A single post-exposure oxime RS194B treatment rapidly reactivates acetylcholinesterase and reverses acute symptoms in macaques exposed to diethylphosphorothioate parathion and chlorpyrifos insecticides.

Millions of individuals globally suffer from inadvertent, occupational or self-harm exposures from organophosphate (OP) insecticides, significantly impacting human health. Similar to nerve agents, insecticides are neurotoxins that target and inhibit acetylcholinesterase (AChE) in central and peripheral synapses in the cholinergic nervous system. Post-exposure therapeutic countermeasures generally include administration of atropine with an oxime to reactivate the OP-inhibited AChE. However, animal model studies and recent clinical trials using insecticide-poisoned individuals have shown minimal clinical benefits of the currently approved oximes and their efficacy as antidotes has been debated. Currently used oximes either reactivate poorly, do not readily cross the blood-brain barrier (BBB), or are rapidly cleared from the circulation and must be repeatedly administered. Zwitterionic oximes of unbranched and simplified structure, for example RS194B, have been developed that efficiently cross the BBB resulting in reactivation of OP-inhibited AChE and dramatic reversal of severe clinical symptoms in mice and macaques exposed to OP insecticides or nerve agents. Thus, a single IM injection of RS194B has been shown to rapidly restore blood AChE and butyrylcholinesterase (BChE) activity, reverse cholinergic symptoms, and prevent death in macaques following lethal inhaled sarin and paraoxon exposure. The present macaque studies extend these findings and assess the ability of post-exposure RS194B treatment to counteract oral poisoning by highly toxic diethylphosphorothioate insecticides such as parathion and chlorpyrifos. These OPs require conversion by P450 in the liver of the inactive thions to the active toxic oxon forms, and once again demonstrated RS194B efficacy to reactivate and alleviate clinical symptoms within 60 mins of a single IM administration. Furthermore, when delivered orally, the Tmax of RS194B at 1-2 h was in the same range as those administered IM but were maintained in the circulation for longer periods greatly facilitating the use of RS194B as a non-invasive treatment, especially in isolated rural settings.

Ablación con RF de arritmia ventricular en paciente con disyunción anular mitral y QT prolongado

Se presenta el caso de una mujer joven con arritmia ventricular compleja, disyunción anular mitral y QT largo. Se muestran los aspectos más relevantes de su presentación clínica, estudio, tratamiento y evolución. Se acompaña una revisión de la literatura.

We present the case of a young woman with complex ventricular arrhythmia, mitral annular disjunction and long QT. The most relevant aspects of its clinical presentation, study, treatment and evolution are shown. A review of the literature is included.

The impact of solvents on the toxicity of the banned parathion insecticide.

The aerial crop dusting and spraying of fields with the phosphorothioate insecticide parathion in the late 1900s, significantly improved crop yields but resulted in high levels of occupational toxicity in handlers and agricultural workers, as well as cases of intentional self-harm poisoning, culminating in its banning in many western countries by early 2000s. However because of the low solubility and volatility of parathion, most available products were formulated using organic solvents e.g. xylene, to increase the efficacy of the aerosols and dusts. In the present study, the toxicity of parathion was assessed when formulated in an aqueous solvents (ethanol/PBS (1:9)), and delivered to macaques as an aerosol. Doses of 780 µg/kg and 1.56 mg/kg were delivered one day apart, using a modified nebulizer calculated to result in lung deposition of ∼480 µg/kg with a similar or larger amount being swallowed; these doses being similar to the estimated lethal oral dose 286ug/kg - 1.43 mg/kg of formulated parathion in humans. Surprisingly, this dose (a combined amount of ∼14 mg) caused only low AChE inhibition and moderate BChE inhibition with no clinical symptoms, indicating that the use of organic solvents may have previously played a critical role in the severity of parathion toxicity following inhalation exposure. In addition, unlike constitutively toxic OPs, which are highly toxic when inhaled, these results are consistent with the idea that phosphorothioate insecticides appear to be more intoxicating following oral than inhalation exposure. However, this still remains uncertain because the presence of organic solvents in the ingested parathion studies was not always known.

