Perceived control ameliorates the impact of adverse childhood experiences on downstream mental health.

BACKGROUND: Previous scholarship has illustrated the pernicious role of adverse childhood experiences (ACEs) in self-reported mental health, namely depressive and anxiety-related symptoms. Given these insights, highlighting protective factors that may diminish the magnitude of this relationship is important. The present study explored the moderating role of perceived control on the relationship between ACEs and depressive and anxiety symptoms, respectively. METHODS: Participants consisted of a US-based non-clinical sample of 567 undergraduate students who completed a battery of surveys related to psychological wellbeing and individual differences. A series of hierarchical linear regression analyses were utilized for hypothesis testing. RESULTS: Consistent with our main hypotheses, perceived control moderated the relationship between ACEs and both anxiety and depressive symptoms, respectively. Namely, at low levels of perceived control, ACEs were associated with significantly greater levels of anxiety and depressive symptoms, respectively. However, for those reporting high levels of perceived control, we found no association between ACEs and self-reported symptoms. CONCLUSION: We offer evidence that perceived control may serve as a protective factor for mental health and wellbeing against the influence of adverse childhood experiences.

Comparison of protection against mpox following mRNA or modified vaccinia Ankara vaccination in nonhuman primates.

In 2022, mpox virus (MPXV) spread worldwide, causing 99,581 mpox cases in 121 countries. Modified vaccinia Ankara (MVA) vaccine use reduced disease in at-risk populations but failed to deliver complete protection. Lag in manufacturing and distribution of MVA resulted in additional MPXV spread, with 12,000 reported cases in 2023 and an additional outbreak in Central Africa of clade I virus. These outbreaks highlight the threat of zoonotic spillover by Orthopoxviruses. mRNA-1769, an mRNA-lipid nanoparticle (LNP) vaccine expressing MPXV surface proteins, was tested in a lethal MPXV primate model. Similar to MVA, mRNA-1769 conferred protection against challenge and further mitigated symptoms and disease duration. Antibody profiling revealed a collaborative role between neutralizing and Fc-functional extracellular virion (EV)-specific antibodies in viral restriction and ospinophagocytic and cytotoxic antibody functions in protection against lesions. mRNA-1769 enhanced viral control and disease attenuation compared with MVA, highlighting the potential for mRNA vaccines to mitigate future pandemic threats.

Ileocolic Intussusception: Iterative Quality Improvement to Address a Recurring Problem.

INTRODUCTION: Recent quality improvement (QI) initiatives indicate that pediatric patients with uncomplicated ileocolic intussusception can be safely discharged from the emergency department (ED) after fluoroscopic reduction. These programs improve patient experience and reduce cost. We sought to build on these efforts by developing a QI initiative at our own institution that included patients transferred from a satellite campus and focused on iterative improvement of our treatment pathway based on continual reassessment of our processes and data. MATERIALS AND METHODS: We formed a multidisciplinary team, established a collaborative open-access clinical pathway, and implemented educational plans for each participating division. Data were tracked prospectively, and process adjustments were made as clinically indicated. In this report, we compare patients treated before and after the QI initiative. RESULTS: There were 155 patients treated before the QI initiative (January 1, 2018-June 30, 2022) and 87 after the initiative began (July 1, 2022-October 31, 2023). There were significant improvements in the rate of ED discharge (4/155 (2.6%) versus 51/87 (59%), P < 0.001) and mean time to discharge (40.7 versus 23.1 h, P = 0.002), while the average cost of a visit fell by 30% (P = 0.012). The mean time to discharge from the ED increased (6.9 versus 11.0 h, P < 0.001), and the rate of readmission was unchanged. For patients transferred from the satellite campus, time to fluoroscopic reduction significantly improved during the initiative (9.4 versus 6.5 h, P = 0.048). CONCLUSIONS: We implemented a QI program for patients with fluoroscopically reduced ileocolic intussusception that was serially adjusted based on continual reassessment of data. The protocol was associated with a decreased admission rate, total cost, and time to hospital discharge.

Sleep and diurnal alternative polyadenylation sites associated with human APA-linked brain disorders.

