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The unique predatory, caching, and impaling behaviors of shrikes (Laniidae) may provide these unusual passerines with alternative provisioning strategies compared to other songbirds, but few studies have determined the impact these unique behaviors have on provisioning rates. Our objectives were to compare the provisioning behavior of male and female Loggerhead Shrikes ( Lanius ludovicianus), and determine how their provisioning behavior was influenced by nestling age. The provisioning behavior of six pairs of Loggerhead Shrikes was videotaped from 15 April to 15 August 2004–2007 in Garrard and Madison counties, Kentucky, USA. For each nest visit by a shrike, the sex of the visiting adult, number of prey items delivered, size of prey, type of prey, and the duration of the nest visit were recorded. Adults made 2169 visits to nests, with males (49%) and females (51%) making similar numbers of visits. Males and females differed in time spent at nests, with males spending less time at nests per visit (mean = 12.0 s, N = 1062) than females (77.0 s, N = 1107). Feeding rates did not differ between the sexes, but feeding rates did increase with nestling age. The size of prey delivered to nestlings also tended to increase with nestling age. Invertebrates comprised 65% of the identified prey items, and cached items made up the remaining 35%. Although many passerine species increase provisioning rates as nestling demand increases, the caching behavior of shrikes may allow adults to reliably increase both feeding rates and prey size as nestling age and demand increase as well as act as buffers when prey availability declines. The caching behavior of shrikes provides them with parental provisioning strategies not available to non-caching songbirds.

OBJECTIVES National guidelines generally recommend 24 hours or less of surgical antibiotic prophylaxis. In a freestanding, regional children’s hospital, we evaluated the duration of antibiotic surgical prophylaxis to identify targets for standardization of practice. METHODS All procedures performed in 2017 were extracted from our local data warehouse; those involving an incision were considered a surgical procedure and correlated to antibiotic data. Antibiotic courses were reviewed if administered for >24 hours, or if the duration or indication for prophylaxis was uncertain. Total duration of prophylaxis (including discharge prescriptions) was calculated in hours for all procedures and categorized by department and by the quantity of prophylaxis received: none, single dose, multiple doses within 24 hours, and >24 hours. Percentage of procedures and total days of potential excess were calculated. RESULTS A total of 15 651 procedures were included; 5009 met criteria for chart review, and after further exclusions, 12 895 procedures were included in the analysis. In total, 55% of all 12 895 procedures received prophylaxis. A single dose was given in 30%. Over 24 hours was administered in 11%, and 14% received multiple doses CONCLUSION In 2017, up to 25% of procedures received potentially unnecessary perioperative prophylaxis, indicating that national guidance specific to pediatrics would have high impact on antibiotic overuse in the pediatric surgical population.

Introduction Success of split-thickness skin grafting (STSG) is a cornerstone of modern burn care and sets the stage for success in acute, rehabilitative and reconstructive care. Shupp et al, proposed a graft loss grading system, which the authors then modified to reflect true clinical practice and changes in management. Purpose of the quality improvement (QI) project was to design, implement and assess this grading system. Methods A modified graft loss grading system was developed and implemented. Burn patients requiring STSG were tracked over a five month period, and initial (first takedown) and subsequent (either outpatient or 7 days after initial assessment) graft loss grades and contributing factors were noted. Assessments were performed an APP and burn surgeon with agreement of an assigned grade. Patient demographic data was recorded. Results 63 patients underwent 66 STSG procedures during the review period (44 males, 19 females). Average age was 33.3 years (range: 1-86). Average % TBSA burn was 10.2% (range 0.2-67%). Obesity was present in 33.3% of patients, cardiac disease (hypertension, coronary artery disease or congestive heart failure) in 21.2%, DM in 21.2% and 24.2% of patients were active smokers. Flame burns represented the etiology in the majority (51.5%) of patients. Overall, 10 patients (16%) on initial assessment and 18 patients (29%) on subsequent assessment had evidence of graft loss. Etiology of graft loss included wound bed viability - the default etiology (10 patients/55%), infection (3 patients/17%) and hematoma/seroma (4 patients/22%). Of the 18 patients, 5 (28%) required re-grafting. Of patients with graft loss, 89% had a comorbidity including DM (28%) and smoking history (28%). Malnutrition was felt to contribute in 3 (17%) of patients. Conclusions A graft loss grading system is a beneficial quality improvement project to characterize the surgical results of burn patients undergoing STSG. This modified grading system better characterizes graft loss outcomes and subsequent changes in management if applicable. Wound bed viability remains a major factor in graft loss, although the majority of these patients had a contributing comorbidity. Applicability of Research to Practice Implementation of a graft loss grading system can be a valuable quality improvement tool that can be employed by burn centers to assessment surgical results.

Background/aim Anticancer peptide PNC-27 binds to HDM-2 protein on cancer cell membranes inducing the formation of cytotoxic transmembrane pores. Herein, we investigated HDM-2 membrane expression and the effect of PNC-27 treatment on human non-stem cell acute myelogenous leukemia cell lines: U937, acute monocytic leukemia; OCI-AML3, acute myelomonocytic leukemia and HL60, acute promyelocytic leukemia. Materials and methods We measured cell surface membrane expression of HDM-2 using flow cytometry. Cell viability was assessed using MTT assay while direct cytotoxicity was measured by lactate dehydrogenase (LDH) release and induction of apoptotic markers annexin V and caspase-3. Results HDM-2 is expressed at high levels in membranes of U937, OCI-AML3 and HL-60 cells. PNC-27 can bind to membrane HDM-2 to induce cell necrosis and LDH release within 4 h. Conclusion Targeting membrane HDM-2 can be a potential strategy to treat leukemia. PNC-27 targeting membrane HDM-2 demonstrated significant anti-leukemia activity in a variety of leukemic cell lines.

