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Objectives: Virtual tabletop exercises (VTTXs) simulate disaster scenarios to help participants improve their emergency-planning capacity. The objectives of our study were to (1) evaluate the effectiveness of a VTTX in improving preparedness capabilities specific to children’s needs among pediatricians and public health practitioners, (2) document follow-up actions, and (3) identify exercise strengths and weaknesses. Methods: In February 2017, we conducted and evaluated a VTTX facilitated via videoconferencing among 26 pediatricians and public health practitioners from 4 states. Using a mixed-methods design, we assessed participants’ knowledge and confidence to fulfill targeted federal preparedness capabilities immediately before and after the exercise. We also evaluated the degree to which participants made progress on actions through surveys 1 month (n = 14) and 6 months (n = 14) after the exercise. Results: Participants reported a greater ability to identify their state’s pediatric emergency preparedness strengths and weaknesses after the exercise (16 of 18) compared with before the exercise (10 of 18). We also observed increases in (1) knowledge of and confidence in performing most pediatric emergency preparedness capabilities and (2) most dimensions of interprofessional collaboration. From 1 month to 6 months after the exercise, participants (n = 14) self-reported making progress in increasing awareness for potential preparedness partners and in conducting similar pediatric exercises (from 4-7 for both). Conclusions: Participants viewed the VTTX positively and indicated increased pediatric emergency preparedness knowledge and confidence. Addressing barriers to improving local pediatric emergency preparedness—particularly long term—is an important target for future tabletop exercises.

Preparing and responding to the needs of children during public health emergencies continues to be challenging. The purpose of this study was to assess the usefulness of a tabletop exercise in initiating pediatric preparedness strategies and assessing the impact of the exercise on participants' understanding of and confidence in their roles during pediatric public health emergencies. A tabletop exercise was developed to simulate a public health emergency scenario involving smallpox in a child, with subsequent spread to multiple states. During the exercise, participants discussed and developed communication, collaboration, and medical countermeasure strategies to enhance pediatric public health preparedness. Exercise evaluation was designed to assess participants' knowledge gained and level of confidence surrounding pediatric public health emergencies. In total, 22 participants identified over 100 communication and collaboration strategies to promote pediatric public health preparedness during the exercise and found that the most beneficial aspect during the exercise was the partnership between pediatricians and public health officials. Participants' knowledge and level of confidence surrounding a pediatric public health emergency increased after the exercise. The tabletop exercise was effective in identifying strategies to improve pediatric public health preparedness as well as enhancing participants' knowledge and confidence surrounding a potential pediatric public health emergency. (Disaster Med Public Health Preparedness. 2018;12:582-586).

Despite children's unique vulnerability, clinical guidance and resources are lacking around the use of radiation medical countermeasures (MCMs) available commercially and in the Strategic National Stockpile to support immediate dispensing to pediatric populations. To better understand the current capabilities and shortfalls, a literature review and gap analysis were performed. A comprehensive review of the medical literature, Food and Drug Administration (FDA)-approved labeling, FDA summary reviews, medical references, and educational resources related to pediatric radiation MCMs was performed from May 2016 to February 2017. Fifteen gaps related to the use of radiation MCMs in children were identified. The need to address these gaps was prioritized based upon the potential to decrease morbidity and mortality, improve clinical management, strengthen caregiver education, and increase the relevant evidence base. Key gaps exist in information to support the safe and successful use of MCMs in children during radiation emergencies; failure to address these gaps could have negative consequences for families and communities. There is a clear need for pediatric-specific guidance to ensure clinicians can appropriately identify, triage, and treat children who have been exposed to radiation, and for resources to ensure accurate communication about the safety and utility of radiation MCMs for children. (Disaster Med Public Health Preparedness. 2019;13:639-646).

