Constitutional chromosomal anomalies in children, fetal alcohol syndrome, and maternal toxicant exposures: A longitudinal cohort study.

DNA alterations in gametes, which may occur either spontaneously or as a result of exposure to genotoxicants, can lead to constitutional chromosomal anomalies in the offspring. Alcohol is an established genotoxicant. The goal of this hypothesis-testing longitudinal cohort study was to evaluate the effect of significant/sustained maternal alcohol exposure on clinically diagnosed constitutional chromosomal anomalies among children diagnosed with fetal alcohol syndrome (FAS). De-identified eligibility and claim healthcare records, prospectively generated from the 1990-2012 Florida Medicaid system within the Independent Healthcare Research Database (IHRD), were analyzed. Children examined were continuously eligible with ≥ 8 outpatient office visits during the 96-month period following birth. Among these children, 377 were diagnosed with FAS and 137,135 were not. The incidence rate of chromosomal anomalies involving segregation (trisomy 13, 18, or 21, n = 625), microdeletions (microdeletion syndromes, n = 39), and point mutations (sickle-cell anemia/cystic fibrosis, n = 2570) were examined using frequency risk ratio (RR) and logistic regression (adjusted odds ratio (aOR) for sex, race, residence, socioeconomic/environmental exposure status, and birth date) models. The incidence rates of chromosomal anomalies involving segregation (RR=5.92, aOR=5.85) and microdeletions (RR=41.6, aOR=34.1) were significantly increased in the FAS cohort as compared to the non-diagnosed cohort, but there was no difference in the incidence rate of point mutations (RR=1.14, aOR=1.29). Maternal toxicant exposure should be considered in the etiology of constitutional chromosomal anomaly in offspring.

Estimated mercury vapor exposure from amalgams among American pregnant women.

This study examined the impact of mercury (Hg) vapor exposure from amalgams among all American pregnant women. Amalgam-Hg vapor exposure among 1,665,890 weighted-pregnant women (n = 37) was examined in the 2015-2020 National Health and Nutrition Examination Survey (NHANES). Correlation coefficients between amalgam surfaces and daily micrograms (µg) of urinary Hg excretion and daily µg of Hg vapor exposure from amalgams per kilogram (Kg) bodyweight were calculated. Daily Hg vapor exposure from amalgams was compared to Hg vapor safety limits. About 600,000 pregnant women (∼36%) had at least one amalgam surface. Median daily urinary Hg excretion was ∼2.5-fold higher among pregnant women with amalgams as compared to pregnant women without amalgams. A significant correlation was observed between the number of amalgam surfaces and daily urinary Hg excretion. Among pregnant women with amalgams, it was estimated that the median daily Hg vapor dose from amalgams was 7.66 µg of Hg and 0.073 µg of Hg/Kg bodyweight. Among all pregnant women, ∼28% received daily Hg vapor doses from amalgams above the least restrictive United States (US) Environmental Protection Agency (EPA) safety limit and ∼36% received above the most restrictive California (CA) EPA safety limit. Given the potential for fetal toxicological effects from prenatal Hg vapor exposure, special emphasis needs to be placed on reducing/eliminating amalgams in pregnancy/women of reproductive age and future studies should evaluate adverse pregnancy outcomes.

Reductions in plasma and urine mercury concentrations following N,N'bis-(2-mercaptoethyl) isophthalamide (NBMI) therapy: a post hoc analysis of data from a randomized human clinical trial.