Elucidation of predictive fluidic biochemical markers to detect and monitor chemical-induced neurodegeneration has been a major challenge due to a lack of understanding of molecular mechanisms driving altered neuronal morphology and function, as well as poor sensitivity in methods to quantify low-level biomarkers in bodily fluids. Here, we evaluated 5 neurotoxicants (acetaminophen [negative control], bisindolylmaleimide-1, colchicine, doxorubicin, paclitaxel, and rotenone) in human-induced pluripotent stem cell-derived neurons to profile secreted microRNAs (miRNAs) at early and late stages of decline in neuronal cell morphology and viability. Based on evaluation of these morphological (neurite outgrowth parameters) and viability (adenosine triphosphate) changes, 2 concentrations of each chemical were selected for analysis in a human 754 miRNA panel: a low concentration with no/minimal effect on cell viability but a significant decrease in neurite outgrowth, and a high concentration with a significant decrease in both endpoints. A total of 39 miRNAs demonstrated significant changes (fold-change ≥ 1.5 or ≤ 0.67, p value < .01) with at least 1 exposure. Further analyses of targets modulated by these miRNAs revealed 38 key messenger RNA targets with roles in neurological dysfunctions, and identified transforming growth factor-beta (TGF-β) signaling as a commonly enriched pathway. Of the 39 miRNAs, 5 miRNAs, 3 downregulated (miR-20a, miR-30b, and miR-30d) and 3 upregulated (miR-1243 and miR-1305), correlated well with morphological changes induced by multiple neurotoxicants and were notable based on their relationship to various neurodegenerative conditions and/or key pathways, such as TGF-β signaling. These datasets reveal miRNA candidates that warrant further evaluation as potential safety biomarkers of chemical-induced neurodegeneration.

Drug-induced neurotoxicity is a leading cause of safety-related attrition for therapeutics in clinical trials, often driven by poor predictivity of preclinical in vitro and in vivo models of neurotoxicity. Over a dozen different iPSC-derived 3D spheroids have been described in recent years, but their ability to predict neurotoxicity in patients has not been evaluated nor compared with the predictive power of nonclinical species. To assess the predictive capabilities of human iPSC-derived neural spheroids (microBrains), we used 84 structurally diverse pharmaceuticals with robust clinical and pre-clinical datasets with varying degrees of seizurogenic and neurodegenerative liability. Drug-induced changes in neural viability and phenotypic calcium bursts were assessed using 7 endpoints based on calcium oscillation profiles and cel-lular ATP levels. These endpoints, normalized by therapeutic exposure, were used to build logistic regression models to establish endpoint cutoffs and evaluate probability for clinical neurotoxicity. The neurotoxicity score calculated from the logistic regression model could distinguish neurotoxic from non-neurotoxic clinical molecules with a specificity as high as 93.33% and a sensitivity of 53.49%, demonstrating a very low false positive rate for the prediction of seizures, convulsions, and neurodegeneration. In contrast, nonclinical species showed a higher sensitivity (75%) but much lower specificity (30.4%). The neural spheroids demonstrated higher likelihood ratio positive and inverse likelihood ratio neg-ative values compared with nonclinical safety studies. This assay has the potential to be used as a predictive assay to detect neurotoxicity in early drug discovery, aiding in the early identification of compounds that eventually may fail due to neurotoxicity.

Introduction Burn is not a required rotation for general surgery residency training. Additionally, mandates on resident work hours have created a deficiency in resident support for many burn programs across the country. Subsequently, the need to transition to an Advanced Practice Provider (APP) service was identified. At our institution, a medium volume (~250 admissions/year) burn center, we created an APP service and evaluated the evolution and lessons learned during the transition. Methods Timeline of recruitment of APPs was reviewed along with the recruitment process, onboarding process and orientation process. Exit interviews were conducted with all APPs who resigned to delineate strengths and weakness of the APP program. Functionality of the institution’s APP recruiter, manager and Lead Burn APP (LAPP) were reviewed as well. Results Between 2014 and 2021 the daytime burn APP service expanded from two to six APPs and the Night House Officer (NHO) APP service was created and expanded to four APPs. Based on thorough review of the APP program, key changes were made including improvements in team communication, daily nurse-driven rounds, the 90-day focused professional performance evaluation (FPPE), enhanced and structured education, and critical care exposure. The need for a LAPP was identified and designated in 2019. The LAPP is responsible for making an equitable schedule, execution of new APP orientation, organizing the 90 day FPPE and ongoing professional performance evaluation (OPPE), monthly APP peer review and APP meetings, coordinating OR coverage, and functioning as an APP advocate at division leadership. The LAPP enacted changes to the existing hiring/onboarding process as described below. All APPs are now recruited through an APP recruiter who discusses the hospital contract and salary as well as organizes the logistics of the interview, formalizes the offer, and aids with the transition to credentialing. All new APPs are given a hospital onboarding checklist, that includes hospital orientation, APP boot camp, simulation and electronic health record training classes. In addition they are given a clinical orientation checklist, which includes BLS/ABLS/ACLS/ATLS certification, exposure to various phases of patient care, tracking of quantitative patient care metrics, participation in monthly burn APP peer review and burn triage simulation. There are subtle differences with the NHO APP clinical checklist. After 90 days of employment a new employee FPPE is held with the LAPP and burn director. This allows for direction of areas to focus on, comprehensive feedback, and discussion about increasing autonomy. Conclusions Through a focused process, APPs can play an integral role in the daily functioning of a burn center. We believe that a similar effective and financially sound model can be created for similar sized units.