Miocardiopatía hipertrófica, anomalía coronaria, enfermedad aterosclerótica y arritmia ventricular coexistiendo en un mismo paciente

Presentamos el caso de un paciente quien presentó un evento presincopal en el que destacan 3 patologías asociadas a muerte súbita de forma independiente: miocardiopatía hipertrófica, origen anómalo coronario y enfermedad arterial coronaria epicárdica; diagnósticos coexistentes. Se describe las patologías, diagnóstico, manejo médico y terapéutico y se revisa la literatura.

A patient presented with a presyncopal event. Three conditions independently associated with sudden death, hypertrophic cardiomyopathy, anomalous origin of coronary arteries and epicardial coronary artery disease were found. Diagnosis, and medical management are described, followed by a review of the literature.

Characterization of Three Variants of SARS-CoV-2 In Vivo Shows Host-Dependent Pathogenicity in Hamsters, While Not in K18-hACE2 Mice.

Animal models are used in preclinical trials to test vaccines, antivirals, monoclonal antibodies, and immunomodulatory drug therapies against SARS-CoV-2. However, these drugs often do not produce equivalent results in human clinical trials. Here, we show how different animal models infected with some of the most clinically relevant SARS-CoV-2 variants, WA1/2020, B.1.617.2/Delta, B.1.1.529/Omicron, and BA5.2/Omicron, have independent outcomes. We show that in K18-hACE2 mice, B.1.617.2 is more pathogenic, followed by WA1, while B.1.1.529 showed an absence of clinical signs. Only B.1.1.529 was able to infect C57BL/6J mice, which lack the human ACE2 receptor. B.1.1.529-infected C57BL/6J mice had different T cell profiles compared to infected K18-hACE2 mice, while viral shedding profiles and viral titers in lungs were similar between the K18-hACE2 and the C57BL/6J mice. These data suggest B.1.1.529 virus adaptation to a new host and shows that asymptomatic carriers can accumulate and shed virus. Next, we show how B.1.617.2, WA1 and BA5.2/Omicron have similar viral replication kinetics, pathogenicity, and viral shedding profiles in hamsters, demonstrating that the increased pathogenicity of B.1.617.2 observed in mice is host-dependent. Overall, these findings suggest that small animal models are useful to parallel human clinical data, but the experimental design places an important role in interpreting the data. Importance: There is a need to investigate SARS-CoV-2 variant phenotypes in different animal models due to the lack of reproducible outcomes when translating experiments to the human population. Our findings highlight the correlation of clinically relevant SARS-CoV-2 variants in animal models with human infections. Experimental design and understanding of correct animal models are essential to interpreting data to develop antivirals, vaccines, and other therapeutic compounds against COVID-19.

Proposed Solutions for Improving Maternal Health Care in Rural America.

Increasing hospital and labor & delivery (L&D) closures have led to declining access to hospital obstetric care in rural areas across the country. These closures increase the burden on women and families living in rural communities, who often must drive long distances for prenatal visits and delivery. The lack of maternal health care in rural America can also result in several adverse maternal and infant outcomes including premature birth, low birth weight, out of hospital births, maternal and infant morbidity and mortality, and increased risk of postpartum depression. The reasons for these closures are multifactorial, and include, workforce shortages, financial viability, low volume of patients, concerns over maintaining the knowledge base and skill sets of the obstetrical health care team required to provide high quality and safe care, as well as medical-legal concerns. The problems of providing and accessing quality maternal and obstetrical care in rural America have not happened overnight, Likewise, the solutions to these problems will also not occur overnight and must also address the multifactorial nature of the problem. However, there are several opportunities to improve access to maternal health care in rural communities. Programs, policies, and funding need to be designed and provided to make these opportunities a reality.

ablación de fibrilación auricular como tratamiento de primera línea: revisión de la literatura / Ablation as a first line treatment for atrial fibrillation: a review