Environmental mercury exposure possesses a significant risk to many human populations. At present there are no effective treatments for acute mercury toxicity. A new compound, N,N'bis-(2-mercaptoethyl) isophthalamide (NBMI), a lipophilic chelating agent was created to tightly/irreversibly bind mercury. A post hoc dose-dependent analysis of NBMI therapy was undertaken on data from a randomized controlled NBMI human treatment trial on 36 Ecuadorian gold miners with elevated urinary mercury concentrations. Study subjects were randomly assigned to receive 100 milligram (mg) NBMI/day, 300 mg NBMI/day, or placebo for 14 days. For each study subject daily mg NBMI dose/Kilogram (Kg) bodyweight were determined and plasma and urine mercury concentrations (micrograms (µg)/Liter (L)) on study day 1 (pre-NBMI treatment), 15 (after 14 days of NBMI treatment) and 45 (30 days after NBMI treatment) were correlated with NBMI dosing using the linear regression statistic in SAS. Regression revealed significant inverse correlations between increasing per mg NBMI/Kg bodyweight/day and reduced concentrations of urinary and plasma mercury on study day 15 (reduced by in urine = 18-20 µg/L and plasma = 2 µg/L) and study day 30 (reduced by in urine = 15-20 µg/L and plasma = 4 µg/L) and significant correlations between reductions in mercury concentrations in urine and plasma. Significant 30% reductions in urinary mercury concentrations per mg NBMI/Kg bodyweight/day administered for 14 days were observed. This study supports the dose-dependent ability of NBMI therapy to significantly reduce mercury concentrations, particularly in the urine, in an acutely mercury exposed human population. NBMI therapy should be evaluated in other mercury exposed populations.

Colon Cancer Risk Following Intestinal Clostridioides difficile Infection: A Longitudinal Cohort Study.

Background: The gut microbiome may play an important role in the etiology and progression of colon cancer. The present hypothesis-testing study compared the colon cancer incidence rate among adults diagnosed with intestinal Clostridioides (formerly Clostridium) difficile (Cdiff) (the Cdiff cohort) to adults not diagnosed with intestinal Cdiff infection (the non-Cdiff cohort). Methods: De-identified eligibility and claim healthcare records within the Independent Healthcare Research Database (IHRD) from a longitudinal cohort of adults (the overall cohort) enrolled in the Florida Medicaid system between 1990 through 2012 were examined. Adults with ≥ 8 outpatient office visits over 8 years of continuous eligibility were examined. There were 964 adults in the Cdiff cohort and 292,136 adults in the non-Cdiff cohort. Frequency and Cox proportional hazards models were utilized. Results: Colon cancer incidence rate in the non-Cdiff cohort remained relatively uniform over the entire study period, whereas a marked increase was observed in the Cdiff cohort within the first 4 years of a Cdiff diagnosis. Colon cancer incidence was significantly increased (about 2.7-fold) in the Cdiff cohort (3.11 per 1,000 person-years) compared to the non-Cdiff cohort (1.16 per 1,000 person-years). Adjustments for gender, age, residency, birthdate, colonoscopy screening, family history of cancer, and personal history of tobacco abuse, alcohol abuse/dependence, drug abuse/dependence, and overweight/obesity, as well as consideration of diagnostic status for ulcerative and infection colitis, immunodeficiency, and personal history of cancer did not significantly change the observed results. Conclusions: This is the first epidemiological study associating Cdiff with an increased risk for colon cancer. Future studies should further evaluate this relationship.

Urine glyphosate exposure and serum sex hormone disruption within the 2013-2014 National Health and Nutrition Examination survey (NHANES).

Glyphosate-based herbicides (GBHs) are one of the most commonly used herbicides worldwide. Numerous in vitro and in vivo model system studies have demonstrated endocrine-disrupting chemical (EDC) properties associated with glyphosate/GBH exposure. The present hypothesis-testing study evaluated the potential inverse dose-dependent relationship between increasing urinary glyphosate and decreasing concentrations of blood sex hormones. Demographic and newly available lab test data from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) were analyzed with survey regression modeling (adjusted for age, gender, race, and country of birth) in Statistical Analysis System (SAS) software. A total of 225, 615, 858 weighted-persons (sample n = 2130 persons) were examined for concentrations of urinary glyphosate and serum sex hormones (including: total testosterone, total estradiol, and sex hormone binding globulin (SHBG)) among males and females, 6 years-old or older. This study revealed about 82% of the population of the United States examined had detectable urinary concentrations of glyphosate. A significant inverse correlation between concentrations of glyphosate and total estradiol and a trend towards an inverse correlation between concentrations of glyphosate and total testosterone were observed. Concentrations of SHBG and glyphosate did not correlate. Ratios of total testosterone:SHBG and total estradiol:SHBG (estimating the fraction of active sex hormones in the blood) were significantly inversely correlated with urinary concentrations of glyphosate. This epidemiological study associates widespread and ongoing glyphosate/GBH exposures with human endocrine-disruptions. Future studies should examine these phenomena in other databases and other endocrine-related disorders.