Disruption of sleep and circadian rhythms are a comorbid feature of many pathologies, and can negatively influence many health conditions, including neurodegenerative disease, metabolic illness, cancer, and various neurological disorders. Genetic association studies linking sleep and circadian disturbances with disease susceptibility have mainly focused on changes in gene expression due to mutations, such as single-nucleotide polymorphisms. The interaction between sleep and/or circadian rhythms with the use of Alternative Polyadenylation (APA) has been largely undescribed, particularly in the context of other disorders. APA is a process that generates various transcript isoforms of the same gene affecting its mRNA translation, stability, localization, and subsequent function. Here we identified unique APAs expressed in rat brain over time-of-day, immediately following sleep deprivation, and the subsequent recovery period. From these data, we performed a secondary analysis of these sleep- or time-of-day associated PASs with recently described APA-linked human brain disorder susceptibility genes.

Player-Facing Casino Employees: Engagement with Responsible Gambling Programming and its Association with Referring Players.

This research explores the engagement of player-facing casino employees with GameSense, a responsible gambling (RG) program, and referral of players to GameSense. We surveyed 280 employees across three casinos in Massachusetts that use this RG program as part of their RG strategy. We found that although most player-facing casino employees were aware of GameSense, slightly over half visited a GameSense Information Center, and about two-thirds interacted with a GameSense Advisor. In terms of the reason for visiting, Latent Class Analysis (LCA) revealed three distinct classes: Comprehensive Interests, RG Interests, and Focused Interests. As for those who have yet to visit, LCA two classes emerged: RG Proficiency Beliefs and Tempered RG Proficiency Beliefs. Engaged employees were more likely to refer players to GameSense, highlighting the need for targeted approaches addressing the diverse interests of player-facing employees for engaging or not engaging with GameSense. These findings underscore the importance of have player-facing casino employees engage with RG programming, and targeted approached for engagement, to enhance the efficacy of RG initiatives, and contribute to a more robust RG framework within the gambling industry.

Vitamin D Maintains Growth and Bone Mineral Density against a Background of Severe Vitamin A Deficiency and Moderate Toxicity in a Swine Model.

Excessive vitamin A (VA) negatively impacts bone. Interactions between VA and vitamin D (VD) in bone health are not well-understood. This study used a traditional two-by-two factorial design. Pigs were weaned and randomized to four treatments (n = 13/group): -A-D, -A+D, +A-D, and +A+D for 3 and 5 wk. Serum, liver, kidney, adrenal glands, spleen, and lung were analyzed by ultra-performance LC. Growth was evaluated by weight measured weekly and BMD by DXA. Weights were higher in -A+D (18.1 ± 1.0 kg) and +A+D (18.2 ± 2.3 kg) at 5 wk than in -A-D (15.5 ± 2.1 kg) and +A-D (15.8 ± 1.5 kg). Serum retinol concentrations were 0.25 ± 0.023, 0.22 ± 0.10, 0.77 ± 0.12, and 0.84 ± 0.28 µmol/L; and liver VA concentrations were 0.016 ± 0.015, 0.0065 ± 0.0035, 2.97 ± 0.43, 3.05 ± 0.68 µmol/g in -A-D, -A+D, +A-D, and +A+D, respectively. Serum 25(OH)D3 concentrations were 1.5 ± 1.11, 1.8 ± 0.43, 27.7 ± 8.91, and 23.9 ± 6.67 ng/mL in -A-D, +A-D, -A+D, +A+D, respectively, indicating a deficiency in -D and adequacy in +D. BMD was highest in +D (p < 0.001). VA and the interaction had no effect on BMD. Dietary VD influenced weight gain, BMD, and health despite VA status.

Derailment is associated with increased depressed mood at lower levels of stress: An experimental approach.

BACKGROUND: As an emergent developmental construct, derailment - an individual difference hallmarked by a temporal discordance of the self - has been positively associated with depressive features, though less is known about the role of stress in this relationship. The aim of the present study was to explore the interaction between derailment and subjective stress on depressed mood. METHODS: 265 adults recruited through Prolific - a crowd sourcing platform were first tasked with completing baseline measures, then were randomly assigned to a low stress or high stress condition. We utilized an adapted version of the Online Trier Stress Test to manipulate stress levels. Next, depressed mood and post-test perceived stress were measured. We analyzed data through STATA using a two-tailed independent samples t-test and multiple linear regression. RESULTS: Findings suggested the experimental manipulation increased subjective stress within the high stress condition compared to the low stress condition (Mdiff = 36.14, SE = 4.4, t = 8.21, p < .001). Further, we found the interaction between derailment and stress conditions was associated with increased depressed mood (ß = -0.11, SE = 0.05, p = .038, R2 = 0.5). Notably, we found significant between-condition differences in depressed mood for those who endorsed either low (d = 0.22, SE = 0.07, p = .003) or moderate levels of derailment (d = 0.11, SE = 0.05, p = .033), but not for those who endorsed high levels of derailment (d = 0.01, SE = 0.07, p = .92). LIMITATIONS: This study utilized self-report measures, which may be susceptible to biased responses. CONCLUSIONS: Derailment may play a role in the persistence of depressed mood regardless of varying contexts of stress.

