Delayed reinforcement of costimulation improves the efficacy of mRNA vaccines in mice.

mRNA vaccines have demonstrated efficacy during the COVID-19 pandemic and are now being investigated for multiple diseases. However, concerns linger about the durability of immune responses, and the high incidence of breakthrough infections among vaccinated individuals highlights the need for improved mRNA vaccines. In this study, we investigated the effects of reinforcing costimulation via 4-1BB, a member of the TNF receptor superfamily, on immune responses elicited by mRNA vaccines.

Breast Milk-Derived Antibodies Impair Vaccine Immunity in Suckling Mice.

Breast milk confers multiple benefits to the neonate, including passive immunity against multiple microorganisms via Abs. However, it remains unclear whether breast milk-derived Abs affect vaccine-induced immunity in the neonate. We evaluated in C57BL/6 and BALB/c mice whether breastfeeding from an mRNA-SARS-CoV-2-vaccinated dam affects vaccine-induced immunity in neonate mice.

Time-dependent enhancement of mRNA vaccines by 4-1BB costimulation.

mRNA vaccines have demonstrated efficacy against COVID-19. However, concerns regarding waning immunity and breakthrough infections have motivated the development of next-generation vaccines with enhanced efficacy. In this study, we investigated the impact of 4-1BB costimulation on immune responses elicited by mRNA vaccines in mice.

Pre-existing immunity modulates responses to mRNA boosters.

mRNA vaccines are effective in preventing severe COVID-19, but breakthrough infections, emerging variants, and waning immunity warrant the use of boosters. Although mRNA boosters are being implemented, the extent to which pre-existing immunity influences the efficacy of boosters remains unclear. In a cohort of individuals primed with the mRNA-1273 or BNT162b2 vaccines, we report that lower antibody levels before boost are associated with higher fold-increase in antibody levels after boost, suggesting that pre-existing antibody modulates the immunogenicity of mRNA vaccines.

Improved control of SARS-CoV-2 by treatment with a nucleocapsid-specific monoclonal antibody.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein is the main antigen in all approved COVID-19 vaccines and is also the only target for monoclonal antibody (mAb) therapies. Immune responses to other viral antigens are generated after SARS-CoV-2 infection, but their contribution to the antiviral response remains unclear. Here, we interrogated whether nucleocapsid-specific antibodies can improve protection against SARS-CoV-2.

Adoptive B cell therapy for chronic viral infection.

T cell-based therapies have been widely explored for the treatment of cancer and chronic infection, but B cell-based therapies have remained largely unexplored. To study the effect of B cell therapy, we adoptively transferred virus-specific B cells into mice that were chronically infected with lymphocytic choriomeningitis virus (LCMV). Adoptive transfer of virus-specific B cells resulted in increase in antibody titers and reduction of viral loads.

Pre-existing immunity modulates responses to mRNA boosters.

mRNA vaccines have shown high efficacy in preventing severe COVID-19, but breakthrough infections, emerging variants and waning antibody levels have warranted the use of boosters. Although mRNA boosters have been widely implemented, the extent to which pre-existing immunity influences the efficacy of boosters remains unclear. In a cohort of individuals primed with the mRNA-1273 or BNT162b2 vaccines, we observed that lower antibody levels before boost were associated with higher fold-increase in antibody levels after boost, suggesting that pre-existing antibody modulates the boosting capacity of mRNA vaccines.

Fractionating a COVID-19 Ad5-vectored vaccine improves virus-specific immunity.

SARS-CoV-2 has caused a global pandemic that has infected more than 250 million people worldwide. Although several vaccine candidates have received emergency use authorization, there is still limited knowledge on how vaccine dosing affects immune responses. We performed mechanistic studies in mice to understand how the priming dose of an adenovirus-based SARS-CoV-2 vaccine affects long-term immunity to SARS-CoV-2.

Cross-protective immunity following coronavirus vaccination and coronavirus infection.

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have shown efficacy against SARS-CoV-2, it is unknown if coronavirus vaccines can also protect against other coronaviruses that may infect humans in the future. Here, we show that coronavirus vaccines elicited cross-protective immune responses against heterologous coronaviruses. In particular, we show that a severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) vaccine developed in 2004 and known to protect against SARS-CoV-1 conferred robust heterologous protection against SARS-CoV-2 in mice.

Limiting the priming dose of a SARS CoV-2 vaccine improves virus-specific immunity.

Since late 2019, SARS-CoV-2 has caused a global pandemic that has infected 128 million people worldwide. Although several vaccine candidates have received emergency use authorization (EUA), there are still a limited number of vaccine doses available. To increase the number of vaccinated individuals, there are ongoing discussions about administering partial vaccine doses, but there is still a paucity of data on how vaccine fractionation affects vaccine-elicited immunity.

Impact of outpatient SARS-CoV-2 infections in minority children.

Data regarding COVID-19 in the adult population and hospitalized children is rapidly evolving, but little is known about children infected with severe acute respiratory syndrome coronavirus 2 who do not require hospitalization.In an observational, retrospective study we analyzed risk factors, demographics and clinical course of non-hospitalized patients ≤ 21 years of age with COVID-19 infection.Of the 1,796 patients evaluated, 170 were infected, and 40 participated in a telephone survey.

Seizure Detection by Critical Care Providers Using Amplitude-Integrated Electroencephalography and Color Density Spectral Array in Pediatric Cardiac Arrest Patients.