Fetal alcohol syndrome and the risk of neurodevelopmental disorders: A longitudinal cohort study.

BACKGROUND: This hypothesis-testing study evaluated the relationship between fetal alcohol syndrome (FAS) and neurodevelopmental disorder (ND) diagnoses within the Independent Healthcare Research Database (IHRD). METHODS: De-identified eligibility and claim healthcare records prospectively generated from the 1990-2012 Florida Medicaid system were analyzed using SAS software. There were 89,766 children continuously eligible with ≥10 outpatient office visits during the 120 month period following birth in the cohort examined. A total of 321 children were diagnosed with FAS. Autism spectrum disorder (ASD) (n = 922), tics (n = 551), attention deficit disorder/attention deficit-hyperactivity disorder (ADD/ADHD) (n = 20,260), mental retardation (MR) (n = 915), and specific delays in development (SDD) (n = 24,630) incidence rates were examined using frequency risk ratio (RR) and logistic regression models. RESULTS: The incidence rate of tics (RR = 5.68), ADD/ADHD (RR = 2.30), MR (RR = 7.83), SDD (RR = 2.88), and ASD (RR = 6.74) were significantly increased among FAS diagnosed children as compared to undiagnosed children. Adjusted (for gender, race, residency, and date of birth) odds ratios (ORs) were significantly increased for tics (OR = 4.87), ADD/ADHD (OR = 3.40), MR (OR = 7.91), SDD (OR = 9.56), and ASD (OR = 6.87) when comparing the FAS diagnosed children to undiagnosed children. CONCLUSION: Tens of thousands of American children with lifetime costs in the billions of US dollars were estimated to be impacted by FAS-associated NDs. These impacts are particularly tragic because FAS is dependent upon lifestyle.

Childhood MMR Vaccination Effectiveness Against Rubella: A Longitudinal Cohort Study.

The vaccine effectiveness (VE) of childhood measles-mumps-rubella (MMR) vaccine to reduce childhood rubella infections in the US during the 1990s/2000s was undertaken in a retrospective longitudinal cohort study. SAS and StatsDirect software were utilized to examine non-identifiable linked eligibility and claim healthcare records prospectively generated from the Florida Medicaid system in the Independent Healthcare Research Database (IHRD). A total of 33 839 children received a single MMR vaccination (vaccinated) and 44 154 children never received a rubella-containing vaccine (unvaccinated) were continuously eligible from 1990 to 2009 for Florida Medicaid within the first 10 years following birth. Cox proportional hazards models determined VE against diagnosed rubella (ICD-9 code: 056.xx). Children receiving MMR were at significantly reduced risk of rubella in unadjusted (VE = 80.7%, 95% confidence interval = 73.7%-85.8%) and adjusted (VE = 78.6%, 95% confidence interval = 70.8%-84.3%) models as compared to unvaccinated children. Between 1991 and 2009, in the combined vaccinated-unvaccinated cohort examined on a yearly basis, a significant inverse correlation between increasing MMR vaccine population coverage and a decreasing incidence rate of diagnosed rubella was observed. This first large-scale population epidemiological study supports the routine use childhood MMR vaccination to significantly reduce childhood rubella infections and also supports its ability to induce "herd immunity." This study, coupled with a recently published epidemiological study showing childhood MMR vaccination significantly reduced measles infections, provide powerful epidemiological evidence strongly supporting MMR vaccination as an effective tool to improve public health.

Reported asthma and dental amalgam exposure among adults in the United States: An assessment of the National Health and Nutrition Examination Survey.