Birth seasonality is a phenomenon whereby populations can be characterized by a single month or season in which births peak. While non-human animal research suggests that seasonal birth-pulses are related to variation in climate and local energy availability, social scientists debate the mechanisms responsible for it in humans. Here we investigate the role of precipitation, temperature, and energy availability on seasonal conception and birth pulses using a historical dataset from the Baja California peninsula - a hot, arid desert that experiences seasonal climatic fluctuations associated with the North American Monsoon. Analyses suggest that 1) local energy availability had a negative relationship with conception pulses; and 2) birth pulses had a positive relationship with local energy availability and a negative relationship with temperature. Taken together, our analyses suggest that women timed conceptions when local energy availability was lowest (challenging expectations of conception rates as simply reflecting ecological influences on female fecundity), so that children were born during the seasonal "green-up" associated with the North American Monsoon. Given our results, we speculate that birth seasonality represents a form of traditional ecological knowledge to improve neonate health and wellbeing.

Introduction: Patients with neurofibromatosis type 1 (NF1) are at risk of developing phaeochromocytomas/paragangliomas (PHAEO/PG). Unlike in other familial PHAEO/PG syndromes, there are no published guidelines regarding screening in asymptomatic or normotensive patients with NF1. This strategy may be associated with preventable morbidities in those patients who ultimately present with symptomatic PHAEO/PG. Objective: To describe the mode of presentation and the incidence of adverse clinical outcomes attributed to PHAEO/PG in NF1. Methods: A retrospective study was performed in a tertiary referral centre in collaboration with a national complex NF1 centre. Hospital records and databases between 1998–2018 were searched. Results: Twenty-seven patients with NF1 and PHAEO/PG were identified. In all but one, PHAEO/PG was diagnosed after NF1. The median age at the time of diagnosis of PHAEO/PG was 43 years (range 22–65) and 21/27 (78%) were females. The diagnosis was mostly incidental in 13/27 (48%) while classical PHAEO/PG symptoms were found in 15/27 (56%), and hypertension was found in 14/27 (52%) of NF1 patients prior to PHAEO/PG diagnosis. No patient had undergone biochemical screening for PHAEO/PG. Metastatic disease was evident in 2/27 patients, 8 suffered potentially avoidable complications attributed to PHAEO/PG (including two deaths). Conclusion: The course of PHAEO/PG in NF1 is associated with an unpredictable presentation and potentially avoidable adverse outcomes. We recommend that routine biochemical screening for PHAEO/PG should be part of the care package offered to all patients with NF1 by regular measurements of plasma free or urinary fractionated metanephrines starting from early adolescence and repeated every 3 years.

Background Community health workers (CHWs) provide preventive care and integrated community case management (iCCM) to people with low healthcare access worldwide. CHW programmes have helped reduce mortality in myriad countries, but little data on malaria supply chain management has been shared. This project evaluated the current composition, use, and delivery of malaria iCCM kit commodities in Mozambique—rapid diagnostic tests (RDTs) and artemether–lumefantrine (AL) treatments—to better tailor existing resources to the needs of CHWs in diverse practice settings. Methods Health facilities in Maputo (low malaria burden), Inhambane (moderate), and Nampula (high) Provinces were selected using probability proportionate to the number of CHWs at each facility. All CHWs and their supervisors at selected facilities were interviewed using a structured questionnaire to document experiences with kit commodities. Data were analysed to assess CHW commodity stock levels by province and season. Results In total, 216 CHWs and 56 supervisors were interviewed at 56 health facilities. CHWs reported receiving an average of 6.7 kits in the last year, although they are intended to receive kits monthly. One-tenth of CHWs reported receiving kits with missing RDTs, and 28% reported lacking some AL treatments. Commodity use was highest in the rainy season. Stockouts were reported by CHWs in all provinces, more commonly in the rainy season. Facility-level stockouts of RDTs or some AL formulation in the past year were reported by 66% of supervisors. Use of CHW kit materials by health facilities was reported by 43% of supervisors; this was most common at facilities experiencing stockouts. Conclusions Variations in geographic and seasonal malaria commodity needs should be considered in CHW kit distribution planning in Mozambique. Improvements in provision of complete, monthly CHW kits are needed in parallel with improvements in the broader commodity system strengthening. The findings of this evaluation can help other CHW programmes determine best practices for management of iCCM supply chains. Electronic supplementary material The online version of this article (10.1186/s12936-019-2682-5) contains supplementary material, which is available to authorized users.

Exposure to environmental chemicals has been shown to have an impact on the epigenome. One example is a known human carcinogen 1,3-butadiene which acts primarily by a genotoxic mechanism, but also disrupts the chromatin structure by altering patterns of cytosine DNA methylation and histone modifications. Sex-specific differences in 1,3-butadiene-induced genotoxicity and carcinogenicity are well established; however, it remains unknown whether 1,3-butadiene-associated epigenetic alterations are also sex-dependent. Therefore, we tested the hypothesis that inhalational exposure to 1,3-butadiene will result in sex-specific epigenetic alterations. DNA damage and epigenetic effects of 1,3-butadiene were evaluated in in liver, lung, and kidney tissues of male and female mice of two inbred strains (C57BL/6J and CAST/EiJ). Mice were exposed to 0 or 425 ppm of 1,3-butadiene by inhalation (6 hr/day, 5 days/week) for 2 weeks. Strain- and tissue-specific differences in 1,3-butadiene-induced DNA adducts and crosslinks we detected in the liver, lung and kidney; however, significant sex-specific differences in DNA damage were observed in the lung of C57BL/6J mice only. In addition, we assessed expression of the DNA repair genes and observed a marked up-regulation of Mgmt in the kidney in female C57BL/6J mice. Sex-specific epigenetic effects of 1,3-butadiene exposure were evident in alterations of cytosine DNA methylation and histone modifications in the liver and lung in both strains. Specifically, we observed a loss of cytosine DNA methylation in the liver and lung of male and female 1,3-butadiene-exposed C57BL/6J mice, whereas hypermethylation was found in the liver and lung in 1,3-butadiene-exposed female CAST/EiJ mice. Our findings suggest that strain and sex-specific effects of 1,3-butadiene on the epigenome may contribute to the known differences in cancer susceptibility.

