Longitudinal Assessment of Glymphatic Changes Following Mild Traumatic Brain Injury: Insights from PVS burden and DTI-ALPS Imaging.

Traumatic brain injury (TBI) even in the mild form may result in long-lasting post-concussion symptoms. TBI is also a known risk to late-life neurodegeneration. Recent studies suggest that dysfunction in the glymphatic system, responsible for clearing protein waste from the brain, may play a pivotal role in the development of dementia following TBI. Given the diverse nature of TBI, longitudinal investigations are essential to comprehending the dynamic changes in the glymphatic system and its implications for recovery. In this prospective study, we evaluated two promising glymphatic imaging markers, namely the enlarged perivascular space (ePVS) burden and Diffusion Tensor Imaging-based ALPS index, in 44 patients with mTBI at two early post-injury time points: approximately 14 days (14Day) and 6-12 months (6-12Mon) post-injury, while also examining their associations with post-concussion symptoms. Additionally, 37 controls, comprising both orthopedic patients and healthy individuals, were included for comparative analysis. Our key findings include: 1) White matter ePVS burden (WM-ePVS) and ALPS index exhibit significant correlations with age. 2) Elevated WM-ePVS burden in acute mTBI (14Day) is significantly linked to a higher number of post-concussion symptoms, particularly memory problems. 3) The increase in the ALPS index from acute (14Day) to the chronic (6-12Mon) phases in mTBI patients correlates with improvement in sleep measures. Furthermore, incorporating WM-ePVS burden and the ALPS index from acute phase enhances the prediction of chronic memory problems beyond socio-demographic and basic clinical information, highlighting their distinct roles in assessing glymphatic structure and activity. Early evaluation of glymphatic function could be crucial for understanding TBI recovery and developing targeted interventions to improve patient outcomes.

Long Term Memory Outcome of Repetitive, Low-Level Dietary Exposure to Domoic Acid in Native Americans.

Domoic acid (DA) is a marine-based neurotoxin that, if ingested via tainted shellfish, is associated with Amnesic Shellfish Poisoning (ASP). These acute effects of elevated DA exposure in humans have been well described. In contrast, the long-term impacts of lower level, repetitive, presumably safe doses of DA (less than 20 ppm) are minimally known. Since Native Americans (NA) residing in coastal communities of the Pacific NW United States are particularly vulnerable to DA exposure, this study focuses on the long-term, 8-year memory outcome associated with their repeated dietary consumption of the neurotoxin. Measures of razor clam consumption, memory, clerical speed and accuracy, and depression were administered over eight years to 500 randomly selected adult NA men and women ages 18-64. Data were analyzed using GEE analyses taking into consideration the year of study, demographic factors, and instrumentation in examining the association between dietary exposure and outcomes. Findings indicated a significant but small decline in total recall memory within the context of otherwise stable clerical speed and accuracy and depression scores. There is reason to believe that a continuum of memory difficulties may be associated with DA exposure, rather than a unitary ASP syndrome.

Predictors of Behavioral Changes After Adenotonsillectomy in Pediatric Obstructive Sleep Apnea: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Adenotonsillectomy (AT) is associated with improved behavior in children with obstructive sleep apnea (OSA). However, it is unknown whether polysomnographic parameters are superior to the parent-reported severity of sleep-disordered breathing (SDB) in predicting behavioral changes after AT. Objective: To ascertain whether polysomnographic parameters vs parent-reported severity of SDB are better predictors of treatment-related behavioral changes in children with OSA. Design, Setting, and Participants: This ad hoc secondary analysis of the Childhood Adenotonsillectomy Trial (CHAT) downloaded and analyzed data from January 1 to January 31, 2020. Children aged 5 to 9 years with a polysomnographic diagnosis of OSA were enrolled in the CHAT and subsequently randomized to undergo either early AT or watchful waiting with supportive care. All outcome measures were obtained at baseline and at follow-up (7 months after randomization). Interventions: Early AT vs watchful waiting with supportive care. Main Outcomes and Measures: Postrandomization changes between the baseline and follow-up periods were derived from (1) T scores in 4 validated behavioral assessments (Conners Global Index parent and teacher versions, Behavior Rating Inventory of Executive Function metacognition index, and Child Behavior Checklist of total, internalizing, and externalizing behavior subscales); (2) 8 aggregated polysomnographic parameters representing the severity of obstruction, hypoxemia, sleep quality, and structure; and (3) the parent-reported severity of SDB measured by the Pediatric Sleep Questionnaire-Sleep-Related Breathing Disorder (PSQ-SRBD) scale. The treatment-related changes in each of the behavioral outcomes attributable to changes in SDB severity (represented by the subjective PSQ-SRBD score and objective polysomnographic parameters) were measured and compared using mediation analysis. Results: A total of 453 children were assessed at baseline, of whom 234 were girls (52%) and the mean (SD) age was 6.6 (1.4) years. The postrandomization changes in 7 of 8 behavioral outcome measures between the baseline and follow-up periods were partially mediated by the changes in PSQ-SRBD scores (range of nonzero causally mediated effects, 2.4-3.5), without contribution from any of the polysomnographic parameters. Conclusions and Relevance: This secondary analysis of a national randomized clinical trial found that most treatment-related behavioral changes in children with OSA were mediated by the changes in parent-reported SDB severity alone. These findings suggest that polysomnographic parameters provide clinicians with limited means to predict the improvement in neurobehavioral morbidity in OSA. Trial Registration: ClinicalTrials.gov Identifier: NCT00560859.