Objective: Mercury (Hg)-based amalgam is a dental restorative material in common use. This hypothesis-testing study evaluated the relationship between dental amalgam exposure and the risk of reported asthma diagnoses in American adults. Methods: A total of 97,861,577 weighted-persons with one or more dental amalgam surfaces (exposed group) and 31,716,558 weighted-persons with one or more other dental surfaces (no dental amalgams, unexposed group) were examined in the 2015-2016 National Health and Nutrition Examination Survey. All persons were 20-80 years old and with known reported asthma status (only newly diagnosed asthma cases were examined). Survey logistic regression and survey frequency modeling in SAS were employed to evaluate the relative incidence rate of reported asthma diagnoses among those in the exposed group compared to the unexposed group. Covariates of gender, race, socioeconomic status, educational status, country of birth, and tobacco exposure were considered. Results: Survey logistic modeling revealed a significantly increased incidence rate of reported asthma in the exposed group as compared to the unexposed group in unadjusted (4.46-fold) and adjusted (4.84-fold) models. A dose-response relationship was observed for the risk of reported asthma per dental amalgam filling surface in unadjusted (1.073) and adjusted (1.076) models. Survey frequency modeling revealed that the frequency of reported asthma (per 10,000 weighted-person years) was 3.66-fold significantly increased in the exposed group (2.06) as compared to the unexposed group (0.56). Conclusion: Increased dental amalgam exposure was associated with an increased risk of reported asthma diagnoses in American adults, but future studies should further evaluate this relationship.

A Longitudinal Cohort Study of Precocious Puberty and Autism Spectrum Disorder.

INTRODUCTION: Autism spectrum disorder (ASD) is defined by persistent deficits in communication, socialization, and stereotypic behaviors. It was previously hypothesized that hormone dysfunction is a frequent occurrence among children diagnosed with an ASD. OBJECTIVES: A hypothesis-testing epidemiological study examined the relationship between precocious puberty (PP) (a known disorder of childhood sex hormone dysfunction) and ASD diagnoses. METHODS: The Independent Healthcare Research Database is composed of de-identified linked eligibility and claims health-care records prospectively generated from the Florida Medicaid system. A cohort of 101,736 children eligible for Florida Medicaid from 1990 to 2009 and continuously eligible with ≥10 outpatient office visits during the 120-month period following birth were examined using SAS and StatsDirect software. There were 1,593 children (15,738 person-years) in the ASD diagnosed cohort utilizing the Diagnostic and Statistical Manual of Mental Disorders, 4th revision criteria (the International Code for Disease, 9th revision [ICD-9] codes: 299.00 or 299.80) and 100,143 children (996,835 person-years) in the undiagnosed cohort. RESULTS: The incidence rate of PP (ICD-9 code: 259.1) was examined using Cox proportional hazards ratio (HR) and frequency models. PP per 10,000 person-years in the ASD cohort (43.2) relative to the undiagnosed cohort (13.7) was significantly increased in frequency modeling (risk ratio = 3.15, p < 0.0001) and Cox proportional HR modeling (adjusted HR = 4.64, p < 0.0001). Further analyses revealed the incidence rate of PP diagnosed after 3 years of age was significantly increased (adjusted HR = 5.16, p < 0.0001) in the ASD cohort relative to the undiagnosed cohort but not for the incidence rate of PP diagnosed before 3 years (adjusted HR = 1.57, p = 0.44). CONCLUSION: This hypothesis-testing study provides strong evidence of an increased incidence rate of PP among children diagnosed with an ASD.

Dental Amalgams and the Incidence Rate of Arthritis among American Adults.

This hypothesis-testing study evaluated the relationship between mercury (Hg)-based dental amalgams and arthritis diagnoses among adults in the United States (US). A total of 86 305 425 weighted-persons with ⩾1 dental amalgam filling surface (DAFS) (exposed group) and 32 201 088 weighted-persons with ⩾1 other dental filling surface (ODFS) (no DAFS, unexposed group) were examined in the 2015 to 2016 National Health and Nutritional Examination Survey (NHANES). All persons were 20 to 80 years-old with known demographic characteristics and arthritis status. Survey logistic regression and survey frequency modeling in SAS were employed with and without adjustment of covariates. The arthritis rate was significantly increased in the exposed group compared to the unexposed group in the unadjusted (7.68-fold) and adjusted (4.89-fold) models. Arthritis (per 10 000 weighted-person-years) was 6.0-fold significantly increased in the exposed group (6.2) compared to the unexposed group (1.06). A significant bimodal dose-dependent relationship between DAFS and arthritis rate was observed. The arthritis rate increased with increasing DAFS (peak among persons with 4-7 DAFS) and, subsequently, decreased among those with >6 DAFS. A significant decrease in arthritis rate among persons with >13 DAFS as compared to those persons with 4 to 7 DAFS was observed. A significant association between DAFS and arthritis risk and a dose-dependent DAFS associated immune-stimulation/immune-suppression with arthritis risk were observed. An estimated additional $96 835 814 US dollars (USD) are spent on annual medical costs and $184 797 680 USD are lost in annual wages from reported new onset arthritis attributably associated with DAFS (annual total cost = $281 633 494 USD).