RESUMEN La ablación con radiofrecuencia (RF) o con Criobalón (CRIO) en pacientes con fibrilación auricular (FA) paroxística y persistente es un tratamiento seguro y eficaz en pacientes seleccionados. Datos recientes demuestran que la ablación proporciona mejores resultados en comparación con fármacos antiarrítmicos (FAA) en el tratamiento de la FA temprana. Los estudios que comparan RF y CRIO mostraron una eficacia y seguridad comparables en el aislamiento de venas pulmonares (PVI) para pacientes con FA paroxística sintomática. OBJETIVOS: Revisar estudios clínicos que comparan el tratamiento de la FA con ablación versus FAA como terapia de primera línea en pacientes con FA sin tratamiento previo. La eficacia y la seguridad se compararán entre las dos cohortes y entre los subgrupos. MÉTODO: Se incluye un total de 6 estudios en los que participaron 1212 pacientes con FA: 609 pacientes fueron aleatorizados a ablación de FA y 603 a tratamiento farmacológico En comparación con el tratamiento con FAA, la ablación se asoció con una reducción en la recurrencia de arritmias auriculares (32,3 % frente a 53 %; riesgo relativo [RR], 0,62; IC del 95 %, 0,51-0,74; P < 0,001; I 2 = 40 %, NNT: 5). El uso de ablación también se asoció con una reducción de las arritmias auriculares sintomáticas (11,8 % frente a 26,4 %; RR, 0,44; IC del 95 %, 0,27-0,72; P = 0,001; I 2 = 54%) y hospitalización (5,6% vs 18,7%; RR, 0,32; IC 95%, 0,19-0,53; P< 0,001) sin diferencias significativas en los eventos adversos graves entre los grupos (4,2 % frente a 2,8 %; RR, 1,52; IC del 95 %, 0,81-2,85; P = 0,19). CONCLUSIÓN: En pacientes con FA paroxística, una estrategia de control precoz del ritmo cardíaco, se asocia con una mayor probabilidad de supervivencia, menos procedimientos repetidos, menos hospitalizaciones y, probablemente, una disminución en la progresión a FA persistente.

INTRODUCTION: Radiofrequency (RF) or cryoballoon (CRYO) ablation in patients with paroxysmal and persistent atrial fibrillation (AF) are safe and effective treatments in selected patients. Recent data show that ablation provides better results compared to antiarrhythmic drugs (AAD) in the treatment of early AF. Studies comparing RF and CRYO showed comparable efficacy and safety in pulmonary vein isolation (PVI) for patients with symptomatic paroxysmal AF. OBJETIVES: Review of clinical trials comparing treatment of AF with ablation versus AAD as first-line therapy in patients with AF with no previous treatment. Efficacy and safety are compared between the two cohorts and between subgroups. METHODS: A total of 6 studies involving -212 AF patients were included: 609 were randomized to AF ablation and 603 to pharmacological treatment. Ablation, compared with AAD, was associated with a reduction in recurrence of atrial arrhythmias (32.3% vs. 53%; relative risk [RR], 0.62; 95% CI, 0.51-0.74, P< 0.001, I2 = 40%, NNT: 5). The use of ablation was also associated with a reduction in symptomatic atrial arrhythmias (11.8% vs. 26.4%; RR, 0.44; 95% CI, 0.27-0.72; P= 0.001; I2 = 54%) and hospitalization (5.6% vs 18.7%; RR, 0.32; 95% CI, 0.19-0.53; P <0.001) with no significant differences in major adverse events (4.2% vs. 2.8%; RR, 1.52; 95% CI, 0.81-2.85; P=0.19). CONCLUSION: In patients with paroxysmal AF, an early cardiac rhythm control with ablation is associated with a higher probability of survival, fewer repeat procedures, fewer hospitalizations, and probably a decrease in progression to persistent AF.

Effects of dance in older adults at risk of falls. Exploratory review.