Racial disparities in access to kidney transplantation (KTX) among African Americans (AAs) have been attributed in part to insufficient patient education. Interventions are needed to provide AAs with culturally sensitive, understandable information that increases their capacity to pursue KTX. Research about the factors that activated patients to pursue KTX is necessary to inform such interventions; however, few studies have yielded this type of information. We conducted focus groups and one-on-one interviews with 26 AA referred, listed, or transplanted patients and 3 nephrologists to explore decisional factors that foster pursuit of KTX. Interviews were recorded and transcribed, and qualitative analytic methods to identify themes and subthemes were applied in an effort to inform message content for a future educational video intervention. Three themes emerged from thematic content analysis: (1) healthcare provider communication, (2) exposure to peer transplant success, and (3) family encouragement. Enabling provider communication techniques include repetition about the KTX option, optimistic messaging about KTX access, and comforting conversations about the KTX process. We identified information based on patient views and experiences to help inspire and develop animated videos designed to activate patients towards KTX. Interventions are needed that address informational gaps and focus on emotion to improve patients’ experiences and ability to understand transplant opportunities.

Introduction Burn peer review (PR) is an important process for quality assurance and process improvement. Our division consists of five burn surgeons, seven advanced practice providers (APPs) and four night house officer (NHO) APPs. As the APPs are intimately integrated within the burn service - both on the inpatient (IP) and outpatient (OP) settings, a subsequent need to create an independent peer review process for the APPs was identified. We describe our process and evaluate the results after two years of a monthly APP PR meeting. Methods All data is entered into a quality management software. Triggers for APP PR include complex discharge, inappropriate OP referral, delay in treatment, OP treatment greater than three weeks without surgical intervention, pressure wound, patient discharge with greater than 30 morphine equivalent dose (MED) of narcotic, readmission or unexpected admission from OP clinic, substance abuse, and self referral. Cases with individual improvement opportunities result in real time direct feedback from the director, lead APP, and peers. These may be escalated to the provider’s ongoing professional performance evaluation (OPPE) or trigger a focused professional performance evaluation (FPPE). Systemic issues identified are referred for multidisciplinary discussion in our Performance Improvement/Quality Assurance (PI/QA) process. Complicated issues involving multiple disciplines may trigger a root cause analysis. If an individual or system issue is not identified, a group discussion about process improvement and standardization of practice ensues. Results From initiation of the Burn APP PR process in May of 2019, to September 2021, there were 37 cases reviewed. Twelve were for indicated triggers and 25 for self-referrals. Breakdown of these cases is as follows: outpatient treatment greater than three weeks without surgical intervention (3), readmission or unexpected admission from outpatient clinic (4), delay in treatment impacting clinic course (5). Self referred cases included graft loss (8), cellulitis (3), venous thromboembolic event (2), and wound dressing discussion (2). There were three cases where clinical issues were identified of which one was referred for root cause analysis, and the other two led to real-time education and feedback from the director. Conclusions PR is important to ensure that high quality patient care standards are met. Autonomous APP practice is important for the function of a team, quality of care delivered, professional satisfaction of the APP, and enables financial optimization for burn centers. Creating an independent burn APP peer review process allows for time-sensitive feedback to patient care related events, improves collaboration and practice standardization, and provides an important educational opportunity for the team.

Birth seasonality is a phenomenon whereby populations can be characterized by a single month or season in which births peak. While non-human animal research suggests seasonal birth-pulses are related to variation in climate and local energy availability, social scientists debate the mechanisms responsible for it in humans. Here we investigate the role of precipitation, temperature, and energy availability on seasonal birth pulses using a historical dataset from the Baja California peninsula - a hot, arid desert that experiences seasonal fluctuations in temperature, precipitation, and energy associated with the North American Monsoonal. Analyses suggest that local energy availability (as measured through NDVI) predicts seasonal birth pulses, while temperature and precipitation do not; however, both are indirectly related to it through their direct effects on NDVI. Our analyses demonstrate the importance of local energy availability on human reproductive timing and suggest that human birth seasonality is a form of traditional ecological knowledge.

Purpose Neurofibromatosis 1 (NF1) is an autosomal dominant condition caused by pathogenic variants of the NF1 gene. A markedly increased risk of breast cancer is associated with NF1. We have determined the breast cancer survival and risk of contralateral breast cancer in NF1. Methods We included 142 women with NF1 and breast cancer from five cohorts in Europe and 335 women without NF1 screened for other familial breast cancers. Risk of contralateral breast cancer and death were assessed by Kaplan–Meier analysis with delayed entry. Results One hundred forty-two women with NF1 were diagnosed for breast cancer at a median age of 46.9 years (range 27.0–84.3 years) and then followed up for 1235 person-years (mean = 8.70 years). Twelve women had contralateral breast cancer with a rate of 10.5 per 1000 years. Cumulative risk for contralateral breast cancer was 26.5% in 20 years. Five and 10-year all-cause survival was 64.9% (95% confidence interval [CI] = 54.8–76.8) and 49.8% (95%CI = 39.3–63.0). Breast cancer–specific 10-year survival was 64.2% (95% CI = 53.5–77.0%) compared with 91.2% (95% CI = 87.3–95.2%) in the non-NF1 age-matched population at increased risk of breast cancer. Conclusion Women with NF1 have a substantial contralateral breast cancer incidence and poor survival. Early start of breast cancer screening may be a way to improve the survival.