Objectives: Determine the accuracy and confidence of critical care medicine providers to identify seizures using amplitude-integrated electroencephalography versus amplitude-integrated electroencephalography combined with color density spectral array electroencephalography (aEEG + CDSA).

Design: Tutorial and questionnaire.

Setting: PICU.

Early Electroencephalographic Background Features Predict Outcomes in Children Resuscitated From Cardiac Arrest.

Objectives: To determine 1) whether early electroencephalographic background features were associated with survival and neurologic outcomes among children resuscitated from cardiac arrest and not treated with therapeutic hypothermia and 2) if addition of electroencephalographic background to commonly used clinical criteria is more predictive of outcome than clinical criteria alone.

Design: Retrospective study.

Setting: PICU and Cardiac ICUs of a tertiary children's hospital.

Strategies to Maximize Enrollment in a Prospective Study of Comatose Children in the PICU.

Objectives: To analyze barriers to recruitment encountered during a prospective study in the PICU and evaluate strategies implemented to improve recruitment.

Design: Prospective observational study of continuous electroencephalogram monitoring in comatose children.

Setting: PICUs at four North American institutions.

Electrographic status epilepticus and long-term outcome in critically ill children.

Objective: Electrographic seizures (ES) and electrographic status epilepticus (ESE) are common in children in the pediatric intensive care unit (PICU) with acute neurologic conditions. We aimed to determine whether ES or ESE was associated with worse long-term outcomes.

Methods: Three hundred children with an acute neurologic condition and encephalopathy underwent clinically indicated EEG monitoring and were enrolled in a prospective observational study.

Electrographic seizures after convulsive status epilepticus in children and young adults: a retrospective multicenter study.

Objective: To describe the prevalence, characteristics, and predictors of electrographic seizures after convulsive status epilepticus (CSE).

Study Design: This was a multicenter retrospective study in which we describe clinical and electroencephalographic (EEG) features of children (1 month to 21 years) with CSE who underwent continuous EEG monitoring.

Results: Ninety-eight children (53 males) with CSE (median age of 5 years) underwent subsequent continuous EEG monitoring after CSE.

Density spectral array for seizure identification in critically ill children.

Purpose: We evaluated the validity and interrater reliability of encephalographer interpretation of color density spectral array EEG for seizure identification was evaluated in critically ill children and explored predictors of accurate seizure identification.

Methods: Conventional EEG tracings from 21 consecutive critically ill children were scored for electrographic seizures. Four 2-hour long segments from each subject were converted to 8-channel color density spectral array displays, yielding 84 images.

Electroencephalography monitoring in critically ill children: current practice and implications for future study design.

Purpose: Survey data indicate that continuous electroencephalography (EEG) (CEEG) monitoring is used with increasing frequency to identify electrographic seizures in critically ill children, but studies of current CEEG practice have not been conducted. We aimed to describe the clinical utilization of CEEG in critically ill children at tertiary care hospitals with a particular focus on variables essential for designing feasible prospective multicenter studies evaluating the impact of electrographic seizures on outcome.

Methods: Eleven North American centers retrospectively enrolled 550 consecutive critically ill children who underwent CEEG.

Electrographic seizures in pediatric ICU patients: cohort study of risk factors and mortality.

Objectives: We aimed to determine the incidence of electrographic seizures in children in the pediatric intensive care unit who underwent EEG monitoring, risk factors for electrographic seizures, and whether electrographic seizures were associated with increased odds of mortality.

Methods: Eleven sites in North America retrospectively reviewed a total of 550 consecutive children in pediatric intensive care units who underwent EEG monitoring. We collected data on demographics, diagnoses, clinical seizures, mental status at EEG onset, EEG background, interictal epileptiform discharges, electrographic seizures, intensive care unit length of stay, and in-hospital mortality.

Treatment of electrographic seizures and status epilepticus in critically ill children: a single center experience.

Purpose: Electrographic seizures (ES) and electrographic status epilepticus (ESE) are common in encephalopathic children in the pediatric intensive care unit (PICU) and associated with worse short-term outcome. Survey data indicate most physicians treat ES and ESE with antiepileptic drugs (AEDs), but few data are available regarding AED usage patterns. We aimed to describe AED usage for ES and ESE in critically ill children.

Pediatric ICU EEG monitoring: current resources and practice in the United States and Canada.

Purpose: To describe current continuous EEG monitoring (cEEG) utilization in critically ill children.

Methods: An online survey of pediatric neurologists from 50 US and 11 Canadian institutions was conducted in August 2011.

Results: Responses were received from 58 of 61 (95%) surveyed institutions.

Electrographic status epilepticus is associated with mortality and worse short-term outcome in critically ill children.

Objectives: Electrographic seizures and electrographic status epilepticus are common in critically ill children. We aimed to determine whether electrographic seizures and electrographic status epilepticus are associated with higher mortality or worse short-term neurologic outcome.

Design: Prospective observational study.

A simple model of tetracycline antibiotic resistance in the aquatic environment (with application to the Poudre River).

Antibiotic resistance is a major concern, yet it is unclear what causes the relatively high densities of resistant bacteria in the anthropogenically impacted environment. There are various possible scenarios (hypotheses): (A) Input of resistant bacteria from wastewater and agricultural sources is significant, but they do not grow in the environment; (B) Input of resistant bacteria is negligible, but the resistant bacteria (exogenous or endogenous) grow due to the selection pressure of the antibiotic; (C) Exogenous bacteria transfer the resistance to the endogenous bacteria and those grow. This paper presents a simple mechanistic model of tetracycline resistance in the aquatic environment.