Climate impacts of alternative beef production systems depend on the functional unit used: Weight or monetary value.

Beef production has been identified as a significant source of anthropogenic greenhouse gas (GHG) emissions in the agricultural sector. United States and Canada account for about a quarter of the world's beef supply. To compare the GHG emission contributions of alternative beef production systems, we conducted a meta-analysis of 32 studies that were conducted between 2001 and 2023. Results indicated that GHG emissions from beef production in North America varied almost fourfold from 10.2 to 37.6 with an average of 21.4 kg CO2e/kg carcass weight (CW). Studies that considered soil C sequestration (C-seq) reported the highest mitigation potential in GHG emissions (80%), followed by growth enhancement technology (16%), diet modification (6%), and grazing management improvement (7%). Our study highlights the implications of using carbon intensity per economic activity (i.e., GHG emissions per monetary unit), compared to the more common metric of intensity on per weight of product basis (GHG emissions per kg CW) for comparisons across differentiated beef cattle products. While a positive association was found between the proportion of lifespan on grassland and the conventional weight-based indicator, grass-finished beef was found to have lower carbon intensity per economic activity than feedlot-finished beef. Our study emphasizes the need to incorporate land use and management effects and soil C-seq as fundamental aspects of beef GHG emissions and mitigation assessments.

Delayed Mucosal Antiviral Responses Despite Robust Peripheral Inflammation in Fatal COVID-19.

BACKGROUND: While inflammatory and immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in peripheral blood are extensively described, responses at the upper respiratory mucosal site of initial infection are relatively poorly defined. We sought to identify mucosal cytokine/chemokine signatures that distinguished coronavirus disease 2019 (COVID-19) severity categories, and relate these to disease progression and peripheral inflammation. METHODS: We measured 35 cytokines and chemokines in nasal samples from 274 patients hospitalized with COVID-19. Analysis considered the timing of sampling during disease, as either the early (0-5 days after symptom onset) or late (6-20 days after symptom onset) phase. RESULTS: Patients that survived severe COVID-19 showed interferon (IFN)-dominated mucosal immune responses (IFN-γ, CXCL10, and CXCL13) early in infection. These early mucosal responses were absent in patients who would progress to fatal disease despite equivalent SARS-CoV-2 viral load. Mucosal inflammation in later disease was dominated by interleukin 2 (IL-2), IL-10, IFN-γ, and IL-12p70, which scaled with severity but did not differentiate patients who would survive or succumb to disease. Cytokines and chemokines in the mucosa showed distinctions from responses evident in the peripheral blood, particularly during fatal disease. CONCLUSIONS: Defective early mucosal antiviral responses anticipate fatal COVID-19 but are not associated with viral load. Early mucosal immune responses may define the trajectory of severe COVID-19.

Efficacy of the Allosteric MEK Inhibitor Trametinib in Relapsed and Refractory Juvenile Myelomonocytic Leukemia: a Report from the Children's Oncology Group.

Juvenile myelomonocytic leukemia (JMML) is a hematologic malignancy of young children caused by mutations that increase Ras signaling output. Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment, but patients with relapsed or refractory (advanced) disease have dismal outcomes. This phase II trial evaluated the safety and efficacy of trametinib, an oral MEK1/2 inhibitor, in patients with advanced JMML. Ten infants and children were enrolled, and the objective response rate was 50%. Four patients with refractory disease proceeded to HSCT after receiving trametinib. Three additional patients completed all 12 cycles permitted on study and continue to receive off-protocol trametinib without HSCT. The remaining three patients had progressive disease with two demonstrating molecular evolution by the end of cycle 2. Transcriptomic and proteomic analyses provided novel insights into the mechanisms of response and resistance to trametinib in JMML. ClinicalTrials.gov Identifier: NCT03190915. Significance: Trametinib was safe and effective in young children with relapsed or refractory JMML, a lethal disease with poor survival rates. Seven of 10 patients completed the maximum 12 cycles of therapy or used trametinib as a bridge to HSCT and are alive with a median follow-up of 24 months. See related commentary by Ben-Crentsil and Padron, p. 1574.