INTRODUCTION: Falls are considered a public health problem in older adults, and their approach should be multidimensional. Dance emerges as an intervention option that allows different schemes to be integrated in movement enhancement. OBJECTIVE: To determine the effects of dance on balance, motor function and activities of daily living in older adults at risk of falling. METHODS: Exploratory review of the effects of dance in older adults at risk of falling in terms of balance, gait, motor function and activities of daily living. Searches were carried out in PubMed, LILACS, Cochrane Central Register of Controlled Trials, PEDro, OTSeeker, full text articles were searched in different virtual libraries (ProQuest, Ovid, Ebsco, Science Direct) and manual search was also carried out. RESULTS: Nineteen studies were found, which report sessions of 45 to 60 minutes for 12 weeks. Dance can be considered a safe intervention that significantly decreases control intervention for balance and gait in older adults. CONCLUSIONS: The results of this work support that dance can be used as an interventional option in older adults at risk of falling.

INTRODUCCIÓN: Las caídas se consideran un problema de salud pública en los adultos mayores y su abordamiento debería ser multidimensional. La danza surge como una opción de intervención que permite integrar diferentes esquemas en la potenciación del movimiento. OBJETIVO: Determinar los efectos de la danza a nivel de equilibrio, función motora y actividades de la vida diaria en adultos mayores con riesgo de caer. MÉTODOS: Revisión exploratoria en torno a cuáles son los efectos de la danza en adultos mayores con riesgo de caer para mejor el equilibrio, la marcha, la función motora y las actividades de la vida diaria. Las búsquedas se llevaron a cabo en PubMed, LILACS, Registro Central Cochrane de Ensayos Clínicos Controlados, PEDro, OTSeeker, artículos en texto completo en las diferentes bibliotecas virtuales (ProQuest, Ovid, Ebsco, Science Direct) y búsqueda manual. RESULTADOS: Se encontraron 19 estudios que reportan sesiones de 45 a 60 minutos durante 12 semanas. La danza puede considerarse una intervención segura que disminuye significativamente la intervención de control para equilibrio y marcha en adultos mayores. CONCLUSIONES: Los resultados de este trabajo sustentan que se puede emplear la danza como una opción interventiva en adultos mayores que presentan riesgo de caer.

Efectos de la danza en adultos mayores con riesgo de caídas. Revisión exploratoria / Effects of dance in older adults at risk of falls. Exploratory review

Resumen Introducción: Las caídas se consideran un problema de salud pública en los adultos mayores y su abordamiento debería ser multidimensional. La danza surge como una opción de intervención que permite integrar diferentes esquemas en la potenciación del movimiento. Objetivo: Determinar los efectos de la danza a nivel de equilibrio, función motora y actividades de la vida diaria en adultos mayores con riesgo de caer. Métodos: Revisión exploratoria en torno a cuáles son los efectos de la danza en adultos mayores con riesgo de caer para mejor el equilibrio, la marcha, la función motora y las actividades de la vida diaria. Las búsquedas se llevaron a cabo en PubMed, LILACS, Registro Central Cochrane de Ensayos Clínicos Controlados, PEDro, OTSeeker, artículos en texto completo en las diferentes bibliotecas virtuales (ProQuest, Ovid, Ebsco, Science Direct) y búsqueda manual. Resultados: Se encontraron 19 estudios que reportan sesiones de 45 a 60 minutos durante 12 semanas. La danza puede considerarse una intervención segura que disminuye significativamente la intervención de control para equilibrio y marcha en adultos mayores. Conclusiones: Los resultados de este trabajo sustentan que se puede emplear la danza como una opción interventiva en adultos mayores que presentan riesgo de caer.