Dose-response assessment for impaired memory from chronic exposure to domoic acid among native American consumers of razor clams.

Domoic acid (DA) is a marine neurotoxin that accumulates in filtering shellfish during harmful algal blooms. A health protection limit of 20 ppm DA in razor clams (RC) has been set based principally upon an episode of acute DA toxicity in humans that included Amnesic Shellfish Poisoning among survivors. The objective of this study was to determine the dose-response relationship between estimated DA exposure through RC consumption and memory loss in Washington state Native Americans from 2005 to 2015. Results from total learning recall (TLR) memory scores were compared before and after the highest DA exposures. A decrease in TLR was related to DA dose (p < 0.01) regardless whether the effect was assumed to be transient or lasting, and whether the dose was expressed as an average daily dose or an average dose per meal. Benchmark dose modeling identified BMDL10 values of 167 ng/kg-day and 2740 ng/kg-meal assuming a transient effect, and 196 ng/kg-day and 2980 ng/kg-meal assuming no recovery of function occurs. These DA dose thresholds for a measurable memory function reduction observed in this study of clam consumers are well below the safe acute dose underpinning the current regulatory DA limit of 20 ppm (ca. 60 µg/kg).

The Short- and Long-Term Impacts of Hurricane Irma on Florida Agricultural Leaders as Early Emergency Responders: The Importance of Workplace Stability.

The impacts of hurricane-related disasters in agricultural communities include extensive losses of fields, orchards, and livestock, the recovery of which could span many years. Agricultural Extension Agents (EAs) try to manage and mitigate these losses, while simultaneously overseeing emergency shelter operations. These non-professional emergency responders face numerous potential stressors, the outcomes of which are minimally known. This study examined the short- and long-term medical and behavioral outcome of 36 University of Florida Agricultural Extension Agents within two months and one year after Hurricane Irma, Florida, USA, taking into consideration personal/home and work-related hurricane impacts. Regression analyses indicated that combined home and work hurricane impacts were associated with greater anxiety, depression, and medical symptoms controlling for age and number of prior hurricane experiences within two months of landfall. One year later, depression symptoms increased as well as the use of negative disengagement coping strategies for which stability of the work environment was protective. The findings suggest that advanced training in emergency response, organization and time management skills, time off and temporary replacement for personally impacted EAs, and workplace stability, including enhanced continuity of operations plans, represent critical elements of health prevention and early intervention for this occupational group.

Health Impact of Hurricanes Irma and Maria on St Thomas and St John, US Virgin Islands, 2017-2018.

Objectives. To assess the health impact of Hurricane Irma and Hurricane Maria on St Thomas, US Virgin Islands.Methods. We collected data from interviews conducted 6 and 9 months after the hurricanes, a review of 597 randomly selected emergency department (ED) encounters, and administrative records from 10 716 ED visits 3 months before, between, and 3 months after the hurricanes.Results. Informants described damaged hospital infrastructure, including flooding, structural damage, and lost staff. The greatest public health impact was on the elderly and persons with chronic diseases. In the setting of loss of the electronic medical record system, ED chart reviews were limited by problems with missing data. ED administrative data demonstrated that posthurricane patients, compared with prehurricane patients, were older and had less severe complaints. There was a significant increase in patients being seen for diabetes-related and respiratory complaints, especially asthma. Suboptimal recordkeeping for medical evacuees limited the ability to assess outcomes for patients with severe illnesses.Conclusions. Hurricanes Irma and Maria caused major disruptions to health care on St Thomas. Emphasis should be given to building a resilient health care system that will optimally respond to future hurricanes.