A longitudinal cohort study of childhood MMR vaccination and seizure disorder among American children.

BACKGROUND: Measles (rubeola) is a highly contagious infectious disease with significant morbidity/mortality. Measles-Mumps-Rubella (MMR) is a live-attenuated vaccine used in the United States (US) to prevent measles. This retrospective longitudinal cohort study evaluated childhood MMR vaccination and the risk of a seizure episode and seizure disorder. METHODS: The Independent Healthcare Research Database (IHRD) composed of records prospectively generated from Florida Medicaid was analyzed using SAS to identify persons continuously enrolled from birth for 120 months. Two cohorts were examined: 23,486 persons received at least one dose of MMR vaccine between 12 and 17 months (vaccinated) and 41,725 persons not receiving a measles-containing vaccine (unvaccinated). The daily incidence rate of an initial seizure episode (ICD-9 code: 780.3x) and seizure disorder (ICD-9 code: 345.xx) following an initial seizure episode diagnoses were examined using Cox proportional hazards ratio (HR) and time-trend models post-MMR vaccination compared to unvaccinated persons and in a self-controlled case-series (SCCS). RESULTS: The daily incidence rate of an initial seizure episode diagnosed from 6 to 11 days post-MMR vaccination in comparison to 12 to17 months among unvaccinated persons was significantly increased (unadjusted HR = 5.73, p < 0.0001 and adjusted HR = 5.94, p < 0.0001) in HR models. The daily incidence rate of an eventual seizure disorder diagnosis among those diagnosed with an initial seizure episode from 6 to 11 days post-MMR vaccination was significantly increased (unadjusted HR = 17.7, p < 0.01 and adjusted HR = 17.4, p < 0.01) in comparison to the daily incidence rate of an eventual seizure disorder diagnosis among those diagnosed with an initial seizure episode from 12 to 17 months among unvaccinated persons. Time-trend analyses revealed a significantly increased rate ratio (RR) for an initial seizure episode (RR = 4.64, p < 0.0001) and seizure disorder (RR = 5.51, p < 0.0001) diagnoses. Time-trend SCCS analyses revealed a significantly increased daily incidence rate of an initial seizure episode (RR = 3.80, p < 0.0001) when comparing periods from 6 to 11 days post-MMR vaccination to 49-60 days post-MMR vaccination. The incidence rate of an eventual seizure disorder diagnosis among those with an initial seizure episode diagnosis from 6 to 11 days post-MMR vaccination compared to 49-60 days post-MMR vaccination was significantly increased (RR = 4.15, p < 0.01). CONCLUSION: Seizure episode and seizure disorder are rare consequences of routine childhood MMR vaccination.

Mercury as a hapten: A review of the role of toxicant-induced brain autoantibodies in autism and possible treatment considerations.