Abstract Introduction: Falls are considered a public health problem in older adults, and their approach should be multidimensional. Dance emerges as an intervention option that allows different schemes to be integrated in movement enhancement. Objective: To determine the effects of dance on balance, motor function and activities of daily living in older adults at risk of falling. Methods: Exploratory review of the effects of dance in older adults at risk of falling in terms of balance, gait, motor function and activities of daily living. Searches were carried out in PubMed, LILACS, Cochrane Central Register of Controlled Trials, PEDro, OTSeeker, full text articles were searched in different virtual libraries (ProQuest, Ovid, Ebsco, Science Direct) and manual search was also carried out. Results: Nineteen studies were found, which report sessions of 45 to 60 minutes for 12 weeks. Dance can be considered a safe intervention that significantly decreases control intervention for balance and gait in older adults Conclusions: The results of this work support that dance can be used as an interventional option in older adults at risk of falling.

Ablación y neuromodulación en tormenta arrítmica: serie de 4 casos y revisión de la literatura / Ablation and neuromodulation in arrhythmic storm: a report of 4 cases and literature review

Resumen: Se presenta una serie de 4 casos clínicos de pacientes con y sin cardiopatía estructural, que tuvieron uno o más episodios de tormenta arrítmica. Se describen los tratamientos con sus resultados y una revisión bibliográfica con los avances en el tema más allá de la ablación con catéter.

Abstract: We present 4 clinical cases of patients with and without structural heart disease, who had one or more episodes of arrhythmic storm. Treatments, results and a bibliographic review with advances beyond catheter ablation are described.

The molecular architecture of Drosophila melanogaster defense against Beauveria bassiana explored through evolve and resequence and quantitative trait locus mapping.

Little is known about the genetic architecture of antifungal immunity in natural populations. Using two population genetic approaches, quantitative trait locus (QTL) mapping and evolve and resequence (E&R), we explored D. melanogaster immune defense against infection with the fungus Beauveria bassiana. The immune defense was highly variable both in the recombinant inbred lines from the Drosophila Synthetic Population Resource used for our QTL mapping and in the synthetic outbred populations used in our E&R study. Survivorship of infection improved dramatically over just 10 generations in the E&R study, and continued to increase for an additional nine generations, revealing a trade-off with uninfected longevity. Populations selected for increased defense against B. bassiana evolved cross resistance to a second, distinct B. bassiana strain but not to bacterial pathogens. The QTL mapping study revealed that sexual dimorphism in defense depends on host genotype, and the E&R study indicated that sexual dimorphism also depends on the specific pathogen to which the host is exposed. Both the QTL mapping and E&R experiments generated lists of potentially causal candidate genes, although these lists were nonoverlapping.

The Effects of Water Volume and Bacterial Concentration on the Water Filtration Assay Used in Zebrafish Health Surveillance.

The number of zebrafish in biomedical research has increased exponentially over the past decades, leading to pressure on the laboratory animal community to develop and refine techniques to monitor zebrafish health so that suitable stocks can be maintained for research. The water filtration assay is a promising technique in which water from a zebrafish system is filtered, and the filter analyzed by PCR. In the present report, we studied how the volume of water tested and the concentration of bacterial pathogens affected test results. To do so, we used stock solutions of 3 zebrafish pathogens: Edwardsiella ictaluri, Aeromonas hydrophila, and Mycobacterium marinum. We used these stocks to create solutions with known concentrations of each pathogen, ranging between 10² and 107 Colony Forming Units (CFU) per ml. One, 2, and 3 L of each solution was filtered using positive pressure, and the filters were submitted to a commercial lab for PCR testing. Results were fit with a logistic regression model, and the probability of obtaining a positive result were calculated. Test sensitivity varied by organism, but in general, test results were positively correlated with the volume of the water filtered and with the concentration of bacteria in solution. We conclude that a positive result can be expected for E. ictaluri at 105 CFU per mL, A. hydrophila at 106 CFU per ml, and M. marinum at 106 CFU per mL, when 3 L of solution are filtered.

Reproductive Health Risks Associated with Occupational and Environmental Exposure to Pesticides.