Prolonged Financial Distress After the Deepwater Horizon Oil Spill Predicts Behavioral Health.

The economic impact of disasters is well known; however, the link between financial loss and behavioral health problems is unknown. Participants included 198 adults of ages 21 to 82, living within 10 miles of the Gulf Coast during the Deepwater Horizon Oil Spill and were involved in the fishing, harvesting, seafood processing, or service/tourism industries. The functional impact of financial resource loss at 2.5 years post spill was measured using the 26-item Financial Life Events Checklist (FLEC). Individuals responded to financial distress by reducing social events and utility bills and changing food-shopping habits. The FLEC significantly predicted higher drug use (Drug Abuse Screening Test), alcohol use (Alcohol Use Disorders Identification Test), mood problems (Profile of Mood States), and depressive symptoms (Beck Depression Inventory II) (p values ≤ 0.05) 4.5 years after the spill. This preliminary study supports the notion that the functional impact of financial loss has a long-term impact on behavioral health after an oil spill.

Repeated Dietary Exposure to Low Levels of Domoic Acid and Problems with Everyday Memory: Research to Public Health Outreach.

Domoic Acid (DA) is a marine-based neurotoxin. Dietary exposure to high levels of DA via shellfish consumption has been associated with Amnesic Shellfish Poisoning, with milder memory decrements found in Native Americans (NAs) with repetitive, lower level exposures. Despite its importance for protective action, the clinical relevance of these milder memory problems remains unknown. The purpose of this study was to determine whether repeated, lower-level exposures to DA impact everyday memory (EM), i.e., the frequency of memory failures in everyday life. A cross-sectional sample of 60 NA men and women from the Pacific NW was studied with measures of dietary exposure to DA via razor clam (RC) consumption and EM. Findings indicated an association between problems with EM and elevated consumption of RCs with low levels of DA throughout the previous week and past year after controlling for age, sex, and education. NAs who eat a lot of RCs with presumably safe levels of DA are at risk for clinically significant memory problems. Public health outreach to minimize repetitive exposures are now in place and were facilitated by the use of community-based participatory research methods, with active involvement of state regulatory agencies, tribe leaders, and local physicians.

The association between razor clam consumption and memory in the CoASTAL Cohort.

This study represents a preliminary effort to examine the possible impacts of chronic, low level Domoic Acid (DA) exposure on memory in the CoASTAL cohort. Five hundred thirteen men and women representing three Native American Tribes were studied with standard measures of cognition and razor clam consumption (a known vector of DA exposure) over a four year period. In addition, a pilot metric of DA concentration exposure was used which took into consideration average DA concentration levels in source beaches as well as consumption. Based upon GEE analysis, controlling for age, sex, race, year, education level, tribe, and employment status, findings indicated that high razor clam consumers (15 or more per month) had isolated decrements on some measures of memory (p=.02 to .03), with other cognitive functions unaffected. The relatively lower memory scores were still within normal limits, thus not clinically significant. The pilot DA exposure metric had no association with any aspect of cognition or behavior. There is a possible association between long term, low level exposure to DA through heavy razor clam consumption and memory. The availability of a reliable biological marker for human exposure to DA is needed.

Harmful Algal Blooms and Public Health.

The five most commonly recognized Harmful Algal Bloom related illnesses include Ciguatera poisoning, Paralytic Shellfish poisoning, Neurotoxin Shellfish poisoning, Diarrheic Shellfish Poisoning and Amnesic Shellfish poisoning. Although they are each the product of different toxins, toxin assemblages or HAB precursors these clinical syndromes have much in common. Exposure occurs through the consumption of fish or shellfish; routine clinical tests are not available for diagnosis; there is no known antidote for exposure; and the risk of these illnesses can negatively impact local fishing and tourism industries. Thus, illness prevention is of paramount importance to minimize human and public health risks. To accomplish this, close communication and collaboration is needed among HAB scientists, public health researchers and local, state and tribal health departments at academic, community outreach, and policy levels.

Communities advancing the studies of Tribal nations across their lifespan: Design, methods, and baseline of the CoASTAL cohort.