BACKGROUND: Mercury has many direct and well-recognized neurotoxic effects. However, its immune effects causing secondary neurotoxicity are less well-recognized. Mercury exposure can induce immunologic changes in the brain indicative of autoimmune dysfunction, including the production of highly specific brain autoantibodies. Mercury, and in particular, Thimerosal, can combine with a larger carrier, such as an endogenous protein, thereby acting as a hapten, and this new molecule can then elicit the production of antibodies. METHODS: A comprehensive search using PubMed and Google Scholar for original studies and reviews related to autism, mercury, autoantibodies, autoimmune dysfunction, and haptens was undertaken. All articles providing relevant information from 1985 to date were examined. Twenty-three studies were identified showing autoantibodies in the brains of individuals diagnosed with autism and all were included and discussed in this review. RESULTS: Research shows mercury exposure can result in an autoimmune reaction that may be causal or contributory to autism, especially in children with a family history of autoimmunity. The autoimmune pathogenesis in autism is demonstrated by the presence of brain autoantibodies (neuroantibodies), which include autoantibodies to: (1) human neuronal progenitor cells; (2) myelin basic protein (MBP); (3) neuron-axon filament protein (NAFP); (4) brain endothelial cells; (5) serotonin receptors; (6) glial fibrillary acidic protein (GFAP); (7) brain derived neurotrophic factor (BDNF); (8) myelin associated glycoprotein (MAG); and (9) various brain proteins in the cerebellum, hypothalamus, prefrontal cortex, cingulate gyrus, caudate putamen, cerebral cortex and caudate nucleus. CONCLUSION: Recent evidence suggests a relationship between mercury exposure and brain autoantibodies in individuals diagnosed with autism. Moreover, brain autoantibody levels in autism are found to correlate with both autism severity and blood mercury levels. Treatments to reduce mercury levels and/or brain autoantibody formation should be considered in autism.

Respiratory conditions in coronavirus disease 2019 (COVID-19): Important considerations regarding novel treatment strategies to reduce mortality.

A novel virus named 2019 novel coronavirus (2019-nCoV/SARS-CoV-2) causes symptoms that are classified as coronavirus disease (COVID-19). Respiratory conditions are extensively described among more serious cases of COVID-19, and the onset of acute respiratory distress syndrome (ARDS) is one of the hallmark features of critical COVID-19 cases. ARDS can be directly life-threatening because it is associated with low blood oxygenation levels and can result in organ failure. There are no generally recognized effective treatments for COVID-19, but treatments are urgently needed. Anti-viral medications and vaccines are in the early developmental stages and may take many months or even years to fully develop. At present, management of COVID-19 with respiratory and ventilator support are standard therapeutic treatments, but unfortunately such treatments are associated with high mortality rates. Therefore, it is imperative to consider novel new therapeutic interventions to treat/ameliorate respiratory conditions associated with COVID-19. Alternate treatment strategies utilizing clinically available treatments such as hyperbaric oxygen therapy (HBOT), packed red blood cell (pRBC) transfusions, or erthropoiesis-stimulating agent (ESA) therapy were hypothesized to increase oxygenation of tissues by alternative means than standard respiratory and ventilator treatments. It was also revealed that alternative treatments currently being considered for COVID-19 such as chloroquine and hydroxychloroquine by increasing hemoglobin production and increasing hemoglobin availability for oxygen binding and acetazolamine (for the treatment of altitude sickness) by causing hyperventilation with associated increasing levels of oxygen and decreasing levels of carbon dioxide in the blood may significantly ameliorate COVID-19 respiratory symptoms. In conclusion, is recommend, given HBOT, pRBC, and ESA therapies are currently available and routinely utilized in the treatment of other conditions, that such therapies be tried among COVID-19 patients with serious respiratory conditions and that future controlled-clinical trials explore the potential usefulness of such treatments among COVID-19 patients with respiratory conditions.

A ten year longitudinal examination of the incidence rate and age of childhood encephalopathy diagnoses in an autism spectrum disorder diagnosed cohort.

Autism spectrum disorder (ASD) is defined by persistent deficits in social communication/interaction and stereotypic behaviors with many diagnosed persons experiencing a developmental regression at >1 year­old. It was hypothesized that progressive childhood encephalopathy is an important etiological factor in ASD pathogenesis. This hypothesis­testing study examined the relationship between diagnosed childhood encephalopathy and ASD. The Independent Healthcare Research Database is composed of de­identified linked eligibility and claim healthcare records prospectively generated from the Florida Medicaid system. A cohort of 101,736 persons eligible for Florida Medicaid from 1990­2009 and continuously eligible with ≥10 outpatient office visits during the 120 month period following birth were examined using SAS software. There were 1,397 persons (7,223 person­years) in the ASD diagnosed cohort and 100,339 persons (980,786 person­years) in the undiagnosed cohort. The incidence rate of encephalopathy was examined using Cox proportional hazards ratio models. In the ASD cohort relative to the undiagnosed cohort, a significantly increased incidence rate of diagnosed encephalopathy was observed in the unadjusted and adjusted models. The risk for an encephalopathy diagnosed at >1 year­old was greater than for an encephalopathy diagnosed at <1 year­old. This study provides important new evidence supporting the hypothesis that a significant number of children with an eventual ASD diagnosis experience a progressive childhood en cephalopathy diagnosed at >1 year­old.