Aerosol exposure to eastern equine encephalitis virus (EEEV) can trigger a lethal viral encephalitis in cynomolgus macaques which resembles severe human disease. Biomarkers indicative of central nervous system (CNS) infection by the virus and lethal outcome of disease would be useful in evaluating potential medical countermeasures, especially for therapeutic compounds. To meet requirements of the Animal Rule, a better understanding of the pathophysiology of EEEV-mediated disease in cynomolgus macaques is needed. In this study, macaques given a lethal dose of clone-derived EEEV strain V105 developed a fever between 2–3 days post infection (dpi) and succumbed to the disease by 6 dpi. At the peak of the febrile phase, there was a significant increase in the delta electroencephalography (EEG) power band associated with deep sleep as well as a sharp rise in intracranial pressure (ICP). Viremia peaked early after infection and was largely absent by the onset of fever. Granulocytosis and elevated plasma levels of IP-10 were found early after infection. At necropsy, there was a one hundred- to one thousand-fold increase in expression of traumatic brain injury genes (LIF, MMP-9) as well as inflammatory cytokines and chemokines (IFN-γ, IP-10, MCP-1, IL-8, IL-6) in the brain tissues. Phenotypic analysis of leukocytes entering the brain identified cells as primarily lymphoid (T, B, NK cells) with lower levels of infiltrating macrophages and activated microglia. Massive amounts of infectious virus were found in the brains of lethally-infected macaques. While no infectious virus was found in surviving macaques, quantitative PCR did find evidence of viral genomes in the brains of several survivors. These data are consistent with an overwhelming viral infection in the CNS coupled with a tremendous inflammatory response to the infection that may contribute to the disease outcome. Physiological monitoring of EEG and ICP represent novel methods for assessing efficacy of vaccines or therapeutics in the cynomolgus macaque model of EEEV encephalitis.

Background Geroscience focuses on interventions to mitigate molecular changes associated with aging. Lifestyle modifications, medications, and social factors influence the aging process, yet the complex molecular mechanisms require an in-depth exploration of the epigenetic landscape. The specific epigenetic clock and predictor effects of a vegan diet, compared to an omnivorous diet, remain underexplored despite potential impacts on aging-related outcomes. Methods This study examined the impact of an entirely plant-based or healthy omnivorous diet over 8 weeks on blood DNA methylation in paired twins. Various measures of epigenetic age acceleration (PC GrimAge, PC PhenoAge, DunedinPACE) were assessed, along with system-specific effects (Inflammation, Heart, Hormone, Liver, and Metabolic). Methylation surrogates of clinical, metabolite, and protein markers were analyzed to observe diet-specific shifts. Results Distinct responses were observed, with the vegan cohort exhibiting significant decreases in overall epigenetic age acceleration, aligning with anti-aging effects of plant-based diets. Diet-specific shifts were noted in the analysis of methylation surrogates, demonstrating the influence of diet on complex trait prediction through DNA methylation markers. An epigenome-wide analysis revealed differentially methylated loci specific to each diet, providing insights into the affected pathways. Conclusions This study suggests that a short-term vegan diet is associated with epigenetic age benefits and reduced calorie intake. The use of epigenetic biomarker proxies (EBPs) highlights their potential for assessing dietary impacts and facilitating personalized nutrition strategies for healthy aging. Future research should explore the long-term effects of vegan diets on epigenetic health and overall well-being, considering the importance of proper nutrient supplementation. Trial registration Clinicaltrials.gov identifier: NCT05297825

Nanoformulations of therapeutic drugs are transforming our ability to effectively deliver and treat a myriad of conditions. Often, however, they are complex to produce and exhibit low drug loading, except for nanoparticles formed via co-assembly of drugs and small molecular dyes, which display drug-loading capacities of up to 95%. There is currently no understanding of which of the millions of small-molecule combinations can result in the formation of these nanoparticles. Here we report the integration of machine learning with high-throughput experimentation to enable the rapid and large-scale identification of such nanoformulations. We identified 100 self-assembling drug nanoparticles from 2.1 million pairings, each including one of 788 candidate drugs and one of 2,686 approved excipients. We further characterized two nanoparticles, sorafenib–glycyrrhizin and terbinafine–taurocholic acid both ex vivo and in vivo. We anticipate that our platform can accelerate the development of safer and more efficacious nanoformulations with high drug-loading capacities for a wide range of therapeutics. Self-assembly of small drugs with organic dyes represents a facile route to synthesize nanoparticles with high drug-loading capability. Here the authors combine a machine learning approach with high-throughput experimental validation to identify which combinations of drugs and excipient lead to successful nanoparticle formation and characterize the therapeutic efficacy of two of them in vitro and in animal models.