The CoASTAL cohort represents the first community cohort assembled to study a HAB related illness. It is comprised of three Native American tribes in the Pacific NW for the purpose of studying the health impacts of chronic, low level domoic acid (DA) exposure through razor clam consumption. This cohort is at risk of domoic acid (DA) toxicity by virtue of their geographic location (access to beaches with a history of elevated DA levels in razor clams) and the cultural and traditional significance of razor clams in their diet. In this prospective, longitudinal study, Wave 1 of the cohort is comprised of 678 members across the lifespan with both sexes represented within child, adult and geriatric age groups. All participants are followed annually with standard measures of medical and social history; neuropsychological functions, psychological status, and dietary exposure. DA concentration levels are measured at both public and reservation beaches where razor clams are sourced and multiple metrics have been piloted to further determine exposure. Baseline data indicates that all cognitive and psychological functions are within normal limits. In addition there is considerable variability in razor clam exposure. Therefore, the CoASTAL cohort offers a unique opportunity to investigate the potential health effects of chronic, low level exposure to DA over time.

Assessment of sodium channel mutations in Makah Tribal members of the U.S. Pacific Northwest as a potential mechanism of resistance to paralytic shellfish poisoning.

The Makah Tribe of Neah Bay, Washington, has historically relied on the subsistence harvest of coastal seafood, including shellfish, which remains an important cultural and ceremonial resource. Tribal legend describes visitors from other tribes that died from eating shellfish collected on Makah lands. These deaths were believed to be caused by paralytic shellfish poisoning, a human illness caused by ingestion of shellfish contaminated with saxitoxins, which are produced by toxin-producing marine dinoflagellates on which the shellfish feed. These paralytic shellfish toxins include saxitoxin, a potent Na+ channel antagonist that binds to the pore region of voltage gated Na+ channels. Amino acid mutations in the Na+ channel pore have been demonstrated to confer resistance to saxitoxin in softshell clam populations exposed to paralytic shellfish toxins present in their environment. Because of the notion of resistance to paralytic shellfish toxins, we aimed to determine if a resistance strategy was possible in humans with historical exposure to toxins in shellfish. We collected, extracted and purified DNA from buccal swabs of 83 volunteer Makah tribal members and sequenced the skeletal muscle Na+ channel (Nav1.4) at nine loci to characterize potential mutations in the relevant saxitoxin binding regions. No mutations of these specific regions were identified after comparison to a reference sequence. This study suggests that any resistance of Makah Tribal members to saxitoxin is not a function of Nav1.4 modification but may be due to mutations in neuronal or cardiac sodium channels or some other mechanism unrelated to sodium channel function.

Perception of risk for Domoic Acid related health problems: A Cross-cultural study.

Risk perception is a complex process that refers to the way people approach, think about and interpret risks in their environment. An important element of risk perception is that it is culturally situated. Since HAB's can present a health risk in many places around the world, looking at cultural parameters for understanding and interpreting risks are important. This study examined how two different groups of people perceive the potential health risks of low level exposure to domoic acid (DA) through razor clam consumption. The risk perceptions of Washington State, USA coastal dwelling Native American nations (NA) were compared to that of a community sample of recreational razor clam harvesters (CRH). Overall, the findings support the hypothesis that cultural and community specific contexts impact the perception of risk of a DA related illness. Specifically, the NA sample was distinguished by worrying more about ocean pollution, attributing DA risks to climate change, expressing concerns about the potential impact of DA on future generations, and feeling better informed than the CRH group. The CRH group were more likely to attribute the DA problem to anthropogenic or industrial causes; and view the risk of health problems as lower than that associated with smoking, high cholesterol, anxiety or depression, alcoholism, high blood pressure or obesity. The CRH group was also more likely to turn to the media for DA related information. Both groups trust the decisions of state and tribe health and natural resources officials and demonstrated a complex pattern of findings that involved gender. It was recommended that risk communication and outreach activities are designed to take into consideration factors that specifically apply to each cultural community.

Dietary Assessment of domoic acid Exposure: What can be learned from traditional methods and new applications for a technology assisted device.