Examining the evidence that ethylmercury crosses the blood-brain barrier.

Scientific research can provide us with factual, repeatable, measurable, and determinable results. As such, scientific research can provide information that can be used in the decision-making process in the care of patients and in public policy. Although it has been suggested that ethylmercury (C2H5Hg+)-containing compounds do not cross the blood-brain barrier (BBB), this review examines the literature that addresses the question as to whether ethylmercury-containing compounds cross the BBB. The review will begin with cellular studies that provide evidence for the passive and active transport of mercury species across the BBB. Then, animal and clinical studies will be presented that specifically examine whether mercury accumulates in the brain after exposure to ethylmercury-containing compounds or Thimerosal (an ethylmercury-containing compound used as a preservative in vaccines and other drugs that metabolizes or degrades to ethylmercury-containing compounds and thiosalicylate). The results indicate that ethylmercury-containing compounds are actively transported across membranes by the L (leucine-preferring)-amino acid transport (LAT) system, the same as methylmercury-containing compounds. Further, 22 studies from 1971 to 2019 show that exposure to ethylmercury-containing compounds (intravenously, intraperitoneally, topically, subcutaneously, intramuscularly, or intranasally administered) results in accumulation of mercury in the brain. In total, these studies indicate that ethylmercury-containing compounds and Thimerosal readily cross the BBB, convert, for the most part, to highly toxic inorganic mercury-containing compounds, which significantly and persistently bind to tissues in the brain, even in the absence of concurrent detectable blood mercury levels.

Down syndrome as a genetic model to evaluate the role of oxidative stress and transsulfuration abnormalities in autism spectrum disorder: A 10-year longitudinal cohort study.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder in which evidence reveals oxidative stress and transsulfuration pathway abnormalities. Down syndrome (DS) is a genetic disorder characterized by similar oxidative stress and transsulfuration pathway abnormalities. This hypothesis-testing longitudinal cohort study determined whether transsulfuration abnormalities and oxidative stress are important susceptibility factors in ASD etiology by evaluating the rate of ASD diagnoses in DS as compared to the general population. The Independent Healthcare Research Database was analyzed for healthcare records prospectively generated in Florida Medicaid. A cohort of 101,736 persons (born: 1990-1999) with ≥10 outpatient office visits and continuously followed for 120 months after birth was examined. There were 942 children in the DS cohort (ICD-9 code: 758.0) and 100,749 children in the undiagnosed cohort (no DS diagnosis). ASD diagnoses were defined as autistic disorder (ICD-9 code: 299.00) or Asperger's disorder/pervasive developmental disorder-not otherwise specified (ICD-9 code: 299.80). ASDs were diagnosed in 5.31% of the DS cohort and 1.34% of the undiagnosed cohort. The risk ratio of being diagnosed with an ASD in the DS cohort as compared to the undiagnosed cohort was 3.97-fold significantly increased with a risk difference of 3.97%. Among children diagnosed with DS, less than 6% were also diagnosed with an ASD. Among children diagnosed with an ASD, less than 5% were also diagnosed with DS. Children diagnosed with DS are apparently more susceptible to ASD diagnosis relative to the general population suggesting oxidative stress and transsulfuration pathway abnormalities are important susceptibility factors in ASD.

A Cross-Sectional Study of Blood Ethylmercury Levels and Cognitive Decline Among Older Adults and the Elderly in the United States.