Drowning.

Drowning is responsible for considerable morbidity and mortality worldwide, and it is estimated that 90% of drownings are preventable. Drowning is defined as "the process of experiencing respiratory impairment from submersion/immersion in liquid." Emergency providers should focus on airway management and rapid delivery of oxygen to interrupt the drowning process and improve patient outcomes. Patients with minimal or no symptoms do not require any specific diagnostic workup, aside from physical examination and 4 to 6 hours of observation prior to discharge. Patients with more severe symptoms may present with rales and foamy secretions, and should be managed with high-concentration oxygen and positive airway pressure.

The dynamics of drowning: Clarifying terminologies and response strategies.

ABSTRACT: Drowning is the process of respiratory impairment from immersion or submersion in a liquid. Worldwide, approximately 360,000 deaths annually can be attributed to drowning. Morbidity and mortality are a result of hypoxia, so the focus during resuscitation should be on airway management and optimizing oxygenation. This article describes several drowning scenarios and discusses appropriate response and treatment algorithms.

Oxygen tension-dependent variability in the cancer cell kinome impacts signaling pathways and response to targeted therapies.

Most cells in solid tumors are exposed to oxygen levels between 0.5% and 5%. We developed an approach that allows collection, processing, and evaluation of cancer and non-cancer cells under physioxia, while preventing exposure to ambient air. This aided comparison of baseline and drug-induced changes in signaling pathways under physioxia and ambient oxygen. Using tumor cells from transgenic models of breast cancer and cells from breast tissues of clinically breast cancer-free women, we demonstrate oxygen-dependent differences in cell preference for epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor beta (PDGFRß) signaling. Physioxia caused PDGFRß-mediated activation of AKT and extracellular regulated kinase (ERK) that reduced sensitivity to EGFR and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) inhibition and maintained PDGFRß+ epithelial-mesenchymal hybrid cells with potential cancer stem cell (CSC) properties. Cells in ambient air displayed differential EGFR activation and were more sensitive to targeted therapies. Our data emphasize the importance of oxygen considerations in preclinical cancer research to identify effective drug targets and develop combination therapy regimens.

Wilderness Medical Society Clinical Practice Guidelines for Medical Direction of Search and Rescue Teams.

The Wilderness Medical Society convened a panel to review available evidence supporting practices for medical direction of search and rescue teams. This panel included of members of the Wilderness Medical Society Search and Rescue Committee, the National Association of EMS Physicians Wilderness Committee, and leadership of the Mountain Rescue Association. Literature about definitions and terminology, epidemiology, currently accepted best practices, and regulatory and legal considerations was reviewed. The panel graded available evidence supporting practices according to the American College of Chest Physicians criteria and then made recommendations based on that evidence. Recommendations were based on the panel's collective clinical experience and judgment when published evidence was lacking.

Repeated High-Dose Vitamin A Supplements, Standard of Care for Treating Xerophthalmia, Leads to Hypervitaminosis A in Piglets.

BACKGROUND: Vitamin A (VA) deficiency and excess negatively affect development, growth, and bone health. The World Health Organization's standard of care for xerophthalmia due to VA deficiency, is 3 high-dose VA supplements of 50,000-200,000 IU, based on age, which may cause hypervitaminosis A in some individuals. OBJECTIVES: This study measured VA status following 3 VA doses in 2 piglet studies. METHODS: In Study 1, 5 groups of piglets (n = 10/group) were weaned 10 d postbirth to VA-free feed and orally administered 0; 25,000; 50,000; 100,000; or 200,000 IU VA ester on days 0, 1, and 7. On days 14 and 15, the piglets underwent the modified relative dose-response (MRDR) test for VA deficiency, and were killed. Tissues were collected for high-pressure liquid chromatography analysis. Study 2 used the same design in 3 groups (n = 13/group) weaned at 16 d and administered 0; 25,000; and 200,000 IU doses. RESULTS: In Study 1 (final weight: 3.6 ± 0.7 kg), liver VA concentration was hypervitaminotic in 40%, 90%, and 100% of 50,000; 100,000; and 200,000 IU groups, respectively. The 25,000 IU group was 100% adequate, and the placebo group was 40% deficient. In Study 2 (final weight: 8.7 ± 0.8 kg), where 200,000 IU could be prescribed to infants with a similar body weight, 31% of the piglets were hypervitaminotic, the 25,000 IU group was 100% VA adequate, and the placebo group was 100% deficient. The MRDR test measured deficiency in 50% and 70% of the placebo group in each study but had 3 false positives among hypervitaminotic piglets in Study 1. CONCLUSIONS: Repeated high-dose VA may cause hypervitaminosis, indicating dose sizes may need reduction. The MRDR resulted in false positives in a hypervitaminotic state during malnutrition and should be paired with serum retinyl ester evaluation to enhance VA status assessment in populations with overlapping interventions.