Gene transcription profiles across tissues are largely defined by the activity of regulatory elements, most of which correspond to regions of accessible chromatin. Regulatory element activity is in turn modulated by genetic variation, resulting in variable transcription rates across individuals. The interplay of these factors, however, is poorly understood. Here we characterize expression and chromatin state dynamics across three tissues—liver, lung, and kidney—in 47 strains of the Collaborative Cross (CC) mouse population, examining the regulation of these dynamics by expression quantitative trait loci (eQTL) and chromatin QTL (cQTL). QTL whose allelic effects were consistent across tissues were detected for 1,101 genes and 133 chromatin regions. Also detected were eQTL and cQTL whose allelic effects differed across tissues, including local-eQTL for Pik3c2g detected in all three tissues but with distinct allelic effects. Leveraging overlapping measurements of gene expression and chromatin accessibility on the same mice from multiple tissues, we used mediation analysis to identify chromatin and gene expression intermediates of eQTL effects. Based on QTL and mediation analyses over multiple tissues, we propose a causal model for the distal genetic regulation of Akr1e1, a gene involved in glycogen metabolism, through the zinc finger transcription factor Zfp985 and chromatin intermediates. This analysis demonstrates the complexity of transcriptional and chromatin dynamics and their regulation over multiple tissues, as well as the value of the CC and related genetic resource populations for identifying specific regulatory mechanisms within cells and tissues., Author summary Genetic variation can drive alterations in gene expression levels and chromatin accessibility, the latter of which defines gene regulatory elements genome-wide. The same genetic variants may associate with both molecular events, and these may be connected within the same causal path: a variant that reduces promoter region chromatin accessibility, potentially by affecting transcription factor binding, may lead to reduced expression of that gene. Moreover, these causal regulatory paths can differ between tissues depending on functions and cellular activity specific to each tissue. We identify cross-tissue and tissue-selective genetic regulators of gene expression and chromatin accessibility in liver, lung, and kidney tissues using a panel of genetically diverse inbred mouse strains. Further, we identify a number of candidate causal mediators of the genetic regulation of gene expression, including a zinc finger protein that helps silence the Akr1e1 gene. Our analyses are consistent with chromatin accessibility playing a role in the regulation of transcription. Our study demonstrates the power of genetically diverse, multi-parental mouse populations, such as the Collaborative Cross, for large-scale studies of genetic drivers of gene regulation that underlie complex phenotypes, as well as identifying causal intermediates that drive variable activity of specific genes and pathways.

Epigenetic effects of environmental chemicals are under intense investigation to fill existing knowledge gaps between environmental/occupational exposures and adverse health outcomes. Chromatin accessibility is one prominent mechanism of epigenetic control of transcription, and understanding of the chemical effects on both could inform the causal role of epigenetic alterations in disease mechanisms. In this study, we hypothesized that baseline variability in chromatin organization and transcription profiles among various tissues and mouse strains influence the outcome of exposure to the DNA damaging chemical 1,3-butadiene. To test this hypothesis, we evaluated DNA damage along with comprehensive quantification of RNA transcripts (RNA-seq), identification of accessible chromatin (ATAC-seq), and characterization of regions with histone modifications associated with active transcription (ChIP-seq for acetylation at histone 3 lysine 27, H3K27ac). We collected these data in the lung, liver, and kidney of mice from two genetically divergent strains, C57BL/6J and CAST/EiJ, that were exposed to clean air or to 1,3-butadiene (~600 ppm) for 2 weeks. We found that tissue effects dominate differences in both gene expression and chromatin states, followed by strain effects. At baseline, xenobiotic metabolism was consistently more active in CAST/EiJ, while immune system pathways were more active in C57BL/6J across tissues. Surprisingly, even though all three tissues in both strains harbored butadiene-induced DNA damage, little transcriptional effect of butadiene was observed in liver and kidney. Toxicologically relevant effects of butadiene in the lung were on the pathways of xenobiotic metabolism and inflammation. We also found that variability in chromatin accessibility across individuals (i.e., strains) only partially explains the variability in transcription. This study showed that variation in the basal states of epigenome and transcriptome may be useful indicators for individuals or tissues susceptible to genotoxic environmental chemicals.

It is well established that genetic variability has a major impact on susceptibility to common diseases, responses to drugs and toxicants, and influences disease-related outcomes. The appreciation that epigenetic marks also vary across the population is growing with more data becoming available from studies in humans and model organisms. In addition, the links between genetic variability, toxicity outcomes and epigenetics are being actively explored. Recent studies demonstrate that gene-by-environment interactions involve both chromatin states and transcriptional regulation, and that epigenetics provides important mechanistic clues to connect expression-related quantitative trait loci (QTL) and disease outcomes. However, studies of Gene×Environment×Epigenetics further extend the complexity of the experimental designs and create a challenge for selecting the most informative epigenetic readouts that can be feasibly performed to interrogate multiple individuals, exposures, tissue types and toxicity phenotypes. We propose that among the many possible epigenetic experimental methodologies, assessment of chromatin accessibility coupled with total RNA levels provides a cost-effective and comprehensive option to sufficiently characterize the complexity of epigenetic and regulatory activity in the context of understanding the inter-individual variability in responses to toxicants.

ObjectiveWe evaluated the usefulness and accuracy of media-reported data for active disaster-related mortality surveillance.MethodsFrom October 29 through November 5, 2012, epidemiologists from the Centers for Disease Control and Prevention (CDC) tracked online media reports for Hurricane Sandy–related deaths by use of a keyword search. To evaluate the media-reported data, vital statistics records of Sandy-related deaths were compared to corresponding media-reported deaths and assessed for percentage match. Sensitivity, positive predictive value (PPV), and timeliness of the media reports for detecting Sandy-related deaths were calculated.ResultsNinety-nine media-reported deaths were identified and compared with the 90 vital statistics death records sent to the CDC by New York City (NYC) and the 5 states that agreed to participate in this study. Seventy-five (76%) of the media reports matched with vital statistics records. Only NYC was able to actively track Sandy-related deaths during the event. Moderate sensitivity (83%) and PPV (83%) were calculated for the matching media-reported deaths for NYC.ConclusionsDuring Hurricane Sandy, the media-reported information was moderately sensitive, and percentage match with vital statistics records was also moderate. The results indicate that online media-reported deaths can be useful as a supplemental source of information for situational awareness and immediate public health decision-making during the initial response stage of a disaster. (Disaster Med Public Health Preparedness. 2017;11:460–466)