Cognitive health is an emerging public health concern for the aging American population. Mercury (Hg) is a toxic element that can cause nervous system damage. This hypothesis-testing study evaluated the relationship between blood ethyl-Hg levels and cognitive decline in an older adult and elderly American population. A total of 1,821,663 weighted-persons between 60-80 years old with detectable blood ethyl-Hg levels within the 2011-2012 National Health and Nutritional Examination Survey were examined. Those persons with blood ethyl-Hg levels greater than the median were deemed the higher ethyl-Hg exposure group and those with ethyl-Hg levels less than the median were deemed the lower ethyl-Hg exposure group. Three tests were utilized to measure cognitive function: 1) Consortium to Establish a Registry for Alzheimer's Disease - Word List Learning (CERAD W-L) delayed recall test, 2) animal fluency test, and 3) Digit Symbol Substitution Test. Each cognitive test score was categorized as higher for those with scores greater than the median and lower for those with scores less than the median. Survey logistic regression modeling with covariates was used to analyze the data for the relationship between blood ethyl-Hg levels and cognitive function scores. Significantly increased risks for lower animal fluency test (odds ratio (OR) = 13.652, p = 0.0029) and CERAD W-L delayed recall test (OR = 6.401, p = 0.0433) scores were observed among the higher ethyl-Hg exposure group as compared to the lower ethyl-Hg exposure group. This study supports the hypothesis that increased ethyl-Hg exposure is associated with significant cognitive decline in older adult and elderly Americans.

Childhood MMR vaccination and the incidence rate of measles infection: a ten year longitudinal cohort study of American children born in the 1990s.

BACKGROUND: Measles (rubeola) is a highly contagious disease with significant morbidity/mortality. Measles-Mumps-Rubella (MMR) is a live-attenuated vaccine used in the United States (US) since the early 1970s to prevent measles infection. This retrospective longitudinal cohort study examined childhood MMR vaccination effectiveness (VE) on preventing diagnosed measles cases. METHODS: The Independent Healthcare Research Database (IHRD) is composed of non-identifiable linked eligibility and claim healthcare records prospectively generated from the Florida Medicaid system. The SAS system was utilized to examine a cohort of 101,736 persons eligible for Florida Medicaid from 1990 to 2009 and continuously eligible with ≥10 outpatient office visits during the 120-month period following birth. There were 32,870 persons (224,492 person-years) in the cohort receiving a single dose of childhood MMR vaccine (vaccinated) and 43,538 persons (434,637 person-years) in an unvaccinated cohort (no exposures to measles-containing vaccine). The frequency of diagnosed measles (ICD-9 code: 055xxx) was examined. Cox proportional hazards models evaluated MMR vaccination and diagnosed measles over time. RESULTS: MMR vaccinated cohort members were at significantly reduced risk of measles in the unadjusted (VE = 83.6, 95% CI = 67.2-91.8%) and adjusted (VE = 80.7, 95% CI = 61.5-83.9%) models as compared to the unvaccinated cohort. VE = 80% among younger MMR recipients (12-15 months), whereas VE = 90% among older MMR recipients (16-20 months) as compared to the unvaccinated cohort. CONCLUSION: Routine childhood MMR vaccination significantly reduced the incidence rate of childhood measles infections, and the VE was greater in the older recipients (16-20 months) than in the younger recipients (12-15 months).

A cross-sectional study of the relationship between reported human papillomavirus vaccine exposure and the incidence of reported asthma in the United States.

OBJECTIVES: Asthma is a chronic disorder that affects persons of all ages impacting the quality of their lives. This cross-sectional hypothesis-testing study evaluated the relationship between human papillomavirus vaccine and the risk of an incident asthma diagnosis in a defined temporal period post-vaccination. METHODS: The 2015-2016 National Health and Nutrition Examination Survey data were examined for a group of 60,934,237 weighted persons between 9 and 26 years old in Statistical Analysis Software. RESULTS: Reported incident asthma significantly clustered in the year of reported human papillomavirus vaccination. When the data were separated by gender, the effects observed remained significant for males but not females. CONCLUSION: The results suggest that human papillomavirus vaccination resulted in an excess of 261,475 asthma cases with an estimated direct excess lifetime cost of such persons being US$42 billion. However, it is unclear what part of the vaccine and/or vaccine medium may have increased an individual's susceptibility to an asthma episode, whether the asthma diagnosis represented one asthma episode or if it is chronic, and how much therapeutic support was needed (if any) and for how long, which would impact cost. Despite the negative findings in this study, routine vaccination is an important public health tool, and the results observed need to be viewed in this context.