A better understanding of factors that are consistently associated with ADHD may inform future prevention strategies. The findings reported here suggest that prenatal and postnatal factors may serve as potential targets for preventing or mitigating the symptoms of ADHD.

Analysis of lncRNA-miRNA-mRNA expression pattern in heart tissue after total body radiation in a mouse model.

BACKGROUND: Radiation therapy is integral to effective thoracic cancer treatments, but its application is limited by sensitivity of critical organs such as the heart. The impacts of acute radiation-induced damage and its chronic effects on normal heart cells are highly relevant in radiotherapy with increasing lifespans of patients. Biomarkers for normal tissue damage after radiation exposure, whether accidental or therapeutic, are being studied as indicators of both acute and delayed effects. Recent research has highlighted the potential importance of RNAs, including messenger RNAs (mRNAs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) as biomarkers to assess radiation damage. Understanding changes in mRNA and non-coding RNA expression will elucidate biological pathway changes after radiation. METHODS: To identify significant expression changes in mRNAs, lncRNAs, and miRNAs, we performed whole transcriptome microarray analysis of mouse heart tissue at 48 h after whole-body irradiation with 1, 2, 4, 8, and 12 Gray (Gy). We also validated changes in specific lncRNAs through RT-qPCR. Ingenuity Pathway Analysis (IPA) was used to identify pathways associated with gene expression changes. RESULTS: We observed sustained increases in lncRNAs and mRNAs, across all doses of radiation. Alas2, Aplnr, and Cxc3r1 were the most significantly downregulated mRNAs across all doses. Among the significantly upregulated mRNAs were cell-cycle arrest biomarkers Gdf15, Cdkn1a, and Ckap2. Additionally, IPA identified significant changes in gene expression relevant to senescence, apoptosis, hemoglobin synthesis, inflammation, and metabolism. LncRNAs Abhd11os, Pvt1, Trp53cor1, and Dino showed increased expression with increasing doses of radiation. We did not observe any miRNAs with sustained up- or downregulation across all doses, but miR-149-3p, miR-6538, miR-8101, miR-7118-5p, miR-211-3p, and miR-3960 were significantly upregulated after 12 Gy. CONCLUSIONS: Radiation-induced RNA expression changes may be predictive of normal tissue toxicities and may indicate targetable pathways for radiation countermeasure development and improved radiotherapy treatment plans.

Whole blood gene expression within days after total-body irradiation predicts long term survival in Gottingen minipigs.

Gottingen minipigs mirror the physiological radiation response observed in humans and hence make an ideal candidate model for studying radiation biodosimetry for both limited-sized and mass casualty incidents. We examined the whole blood gene expression profiles starting one day after total-body irradiation with increasing doses of gamma-rays. The minipigs were monitored for up to 45 days or time to euthanasia necessitated by radiation effects. We successfully identified dose- and time-agnostic (over a 1-7 day period after radiation), survival-predictive gene expression signatures derived using machine-learning algorithms with high sensitivity and specificity. These survival-predictive signatures fare better than an optimally performing dose-differentiating signature or blood cellular profiles. These findings suggest that prediction of survival is a much more useful parameter for making triage, resource-utilization and treatment decisions in a resource-constrained environment compared to predictions of total dose received. It should hopefully be possible to build such classifiers for humans in the future.

Development of Novel Video-Based First Responder Opioid Hazard Refresher Training.

First responders encounter many hazards in the execution of their duties, and exposure to hazardous materials such as opioids is a primary safety concern. The ongoing opioid crisis in the United States continues to be a major public health issue, with overdose deaths from opioids reaching epidemic levels. Although responders frequently encounter opioids, available data on safety and risk are not always well-communicated, and we identified a need for refresher and just-in-time training products on this topic. In response, we created a training video series that is informative, concise, and visually appealing. The video series, available on YouTube, was tested with a small initial population, with findings suggesting key questions for a larger study focused on integration of the refresher training with existing programs to optimize retention and adoption of safety practices.

Gene Expression Profiles from Heart, Lung and Liver Samples of Total-Body-Irradiated Minipigs: Implications for Predicting Radiation-Induced Tissue Toxicity.

In the event of a major accidental or intentional radiation exposure incident, the affected population could suffer from total- or partial-body exposures to ionizing radiation with acute exposure to organs that would produce life-threatening injury. Therefore, it is necessary to identify markers capable of predicting organ-specific damage so that appropriate directed or encompassing therapies can be applied. In the current work, gene expression changes in response to total-body irradiation (TBI) were identified in heart, lungs and liver tissue of Göttingen minipigs. Animals received 1.7, 1.9, 2.1 or 2.3 Gy TBI and were followed for 45 days. Organ samples were collected at the end of day 45 or sooner if the animal displayed morbidity necessitating euthanasia. Our findings indicate that different organs respond to TBI in a very specific and distinct manner. We also found that the liver was the most affected organ in terms of gene expression changes, and that lipid metabolic pathways were the most deregulated in the liver samples of non-survivors (survival time <45 days). We identified organ-specific gene expression signatures that accurately differentiated non-survivors from survivors and control animals, irrespective of dose and time postirradiation. At what point did these radiation-induced injury markers manifest and how this information could be used for applying intervention therapies are under investigation.

Microarray analysis of miRNA expression profiles following whole body irradiation in a mouse model.

CONTEXT: Accidental exposure to life-threatening radiation in a nuclear event is a major concern; there is an enormous need for identifying biomarkers for radiation biodosimetry to triage populations and treat critically exposed individuals. OBJECTIVE: To identify dose-differentiating miRNA signatures from whole blood samples of whole body irradiated mice. METHODS: Mice were whole body irradiated with X-rays (2 Gy-15 Gy); blood was collected at various time-points post-exposure; total RNA was isolated; miRNA microarrays were performed; miRNAs differentially expressed in irradiated vs. unirradiated controls were identified; feature extraction and classification models were applied to predict dose-differentiating miRNA signature. RESULTS: We observed a time and dose responsive alteration in the expression levels of miRNAs. Maximum number of miRNAs were altered at 24-h and 48-h time-points post-irradiation. A 23-miRNA signature was identified using feature selection algorithms and classifier models. An inverse correlation in the expression level changes of miR-17 members, and their targets were observed in whole body irradiated mice and non-human primates. CONCLUSION: Whole blood-based miRNA expression signatures might be used for predicting radiation exposures in a mass casualty nuclear incident.