Acute aflatoxin exposure can cause death and disease (aflatoxicosis) in humans. Aflatoxicosis fatality rates have been documented to be as high as 40% in Kenya. The inclusion in the diet of calcium silicate 100 (ACCS100), a calcium montmorillonite clay, may reduce aflatoxin bioavailability, thus potentially decreasing the risk of aflatoxicosis. We investigated the efficacy, acceptability and palatability of ACCS100 in a population in Kenya with recurring aflatoxicosis outbreaks. Healthy adult participants were enrolled in this double-blinded, crossover clinical trial in 2014. Following informed consent, participants (n = 50) were randomised to receive either ACCS100 (3 g day−1) or placebo (3 g day−1) for 7 days. Treatments were switched following a 5-day washout period. Urine samples were collected daily and assessed for urinary aflatoxin M1 (AFM1). Blood samples were collected at the beginning and end of the trial and assessed for aflatoxin B1-lysine adducts from serum albumin (AFB1-lys). AFM1 concentrations in urine were significantly reduced while taking ACCS100 compared with calcium carbonate placebo (β = 0.49, 95% confidence limit = 0.32–0.75). The 20-day interval included both the placebo and ACCS100 treatments as well as a washout period. There were no statistically significant differences in reported taste, aftertaste, appearance, colour or texture by treatment. There were no statistically significant differences in self-reported adverse events by treatment. Most participants would be willing to take ACCS100 (98%) and give it to their children (98%). ACCS100 was effective, acceptable and palatable. More work is needed to test ACCS100 among vulnerable populations and to determine if it remains effective at the levels of aflatoxin exposure that induce aflatoxicosis.

Objectives Aqueduct stenosis (AS) and fourth ventricle outflow obstruction are rare associations of neurofibromatosis type 1 (NF1), resulting in ventriculomegaly and hydrocephalus requiring surgical treatment. This study aims to identify the prevalence of AS and its patterns of clinical presentation, aetiology and treatment in the paediatric complex NF1 population. Patients and methods Patients with NF-1 aged 0-18 years were recruited from the Regional Genetic Family Register, following institutional review board approval. Magnetic resonance imaging data and clinical documents were reviewed with respect to clinical presentation, degree of ventriculomegaly, aetiological factors and management of AS and fourth ventricle outflow obstruction. Results 24 of the 233 paediatric patients seen within the NHS highly specialised service for complex NF1 were found to have AS or and fourth ventricle outflow obstruction. This included 13 males and 11 females with a mean age of 9 years 5 months (range 8 months - 17 years). The majority of patients with AS or fourth ventricle outflow obstruction presented with symptoms of raised intracranial pressure associated with ventriculomegaly and/or hydrocephalus (n = 18). However, in 25 % of patients, AS was an incidental finding on MRI and was observed both in the presence (n = 2) and absence (n = 4) of ventriculomegaly. In the majority of cases a single cause of AS was identified (n = 16), of which tectal plate thickening (n = 7) was most frequently observed. The remaining 8 patients had multiple causes of AS, in which tectal plate thickening (n = 7) and aqueductal webs (n = 5) were the most common observations. Surgery was performed on all patients with evidence of raised pressure (n = 8) by performing endoscopic third ventriculostomy (ETV) (n = 5) or ventriculoperitoneal (VP)-shunting (n = 3). Tectal plate thickening was most frequently observed in patients who underwent ETV (n = 3), followed by aqueductal web (n = 1) and T2-signal changes in the tectal plate (n = 1). Patients treated with VP-shunt had 4th ventricle outflow obstruction (n = 2) and a tectal plate tumour (n = 1). Conclusion This study identifies that AS is more prevalent amongst the paediatric complex NF-1 population than previously reported, occurring in 10 % of cases. Our findings demonstrate that AS is most commonly symptomatic in presentation but can be asymptomatic in 25 % of paediatric complex NF1 patients. In this population, AS can occur both in the presence and absence of ventriculomegaly and therefore requires careful monitoring for development of hydrocephalus. In this study, over one third of patients (9 of 24 patients) with AS eventually required treatment.

AimThis study describes the prevalence and severity of perceived fatigue in a young neurofibromatosis type 1 (NF1) population.MethodsEthical approval was obtained and NF1 affected Individuals aged 2–18 years from the Manchester's NF1 clinic invited along with any unaffected siblings. The PedsQL Multidimensional Fatigue Scale Parental and child report was used. This validated measure explores cognitive, physical and sleep/rest domains on a 0–100 scale. Higher scores indicate less fatigue. Fatigue scores in affected children were compared to unaffected siblings after adjusting for age, sex and Index of Multiple Deprivation and with published population standards using z‐scores.ResultsA total of 286 families were invited and 75 affected and 16 siblings participated. There were significant differences between NF1 and controls in the aggregated fatigue core (child report 55 ± 19 vs. 75 (14), P P = 0.001) and the three sub‐domains: cognitive (child 48 ± 27 vs. 75 ± 23, P P P = 0.018). Similar differences were seen when compared with published controls (aggregated child z‐score −1.9 ± 1.4, P P ConclusionThis study suggests that children with NF1 are affected by perceived fatigue when compared with healthy children who do not have NF1.