Copper-Catalyzed Dearomative 1,2-Hydroamination.

Catalytic olefin hydroamination reactions are some of the most atom-economical transformations that bridge readily available starting materials-olefins and high-value-added amines. Despite significant advances in this field over the last two decades, the formal hydroamination of nonactivated aromatic compounds remains an unsolved challenge. Herein, we report the extension of olefin hydroamination to aromatic π-systems by using arenophile-mediated dearomatization and Cu-catalysis to perform 1,2-hydroamination on nonactivated arenes. This strategy was applied to a variety of substituted arenes and heteroarenes to provide general access to structurally complex amines. We conducted DFT calculations to inform mechanistic understanding and rationalize unexpected selectivity trends. Furthermore, we developed a practical, scalable desymmetrization to deliver enantioenriched dearomatized products and enable downstream synthetic applications. We ultimately used this dearomative strategy to efficiently synthesize a collection of densely functionalized small molecules.

Atopic Dermatitis.

Atopic dermatitis (AD) is a common, chronic relapsing, and remitting inflammatory skin disease that is characterized by erythematous, scaly, and pruritic lesions often located over the flexural surfaces. Treatment goals of AD include the reduction of itching and burning, as well as the reduction of skin changes. Treatment of AD includes emollients and skin care, topical therapies including topical corticosteroids and steroid-sparing therapies, systemic therapies, and phototherapy.

Comparison of stochastic and deterministic models for gambiense sleeping sickness at different spatial scales: A health area analysis in the DRC.

The intensification of intervention activities against the fatal vector-borne disease gambiense human African trypanosomiasis (gHAT, sleeping sickness) in the last two decades has led to a large decline in the number of annually reported cases. However, while we move closer to achieving the ambitious target of elimination of transmission (EoT) to humans, pockets of infection remain, and it becomes increasingly important to quantitatively assess if different regions are on track for elimination, and where intervention efforts should be focused. We present a previously developed stochastic mathematical model for gHAT in the Democratic Republic of Congo (DRC) and show that this same formulation is able to capture the dynamics of gHAT observed at the health area level (approximately 10,000 people). This analysis was the first time any stochastic gHAT model has been fitted directly to case data and allows us to better quantify the uncertainty in our results. The analysis focuses on utilising a particle filter Markov chain Monte Carlo (MCMC) methodology to fit the model to the data from 16 health areas of Mosango health zone in Kwilu province as a case study. The spatial heterogeneity in cases is reflected in modelling results, where we predict that under the current intervention strategies, the health area of Kinzamba II, which has approximately one third of the health zone's cases, will have the latest expected year for EoT. We find that fitting the analogous deterministic version of the gHAT model using MCMC has substantially faster computation times than fitting the stochastic model using pMCMC, but produces virtually indistinguishable posterior parameterisation. This suggests that expanding health area fitting, to cover more of the DRC, should be done with deterministic fits for efficiency, but with stochastic projections used to capture both the parameter and stochastic variation in case reporting and elimination year estimations.

Accelerating Progress Towards the 2030 Neglected Tropical Diseases Targets: How Can Quantitative Modeling Support Programmatic Decisions?

Over the past decade, considerable progress has been made in the control, elimination, and eradication of neglected tropical diseases (NTDs). Despite these advances, most NTD programs have recently experienced important setbacks; for example, NTD interventions were some of the most frequently and severely impacted by service disruptions due to the coronavirus disease 2019 (COVID-19) pandemic. Mathematical modeling can help inform selection of interventions to meet the targets set out in the NTD road map 2021-2030, and such studies should prioritize questions that are relevant for decision-makers, especially those designing, implementing, and evaluating national and subnational programs. In September 2022, the World Health Organization hosted a stakeholder meeting to identify such priority modeling questions across a range of NTDs and to consider how modeling could inform local decision making. Here, we summarize the outputs of the meeting, highlight common themes in the questions being asked, and discuss how quantitative modeling can support programmatic decisions that may accelerate progress towards the 2030 targets.