A marked reduction in fertility and an increase in adverse reproductive outcomes during the last few decades have been associated with occupational and environmental chemical exposures. Exposure to different types of pesticides may increase the risks of chronic diseases, such as diabetes, cancer, and neurodegenerative disease, but also of reduced fertility and birth defects. Both occupational and environmental exposures to pesticides are important, as many are endocrine disruptors, which means that even very low-dose exposure levels may have measurable biological effects. The aim of this review was to summarize the knowledge collected between 2000 and 2020, to highlight new findings, and to further interpret the mechanisms that may associate pesticides with infertility, abnormal sexual maturation, and pregnancy complications associated with occupational, environmental and transplacental exposures. A summary of current pesticide production and usage legislation is also included in order to elucidate the potential impact on exposure profile differences between countries, which may inform prevention measures. Recommendations for the medical surveillance of occupationally exposed populations, which should be facilitated by the biomonitoring of reduced fertility, is also discussed.

Maternal Food and Beverage Consumption Behaviors and Discrepant Phthalate Exposure by Race.

Background: Differential exposure to endocrine-disrupting chemicals, including phthalate diesters, may contribute to persistent racial/ethnic disparities in women's reproductive health outcomes. We sought to characterize sources of gestational exposure to these agents that may differ according to maternal race. Methods: We enrolled pregnant Black (n = 198), including African American, and White (n = 197) women during the second trimester, and measured eight phthalate monoester metabolites in urine. We assessed confounder-adjusted associations between multiple food and beverage consumption habits, summarized using a principal component analysis, as predictors of maternal urinary phthalate metabolite levels, stratified by race. Results: Whites reported significantly greater unprocessed food consumption (42.5% vs. 32.0%; p < 0.001) and storage of food in clear unbreakable plastic containers (66.5% vs. 49.3%; p < 0.001) than Blacks, while Blacks consumed more canned fruits and vegetables (23.5% vs. 12.2%; p < 0.001) than Whites. Using plastics for food storage, microwaving in plastic containers, and using hard plastic water bottles was associated with urinary phthalate concentrations, especially DEHP metabolites (e.g., mean difference = 5.13%; 95% CI: 3.05, 7.25). These associations were driven primarily by Black pregnant women. Conclusions: Targeted interventions to reduce maternal exposure to phthalates need to be designed with specific attention to differences in food and beverage consumption behaviors among Black and White women.

Associations Between Speech Perception, Vocabulary, and Phonological Awareness Skill in School-Aged Children With Speech Sound Disorders.

Purpose Prior studies report conflicting descriptions of the relationships between phonological awareness (PA), vocabulary, and speech perception in preschoolers with speech disorders. This study sought to determine the nature of these relationships in a sample of school-aged children with residual speech sound errors affecting /ɹ/. Method Participants included 110 children aged 7;0-17;4 (years;months) with residual errors impacting /ɹ/. Data on perceptual acuity and perceptual bias in an /ɹ/ identification task, receptive vocabulary, and PA were obtained. A theoretically and empirically motivated path model was constructed with vocabulary mediating the relationship between two measures of speech perception and PA. Model parameters were determined through maximum likelihood estimation with standard errors that were robust to nonnormality. Monte Carlo simulation was used to examine achieved power at the current sample size. Results The saturated path model explained 19% of the variance in PA. The direct path between age-adjusted perceptual acuity and PA was significant, as was the direct path between vocabulary and PA. Contrary to our hypothesis, there was no evidence in the current sample that vocabulary skill mediated the relationship between speech perception and PA. Each individual path was adequately powered at the current sample size. Conclusions The overall model provided evidence for a continued relationship between speech perception, measured by perceptual acuity of the sound in error, and PA in school-aged children with residual speech errors. Thus, measures of speech perception remain relevant to the assessment of school-aged children and adolescents in this population. Supplemental Material https://doi.org/10.23641/asha.13641275.

Generation of genetically tailored porcine liver cancer cells by CRISPR/Cas9 editing.