Neurofibromatosis 1 (NF1) is an autosomal dominant condition caused by pathogenic variants of the NF1 gene. A markedly increased risk of breast cancer is associated with NF1. We have determined the breast cancer survival and risk of contralateral breast cancer in NF1.We included 142 women with NF1 and breast cancer from five cohorts in Europe and 335 women without NF1 screened for other familial breast cancers. Risk of contralateral breast cancer and death were assessed by Kaplan-Meier analysis with delayed entry.One hundred forty-two women with NF1 were diagnosed for breast cancer at a median age of 46.9 years (range 27.0-84.3 years) and then followed up for 1235 person-years (mean = 8.70 years). Twelve women had contralateral breast cancer with a rate of 10.5 per 1000 years. Cumulative risk for contralateral breast cancer was 26.5% in 20 years. Five and 10-year all-cause survival was 64.9% (95% confidence interval [CI] = 54.8-76.8) and 49.8% (95%CI = 39.3-63.0). Breast cancer-specific 10-year survival was 64.2% (95% CI = 53.5-77.0%) compared with 91.2% (95% CI = 87.3-95.2%) in the non-NF1 age-matched population at increased risk of breast cancer.Women with NF1 have a substantial contralateral breast cancer incidence and poor survival. Early start of breast cancer screening may be a way to improve the survival.

Background: Interindividual variability in susceptibility remains poorly characterized for environmental chemicals such as tetrachloroethylene (PERC). Development of population-based experimental models provide a potential approach to fill this critical need in human health risk assessment. Objectives: In this study, we aimed to better characterize the contribution of glutathione (GSH) conjugation to kidney toxicity of PERC and the degree of associated interindividual toxicokinetic (TK) and toxicodynamic (TD) variability by using the Collaborative Cross (CC) mouse population. Methods: Male mice from 45 strains were intragastrically dosed with PERC (1,000mg/kg) or vehicle (5% Alkamuls EL-620 in saline), and time-course samples were collected for up to 24 h. Population variability in TK of S-(1,2,2-trichlorovinyl)GSH (TCVG), S-(1,2,2-trichlorovinyl)-L-cysteine (TCVC), and N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine (NAcTCVC) was quantified in serum, liver, and kidney, and analyzed using a toxicokinetic model. Effects of PERC on kidney weight, fatty acid metabolism–associated genes [Acot1 (Acyl-CoA thioesterase 1), Fabp1 (fatty acid-binding protein 1), and Ehhadh (enoyl-coenzyme A, hydratase/3-hydroxyacyl coenzyme A dehydrogenase)], and a marker of proximal tubular injury [KIM-1 (kidney injury molecule-1)/Hepatitis A virus cellular receptor 1 (Havcr1)] were evaluated. Finally, quantitative data on interstrain variability in both formation of GSH conjugation metabolites of PERC and its kidney effects was used to calculate adjustment factors for the interindividual variability in both TK and TD. Results: Mice treated with PERC had significantly lower kidney weight, higher kidney-to-body weight (BW) ratio, and higher expression of fatty acid metabolism–associated genes (Acot1, Fabp1, and Ehhadh) and a marker of proximal tubular injury (KIM-1/Havcr1). Liver levels of TCVG were significantly correlated with KIM-1/Havcr1 in kidney, consistent with kidney injury being associated with GSH conjugation. We found that the default uncertainty factor for human variability may be marginally adequate to protect 95%, but not more, of the population for kidney toxicity mediated by PERC. Discussion: Overall, this study demonstrates the utility of the CC mouse population in characterizing metabolism–toxicity interactions and quantifying interindividual variability. Further refinement of the characterization of interindividual variability can be accomplished by incorporating these data into in silico population models both for TK (such as a physiologically based pharmacokinetic model), as well as for toxicodynamic responses. https://doi.org/10.1289/EHP5105

Objective The Peace Corps’ disease surveillance for Peace Corps Volunteers (PCVs) was incorporated into an electronic medical records (EMR) system in 2015. We evaluated this EMR-based surveillance system, focusing particularly on malaria as it is deadly but preventable. Materials and Methods In 2016, we administered a survey to Peace Corps Medical Officers (PCMOs), who manage PCVs’ medical care, and semistructured phone interviews to headquarters staff. We assessed the structure of the surveillance system and its utility to stakeholders, evaluated surveillance case definitions for malaria, and compared clinical information in the EMR for malaria cases captured by surveillance during the first half of 2016. Results Of 131 PCMOs, 77 (59%) completed the survey. Of 53 respondents in malaria-endemic nations, 98% believed most PCVs contact them about possible malaria. Of 134 cases with a malaria clinical diagnosis in the EMR between January and August 2016, 58 (43% sensitivity) were reported to the surveillance system by PCMOs. The remaining cases in the surveillance system were added during data cleaning, which is time-intensive. Among the 48 malaria cases identified by surveillance between January and June 2016, positive predictive value was 67%. Discussion Areas for improvement include streamlining PCMO documentation, refining case definitions, and improving data quality. With such improvements, surveillance data can be used to inform epidemiological analysis, clinical care, health education, and policy. Conclusion The EMR is an important tool for malaria surveillance among PCVs and, with the refinements mentioned, could serve as a framework for other multinational organizations to monitor their staff.

Metabolism of 1,3-butadiene, a known human and rodent carcinogen, results in formation of reactive epoxides, a key event in its carcinogenicity. Although mice exposed to 1,3-butadiene present DNA adducts in all tested tissues, carcinogenicity is limited to liver, lung, and lymphoid tissues. Previous studies demonstrated that strain- and tissue-specific epigenetic effects in response to 1,3-butadiene exposure may influence susceptibly to DNA damage and serve as a potential mechanism of tissue-specific carcinogenicity. This study aimed to investigate interindividual variability in the effects of 1,3-butadiene using a population-based mouse model. Male mice from 20 Collaborative Cross strains were exposed to 0 or 635 ppm 1,3-butadiene by inhalation (6 h/day, 5 days/week) for 2 weeks. We evaluated DNA damage and epigenetic effects in target (lung and liver) and nontarget (kidney) tissues of 1,3-butadiene-induced carcinogenesis. DNA damage was assessed by measuring N-7-(2,3,4-trihydroxybut-1-yl)-guanine (THB-Gua) adducts. To investigate global histone modification alterations, we evaluated the trimethylation and acetylation of histones H3 and H4 across tissues. Changes in global cytosine DNA methylation were evaluated from the levels of methylation of LINE-1 and SINE B1 retrotransposons. We quantified the degree of variation across strains, deriving a chemical-specific human variability factor to address population variability in carcinogenic risk, which is largely ignored in current cancer risk assessment practice. Quantitative trait locus mapping identified four candidate genes related to chromatin remodeling whose variation was associated with interstrain susceptibility. Overall, this study uses 1,3-butadiene to demonstrate how the Collaborative Cross mouse population can be used to identify the mechanisms for and quantify the degree of interindividual variability in tissue-specific effects that are relevant to chemically induced carcinogenesis.

