Delirium Associated with COVID-19 in Critically ill Children: An Observational Cohort Study.

OBJECTIVE: Delirium is an under-recognized problem in critically ill children. Although delirium is common in adults hospitalized with COVID-19, the relationship between pediatric COVID-19 and delirium has not been described. To address this gap, we characterized delirium in critically ill children with different manifestations of COVID-19 and investigated associations among demographic, disease, and treatment factors. We hypothesized that multisystem inflammatory syndrome in children (MIS-C) would be associated with a higher incidence of delirium given its underlying pathophysiology of hyperinflammation. DESIGN: Retrospective, single-center cohort study. SETTING: Quaternary-care pediatric intensive care unit (PICU). PATIENTS: Children less than 18 years of age hospitalized in the PICU between March 2020 and March 2023 with either active SARS-CoV-2 infection or serological evidence of prior infection. MEASUREMENTS AND MAIN RESULTS: The cohort included 149 PICU hospitalizations among children with evidence of COVID-19. Patients were categorized by reason for PICU admission: 75 (50%) for COVID-19 respiratory disease, 36 (24%) MIS-C, and 38 (26%) any other primary reason with positive COVID-19 testing. Delirium was diagnosed in 43 (29%) patients. Delirium incidence was highest in patients requiring invasive mechanical ventilation (IMV) (56% vs 7.5% in patients who did not require IMV, p < .001). Patients who were exposed to opioids, dexmedetomidine, paralytics or benzodiazepines more frequently experienced delirium compared to those unexposed (p < .001, p < .001, p < .001 and p = .001, respectively). After multivariable adjustment, delirium was associated with IMV (HR 3 [95% CI 1.5-5.7]), female sex (HR 2.4 [1.2-4.7]), and developmental disability (HR 3.4 [95% CI 1-11.1]). There was no association between delirium and reason for PICU hospitalization. CONCLUSIONS: Delirium was common among children hospitalized with COVID-19. The overall incidence was much less than has been reported in adults with COVID-19. Delirium reduction efforts should focus on children with developmental disability and minimizing ongoing risks during IMV.

A comparison of the activity, lysosomal stability, and efficacy of legumain-cleavable and cathepsin cleavable ADC linkers.

1. Over the past two decades antibody-drug conjugates (ADCs) have emerged as a highly effective drug delivery technology. ADCs utilize a monoclonal antibody, a chemical linker, and a therapeutic payload to selectively deliver highly potent pharmaceutical agents to specific cell types.2. Challenges such as premature linker cleavage and clearance due to linker hydrophobicity have adversely impacted the stability and safety of ADCs. While there are various solutions to these challenges, our team has focused on replacement of hydrophobic ValCit linkers (cleaved by CatB) with Asn-containing linkers that are cleaved by lysosomal legumain.3. Legumain is abundantly present in lysosomes and is known to play a role in tumor microenvironment dynamics. Herein, we directly compare the lysosomal cleavage, cytotoxicity, plasma stability, and efficacy of a traditional cathepsin cleavable ADC to a matched Asn-containing legumain-cleavable ADC.4. We demonstrate that Asn-containing linker sequences are specifically cleaved by lysosomal legumain and that Asn-linked MMAE ADCs are broadly active against a variety of tumors, even those with low legumain expression. Finally, we show that AsnAsn-linked ADCs exhibit comparable or improved efficacy to traditional ValCit-linked ADCs. Our study paves the way for replacement of the traditional ValCit linker technology with more hydrophilic Asn-containing peptide linker sequences.

Testing the heat treatment dose for Agrilus planipennis (Coleoptera: Buprestidae) prepupae using the Humble water bath.