Three Tribal Nations in the Pacific Northwest United States comprise the members of the CoASTAL cohort. These populations may be at risk for neurobehavioral impairment, i.e., amnesic shellfish poisoning, from shellfish consumption as a result of repeated, low-level domoic acid (DA) exposure present in local clams. Previous work with this cohort confirmed a high proportion of clam consumers with varying levels of potential exposure over time. Since clams are an episodically consumed food, traditional dietary records do not fully capture exposure. Frequency questionnaires can capture accumulated doses over time and this data can be used to examine dose-response relationships with periodic studies of memory and learning. However, frequency questionnaires cannot be used to assess consumption and memory response in real time. To address this shortcoming, a modified technology assisted dietary assessment (TADA) iPod application was developed to capture images of the clam meal, sourcing data, and associated memory functioning within 24 hours and seven days after consumption. This methodology was piloted with razor clam meals consumed by members from the CoASTAL cohort. Preliminary findings suggest that the TADA iPod application is potentially useful in collecting real-time data with respect to razor clam consumption, as well as one day and seven day memory outcome data. This technology holds promise for addressing the challenges of other HAB related dietary exposure outcome studies.

Gene Expression Patterns in Peripheral Blood Leukocytes in Patients with Recurrent Ciguatera Fish Poisoning: Preliminary Studies.

Ciguatera fish poisoning (ciguatera) is a common clinical syndrome in areas where there is dependence on tropical reef fish for food. A subset of patients develops recurrent and, in some instances, chronic symptoms, which may result in substantial disability. To identify possible biomarkers for recurrent/chronic disease, and to explore correlations with immune gene expression, peripheral blood leukocyte gene expression in 10 ciguatera patients (7 recurrent, 3 acute) from the U.S. Virgin Islands, and 5 unexposed Florida controls were evaluated. Significant differences in gene expression were noted when comparing ciguatera patients and controls; however, it was not possible to differentiate between patients with acute and recurrent disease, possibly due to the small sample sizes involved.

Harmful algal blooms and public health.

The five most commonly recognized Harmful Algal Bloom-related illnesses are ciguatera poisoning, paralytic shellfish poisoning, neurotoxic shellfish poisoning (NSP), amnesic shellfish poisoning, and diarrhetic shellfish poisoning. Although these exposures result from exposure to different toxins or toxin congeners, these clinical syndromes have much in common. Exposure occurs through the consumption of fish, shellfish, or through exposure to aerosolized NSP toxins. Routine clinical tests are not available for the diagnosis of harmful algal bloom related illnesses, there is no known antidote for exposure, and the risk of these illnesses can negatively impact local fishing and tourism industries. The absence of exposure risk or diagnostic certainty can also precipitate a chain of events that results in considerable psychological distress for coastal populations. Thus, illness prevention is of paramount importance to minimize human and public health risks. To accomplish this, further transdisciplinary research, close communication and collaboration are needed among HAB scientists, public health researchers, and local, state and tribal health departments at academic, community outreach, and policy levels.

The association between razor clam consumption and memory in the CoASTAL cohort.

This study represents a preliminary effort to examine the potential impacts of chronic, low level domoic acid (DA) exposure on memory in the CoASTAL cohort over the first four years of data collection (Wave 1). Five hundred and thirteen adult men and women representing three Native American Tribes were studied annually with standard measures of cognition and razor clam consumption (a known vector of DA exposure) over a four-year period. In addition, a pilot metric of DA concentration exposure was used which took into consideration average DA concentration levels in source beaches, as well as the amount consumed. Based upon generalized estimating equations (GEE) analysis, controlling for age, sex, race, year, education level, tribe, and employment status, findings indicated that high razor clam consumers (15 or more per month) had isolated decrements on some measures of memory (p=0.02-0.03), with other cognitive functions unaffected. The relatively lower memory scores were still within normal limits, and were thus not clinically significant. The pilot DA exposure metric had no association with any other aspect of cognition or behavior. There is a possible association between long-term, low-level exposure to DA through heavy razor clam consumption and memory functioning.

Gene expression patterns in peripheral blood leukocytes in patients with recurrent ciguatera fish poisoning: Preliminary studies.

Ciguatera fish poisoning (ciguatera) is a common clinical syndrome in areas where there is dependence on tropical reef fish for food. A subset of patients develops recurrent and, in some instances, chronic symptoms, which may result in substantial disability. To identify possible biomarkers for recurrent/chronic disease, and to explore correlations with immune gene expression, peripheral blood leukocyte gene expression in 10 ciguatera patients (7 recurrent and 3 acute) from the U.S. Virgin Islands, and 5 unexposed Florida controls were evaluated. Significant differences in gene expression were noted when comparing ciguatera patients and controls; however, it was not possible to differentiate between patients with acute and recurrent disease, possibly due to the small sample sizes involved.