According to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), Female Sexual Dysfunction is defined as a sexual problem associated with personal distress. It can be caused by any of the following: lack of sexual desire, impaired arousal, inability to achieve orgasm, or pain with sexual activity. Several studies have demonstrated the negative impact chemotherapy has on sexual functioning, short term and long term in women undergoing breast cancer treatment. Most of the research that has been done in this area only evaluated this problem in premenopausal women. The limited studies investigating this in postmenopausal women have found similar effects in this population group. The goal of this study is to assess sexual dysfunction in high risk postmenopausal women with breast cancer undergoing adjuvant therapy. We want to define this problem in this poorly studied subgroup, and to assess the degree of dysfunction, time course over which it occurs, and the particular sexual domains this occurs in. T This longitudinal study will assess sexual functioning utilizing two survey tools- the Female Sexual Function Index (FSFI), and the Female Sexual Distress Scale (FSDS-R). The FSFI is a 19- item questionnaire that assesses six domains of sexual functioning: desire, arousal, lubrication, orgasm, satisfaction, and pain The FSFI has been proven to have excellent validity and reliability in determining sexual dysfunction in healthy women, as well as women with various cancers including breast cancer. It was designed to be easy to use, and can be used in heterosexual, as well as homosexual women. To be consistent with the DSM 5’s definition of sexual dysfunction regarding personal distress, which is not evaluated in the FSFI, the FSDS-R will be utilized. This is a 13-item questionnaire, which has demonstrated excellent validity and reliability in determining sexual distress associated with sexual dysfunction. Participants will serve as their own control while assessing any change in sexual functioning over the course of the administration of 2-3 survey sets. The 1st set of surveys will be administered prior to receiving any treatments, this will serve as a baseline assessment for future comparison. The last 1-2 survey sets will be administered 6 months to 1 year after the initiation of adjuvant therapy. Data will be analyzed with a Repeated Measures ANOVA if statistical assumptions are met. If statistical assumptions are not met the Friedman ANOVA will be used. Post-Hoc testing will be conducted if significant main effects are found. At this time, 13 patients are currently enrolled in this trial. The number of participants for this study to achieve statistical power was calculated to be n=42. This calculation was based on one treatment group, with three observations across time, a correlation amount of repeated measures of 0.5, and a non-sphericity correction of 1.0. The assumed effect size was small to moderate with an F=0.20, an alpha of 0.05, and a beta of 0.20. Eligibility Criteria for this trial: •Must be a postmenopausal female •Diagnosed with Stage I, II, or III breast cancer •Not currently receiving endocrine therapy or chemotherapy•Plans with their physician to receive adjuvant therapy For more information please contact: Heidi Worth, MD PGY2 Internal Medicine Resident University of Tennessee Medical Center, Knoxville 904-540-1286 hworth@utmck.edu Citation Format: Heidi Worth, Timothy Panella, Clayton Bell, Mark Rasnake, Patricia Roberson, Lauren Lewis. A longitudinal study assessing sexual dysfunction in postmenopausal women with breast cancer undergoing adjuvant treatment [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-02-01.

In September 2013, the Hawaii Department of Health (HDOH) was notified of seven adults who developed acute hepatitis after taking OxyELITE Pro™, a weight loss and sports dietary supplement. CDC assisted HDOH with their investigation, then conducted case-finding outside of Hawaii with FDA and the Department of Defense (DoD). We defined cases as acute hepatitis of unknown etiology that occurred from April 1, 2013, through December 5, 2013, following exposure to a weight loss or muscle-building dietary supplement, such as OxyELITE Pro™. We conducted case-finding through multiple sources, including data from poison centers (National Poison Data System [NPDS]) and FDA MedWatch. We identified 40 case-patients in 23 states and two military bases with acute hepatitis of unknown etiology and exposure to a weight loss or muscle building dietary supplement. Of 35 case-patients who reported their race, 15 (42.9%) reported white and 9 (25.7%) reported Asian. Commonly reported symptoms included jaundice, fatigue, and dark urine. Twenty-five (62.5%) case-patients reported taking OxyELITE Pro™. Of these 25 patients, 17 of 22 (77.3%) with available data were hospitalized and 1 received a liver transplant. NPDS and FDA MedWatch each captured seven (17.5%) case-patients. Improving the ability to search surveillance systems like NPDS and FDA MedWatch for individual and grouped dietary supplements, as well as coordinating case-finding with DoD, may benefit ongoing surveillance efforts and future outbreak responses involving adverse health effects from dietary supplements. This investigation highlights opportunities and challenges in using multiple sources to identify cases of suspected supplement associated adverse events. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

The aim of this study was to determine if a novel naloxone training program with a focus on situational stress management yields better results than the currently recommended state training in a simulated overdose response.Students were randomized to receive either the state training or a novel training developed by the Wilkes University Nesbitt School of Pharmacy. After their respective training, each student individually completed a live simulated overdose response with an added stressor of a panicked bystander. A checklist was used to evaluate students during the simulation, and the results were compared.The average grade for the novel training students was 89% compared with 64% for the state training students (P0.001). There was no statistically significant difference in time to complete the simulation.Students who underwent the novel training received the state training. The novel training appears to be effective in preparing students to manage a live opioid overdose.