The lethal heat treatment dose (time and temperature) for the prepupal life stage of Agrilus planipennis Fairmaire (Coleoptera: Buprestidae), emerald ash borer (EAB), was determined through an in vitro application using a carefully calibrated heat treatment apparatus. The lethal and sublethal effects of heat on A. planipennis prepupae were assessed through a ramped heat delivery application, simulating industrial kilns and conventional heat chamber operations, for treatments combining target temperatures of 54 °C, 55 °C, and 56 °C, and exposure durations of 0 min (i.e., kiln temperature ramp only), 15 min, or 30 min. Prepupal EAB larvae did not survive exposure to 56 °C for 15 min or longer, or to 55 °C for 30 min. Sublethal effects were observed for all other treatments. Sublethal effects included delayed development and failure to complete the pupal and adult life stages.

Plasticity drives extreme cold tolerance of emerald ash borer (Agrilus planipennis) during a polar vortex.

Invasive species must often survive combinations of environmental conditions that differ considerably from their native range; however, for a given species it is unclear whether improved tolerance is the result of phenotypic plasticity or genetic adaptation (or both). Agrilus planipennis (Coleoptera: Buprestidae; the emerald ash borer) is an invasive pest of Fraxinus trees in North America and Europe. Previous studies in SW Ontario, Canada, showed that A. planipennis is freeze avoidant, preventing internal ice formation by accumulating Molar concentrations of glycerol in its hemolymph and depressing its supercooling point (SCP, the temperature at which it freezes). The cold tolerance of these SW Ontario animals was used to predict potential distribution, revealing that some Canadian cities should be too cold to allow populations to persist. However, a small population of A. planipennis has persisted in Winnipeg, Manitoba, Canada, through several severe 'polar vortex' events. In 2018/19, we collected A. planipennis larvae and prepupae from Winnipeg, MB and Southern Ontario, and found that individuals from Winnipeg were extremely cold tolerant - with SCPs as low as -52°C in prepupae (compared to -32°C in SW Ontario), and observed survival of unfrozen individuals exposed to -50°C for one hour. This cold tolerance was accompanied by higher hemolymph osmolality and glycerol concentration than in the SW Ontario individuals. To distinguish between phenotypic plasticity and local adaptation, in 2020/21 we overwintered Winnipeg-sourced individuals either outdoors in SW Ontario or in a simulated Winnipeg winter. Simulated Winnipeg winter individuals had cold tolerance similar to those overwintered in Winnipeg, while SW Ontario overwintered individuals had cold tolerance similar to those collected previously in the region. The simulated winter individuals had higher hemolymph glycerol concentrations than SW Ontario overwintered animals, at least in part due to greater dehydration. Thus, A. planipennis are cold-tolerant enough to survive some of the harshest winters where their host trees can grow, and most likely attain this cold tolerance via phenotypic plasticity. These findings raise the importance of delineating sensitivity of conclusions to unexpected phenotypic plasticity when predicting potential distributions of new invasives or responses to climate change.

Assessment of the Systems Approach for the Phytosanitary Treatment of Wood Infested With Wood-Boring Insects.

Addressing the risk from pests present in wood and wood products destined for international trade is an essential step towards minimizing the movement, introduction and establishment of invasive species. One method of managing the pest risk associated with wood commodities is the use of a systems approach that incorporates multiple independent measures applied along a production pathway. However, quantifying the reduction of risk can be difficult because the approach requires raw material infested with the pest of interest at a sufficient density to be able to quantify changes in pest abundance. We tested a systems approach for the production of sawn wood using green ash, Fraxinus pennsylvanica Marshall (Lamiales: Oleaceae), infested with emerald ash borer, Agrilus planipennis Fairmaire (Coleoptera: Buprestidae), by quantifying the change in pest density during the milling process and the precise effect of heat treatment on insects in situ. Greater than 90% of emerald ash borer were removed at the first step of the milling process (debarking) and >99% were removed before the production of green sawn wood. No insects survived kilning or heat treatment. All life stages of emerald ash borer were killed at 56°C and above. Heat, however, had no sublethal effect on emerald ash borer performance. These results show that the application of a systems approach to mitigate emerald ash borer in heat-treated, sawn wood is effective. Moreover, the model-system approach developed in this study can be a template for investigating the effect of systems approaches for other phloem-feeding insects.