Exclusive breastfeeding (EBF)—giving infants only breast-milk (and medications, oral rehydration salts and vitamins as needed) with no additional food or drink for their first six months of life—is one of the most effective strategies for preventing child mortality 1 – 4 . Despite these advantages, only 37% of infants under 6 months of age in Africa were exclusively breastfed in 2017 5 , and the practice of EBF varies by population. Here, we present a fine-scale geospatial analysis of EBF prevalence and trends in 49 African countries from 2000–2017, providing policy-relevant administrative- and national-level estimates. Previous national-level analyses found that most countries will not meet the World Health Organization’s Global Nutrition Target of 50% EBF prevalence by 2025 6 . Our analyses show that even fewer will achieve this ambition in all subnational areas. Our estimates provide the ability to visualize subnational EBF variability and identify populations in need of additional breastfeeding support. Exclusive breastfeeding in Africa is highly varied within and between countries, with many countries unlikely to reach World Health Organization 2025 targets without urgent action.

New antibiotics are needed to combat rising levels of resistance, with new Mycobacterium tuberculosis (Mtb) drugs having the highest priority. However, conventional whole-cell and biochemical antibiotic screens have failed. Here we develop a strategy termed PROSPECT (primary screening of strains to prioritize expanded chemistry and targets), in which we screen compounds against pools of strains depleted of essential bacterial targets. We engineered strains that target 474 essential Mtb genes and screened pools of 100–150 strains against activity-enriched and unbiased compound libraries, probing more than 8.5 million chemical–genetic interactions. Primary screens identified over tenfold more hits than screening wild-type Mtb alone, with chemical–genetic interactions providing immediate, direct target insights. We identified over 40 compounds that target DNA gyrase, the cell wall, tryptophan, folate biosynthesis and RNA polymerase, as well as inhibitors that target EfpA. Chemical optimization yielded EfpA inhibitors with potent wild-type activity, thus demonstrating the ability of PROSPECT to yield inhibitors against targets that would have eluded conventional drug discovery. A high-throughput chemical–genetic screening approach for the discovery of targets and chemicals to treat Mycobacterium tuberculosis yields tenfold more hit compounds than conventional whole-cell screening methods.

The lack of tools to reliably detect RanBP9 in vivo has significantly hampered progress in understanding the biological functions of this scaffold protein. We report here the generation of a novel mouse strain, RanBP9-TT, in which the endogenous protein is fused with a double (V5-HA) epitope tag at the C-terminus. We show that the double tag does not interfere with the essential functions of RanBP9. In contrast to RanBP9 constitutive knock-out animals, RanBP9-TT mice are viable, fertile and do not show any obvious phenotype. The V5-HA tag allows unequivocal detection of RanBP9 both by IHC and WB. Importantly, immunoprecipitation and mass spectrometry analyses reveal that the tagged protein pulls down known interactors of wild type RanBP9. Thanks to the increased detection power, we are also unveiling a previously unknown interaction with Nucleolin, a protein proposed as an ideal target for cancer treatment. In summary, we report the generation of a new mouse line in which RanBP9 expression and interactions can be reliably studied by the use of commercially available αtag antibodies. The use of this line will help to overcome some of the existing limitations in the study of RanBP9 and potentially unveil unknown functions of this protein in vivo such as those linked to Nucleolin.

PurposeFor patients who select a specialty hospital for cancer treatment, the wait time until the initial consultation leaves patients anxious and delays treatment. To improve quality of care, we implemented an enhanced patient clinical streamlining (EPACS) process that establishes an early connection and coordinates care before the first surgical outpatient visit at our specialty cancer center.MethodsDuring a pre-visit EPACS phone call to new patients, an advanced practice provider (APP) collected medical history and ordered work-up tests or consultations if feasible. First visit cancellation rate, number of patients who started treatment, time to start of treatment, and satisfaction by the care team and patient were compared between patients treated with versus without EPACS.ResultsAmong 5062 consecutive new patients, 720 (14%) received an EPACS call and 4342 did not (86%); work-up was ordered pre-visit in 34% and 16%, respectively. Fewer EPACS patients cancelled the first visit (4.6% vs. 12%, p < 0.001), more started treatment (55% vs. 50%, p = 0.037), and their time to treatment was shorter, but not significantly (median 17 vs. 19 days, p = 0.086). Patient interaction was considered to be improved by EPACS by 17 of 17 APPs and 14 of 16 surgeons, and outpatient clinic efficiency by 14 of 17 APPs and 13 of 16 surgeons. EPACS reduced anxiety and increased preparedness for the first visit in 29 of 31 patients.ConclusionsEPACS improved effectiveness, timeliness, and physician and patient satisfaction with health care at our cancer center.