Pigs provide a valuable large animal model for several diseases due to their similarity with humans in anatomy, physiology, genetics and drug metabolism. We recently generated a porcine model for TP53R167H and KRASG12D driven hepatocellular carcinoma (HCC) by autologous liver implantation. Here we describe a streamlined approach for developing genetically tailored porcine HCC cells by CRISPR/Cas9 gene editing and isolation of homogenous genetically validated cell clones. The combination of CRISPR/Cas9 editing of HCC cells described herein with the orthotopic HCC model enables development of various porcine HCC models, each with a specific mutational profile. This allows modeling the effect of different driver mutation combinations on tumor progression and in vivo testing of novel targeted therapeutic approaches in a clinically relevant large animal model.

Development and comprehensive characterization of porcine hepatocellular carcinoma for translational liver cancer investigation.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. New animal models that faithfully recapitulate human HCC phenotypes are required to address unmet clinical needs and advance standard-of-care therapeutics. This study utilized the Oncopig Cancer Model to develop a translational porcine HCC model which can serve as a bridge between murine studies and human clinical practice. Reliable development of Oncopig HCC cell lines was demonstrated through hepatocyte isolation and Cre recombinase exposure across 15 Oncopigs. Oncopig and human HCC cell lines displayed similar cell cycle lengths, alpha-fetoprotein production, arginase-1 staining, chemosusceptibility, and drug metabolizing enzyme expression. The ability of Oncopig HCC cells to consistently produce tumors in vivo was confirmed via subcutaneous (SQ) injection into immunodeficient mice and Oncopigs. Reproducible development of intrahepatic tumors in an alcohol-induced fibrotic microenvironment was achieved via engraftment of SQ tumors into fibrotic Oncopig livers. Whole-genome sequencing demontrated intrahepatic tumor tissue resembled human HCC at the genomic level. Finally, Oncopig HCC cells are amenable to gene editing for development of personalized HCC tumors. This study provides a novel, clinically-relevant porcine HCC model which holds great promise for improving HCC outcomes through testing of novel therapeutic approaches to accelerate and enhance clinical trials.

Application of systematic evidence mapping to assess the impact of new research when updating health reference values: A case example using acrolein.

BACKGROUND: The environmental health community needs transparent, methodologically rigorous, and rapid approaches for updating human health risk assessments. These assessments often contain reference values for cancer and/or noncancer effects. Increasingly, the use of systematic review methods are preferred when developing these assessments. Systematic evidence maps are a type of analysis that has the potential to be very helpful in the update process, especially when combined with machine-learning software advances designed to expedite the process of conducting a review. OBJECTIVES: To evaluate the applicability of evidence mapping to determine whether new evidence is likely to result in a change to an existing health reference value, using inhalation exposure to the air pollutant acrolein as a case example. METHODS: New literature published since the 2008 California Environmental Protection Agency's Office of Environmental Health Hazard Assessment (OEHHA) Reference Exposure Level (REL) for acrolein was assessed. Systematic review methods were used to search the literature and screening included the use of machine-learning software. The Populations, Exposures, Comparators and Outcomes (PECO) criteria were kept broad to identify studies that characterized acute and chronic exposure and could be informative for hazard characterization. Studies that met the PECO criteria after full-text review were briefly summarized before their suitability for chronic point of departure (POD) derivation and calculation of a reference value was considered. Studies considered potentially suitable underwent a targeted evaluation to determine their suitability for use in dose-response analysis. RESULTS: Over 15,000 studies were identified from scientific databases. Both machine-learning and manual screening processes were used to identify 60 studies considered PECO-relevant after full-text review. Most of these PECO-relevant studies were short-term exposure animal studies (acute or less than 1 month of exposure) and considered less suitable for deriving a chronic reference value when compared to the subchronic study in rats used in the 2008 OEHHA assessment. Thirteen epidemiological studies were identified but had limitations in the exposure assessment that made them less suitable for dose-response compared to the subchronic rat study. Among the 13 studies, there were four controlled trial studies that have the potential to be informative for future acute reference value derivation. Thus, the 2008 subchronic rat study used by OEHHA appears to still be the most appropriate study for chronic reference value derivation. In addition, advances in dosimetric modeling for gases, including new evidence pertinent to acrolein, could be considered when updating existing acrolein toxicity values. CONCLUSIONS: Evidence mapping is a very useful tool to assess the need for updating an assessment based on understanding the potential impact of new studies on revising an existing health reference value. In this case example, the focus was to identify studies suitable for chronic exposure dose-response analysis, while also identifying studies that may be important to consider for acute exposure scenarios, hazard identification, or for future research. This allows the evidence map to be a useful resource for a range of decision-making contexts. Specialized systematic review software increased the efficiency of the process in terms of human resources and time to conduct the analysis.

Behavioral Effects of Cage Size and Environmental Enrichment in New Zealand White Rabbits.

One of the goals of environmental enrichment is to encourage species-typical behaviors, while discouraging abnormal behaviors or stereotypies. Assessing the effectiveness of various enrichment modalities can be challenging, particularly for prey species such as rabbits that exhibit freezing responses in the presence of people. In this study, we housed rabbits in 3 different sized cages and observed their behaviors. The 3 cage sizes were our standard rabbit housing cage, a medium sized cage, and a large run. Based on analysis of the recordings, ethograms were constructed and behaviors were quantified. The rabbits in large runs spent more time performing active, exploratory behaviors (431 ± 74 s) than rabbits in the standard cages(184 ± 55 s). However, space constraints inside research facilities often make it impractical to house rabbits in large runs.Therefore, we decided to explore if enrichment devices could promote the expression of active behaviors, similar to those displayed by rabbits housed in the large runs. We selected 3 devices: a hanging toy, a destructible device, and a dig bin. All 3 enrichment devices promoted more time spent performing active, exploratory behaviors (389 ± 48, 463 ± 50, and 420 ± 44 s,respectively), compared with control rabbits housed without an enrichment device (226 ± 53 s). We also analyzed the fecal glucocorticoids of rabbits after shipping or surgery to determine if enrichment devices could mitigate the physiologic impact of these stressors. We found no significant differences in fecal glucocorticoid levels between rabbits that experienced the stressor and rabbits that did not, or between rabbits with or without enrichment devices. Overall, the provision of largercaging and/or addition of enrichment devices encouraged a broad spectrum of active, species-typical rabbit behaviors, suggestiveof improved animal welfare.

Increase in morbidity and mortality in a shipment of red-eared slider turtles (Trachemys scripta elegans).

A cohort of captive-bred red-eared slider turtles, Trachemys scripta, was received from a commercial vendor. Shortly after arrival, several turtles presented as lethargic with subjectively pale skin and multifocal areas of cotton-like tufts in the mouth area and distal extremities. The water was treated with a commercial anti-fungal and anti-bacterial preparation of Victoria Green B and acriflavine. Despite treatment, 10 turtles were euthanized and others demonstrated persistent clinical signs. A live turtle was submitted to a commercial diagnostic laboratory for microbiologic and histologic evaluation. Seven cultures were obtained from this turtle and numerous organisms grew from each culture, including Flavobacterium sp. Blood film analysis demonstrated intracytoplasmic gamonts of Haemogregarina sp. within erythrocytes. On necropsy, internal organs appeared to be slightly more adhered within the coelomic cavity than normal. The urinary bladder was markedly distended with turbid, dark yellow urine. Microscopic evaluation of the tissues revealed significant parasitism with Myxidium sp., Spirorchis sp. and Neopolystoma orbiculare. No fungal organisms were identified on histology or grown in culture. While there are scattered reports of these pathogens in freshwater turtles, none of the cases reported describe such extensive co-infections. It is likely that complicated infection and shipping stress exacerbated clinical signs typically seen with these organisms. Efforts to minimize stress and administration of prophylactic antiparasitic agents during the acclimation period may aid in reducing the consequences of internal parasitism in aquatic turtles.