Background

Air pollution exposure is ubiquitous with demonstrated effects on morbidity and mortality. A growing literature suggests that prenatal air pollution exposure impacts neurodevelopment. We posit that the Environmental influences on Child Health Outcomes (ECHO) program will provide unique opportunities to fill critical knowledge gaps given the wide spatial and temporal variability of ECHO participants.

Objectives

We briefly describe current methods for air pollution exposure assessment, summarize existing studies of air pollution and neurodevelopment, and synthesize this information as a basis for recommendations, or a blueprint, for evaluating air pollution effects on neurodevelopmental outcomes in ECHO.

Methods

We review peer-reviewed literature on prenatal air pollution exposure and neurodevelopmental outcomes, including autism spectrum disorder, attention deficit hyperactivity disorder, intelligence, general cognition, mood, and imaging measures. ECHO meta-data were compiled and evaluated to assess frequency of neurodevelopmental assessments and prenatal and infancy residential address locations. Cohort recruitment locations and enrollment years were summarized to examine potential spatial and temporal variation present in ECHO.

Discussion

While the literature provides compelling evidence that prenatal air pollution affects neurodevelopment, limitations in spatial and temporal exposure variation exist for current published studies. As >90% of the ECHO cohorts have collected a prenatal or infancy address, application of advanced geographic information systems-based models for common air pollutant exposures may be ideal to address limitations of published research.

Conclusions

In ECHO we have the opportunity to pioneer unifying exposure assessment and evaluate effects across multiple periods of development and neurodevelopmental outcomes, setting the standard for evaluation of prenatal air pollution exposures with the goal of improving children's health.

Background

The etiology and natural history of Parkinson's disease (PD) are not well understood. Some non-motor symptoms such as hyposmia, rapid eye movement sleep behavior disorder, and constipation may develop during the prodromal stage of PD and precede PD diagnosis by years.

Objectives

We examined the promise and pitfalls of research on premotor symptoms of PD and developed priorities and strategies to understand their clinical and etiological implications.

Methods

This review was based on a workshop, Parkinson's Disease Premotor Symptom Symposium, held 7-8 June 2012 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina.

Discussion

Research on premotor symptoms of PD may offer an excellent opportunity to characterize high-risk populations and to better understand PD etiology. Such research may lead to evaluation of novel etiological hypotheses such as the possibility that environmental toxicants or viruses may initiate PD pathogenesis in the gastrointestinal tract or olfactory bulb. At present, our understanding of premotor symptoms of PD is in its infancy and faces many obstacles. These symptoms are often not specific to PD and have low positive predictive value for early PD diagnosis. Further, the pathological bases and biological mechanisms of these premotor symptoms and their relevance to PD pathogenesis are poorly understood.

Conclusion

This is an emerging research area with important data gaps to be filled. Future research is needed to understand the prevalence of multiple premotor symptoms and their etiological relevance to PD. Animal experiments and mechanistic studies will further understanding of the biology of these premotor symptoms and test novel etiological hypothesis.

Background

Development of safe and effective SARS-CoV-2 therapeutics is a high priority. Amubarvimab and romlusevimab are noncompeting anti-SARS-CoV-2 monoclonal antibodies with an extended half-life.

Objective

To assess the safety and efficacy of amubarvimab plus romlusevimab.

Design

Randomized, placebo-controlled, phase 2 and 3 platform trial. (ClinicalTrials.gov: NCT04518410).

Setting

Nonhospitalized patients with COVID-19 in the United States, Brazil, South Africa, Mexico, Argentina, and the Philippines.

Patients

Adults within 10 days onset of symptomatic SARS-CoV-2 infection who are at high risk for clinical progression.

Intervention

Combination of monoclonal antibodies amubarvimab plus romlusevimab or placebo.

Measurements

Nasopharyngeal and anterior nasal swabs for SARS-CoV-2, COVID-19 symptoms, safety, and progression to hospitalization or death.

Results

Eight-hundred and seven participants who initiated the study intervention were included in the phase 3 analysis. Median age was 49 years (quartiles, 39 to 58); 51% were female, 18% were Black, and 50% were Hispanic or Latino. Median time from symptom onset at study entry was 6 days (quartiles, 4 to 7). Hospitalizations and/or death occurred in 9 (2.3%) participants in the amubarvimab plus romlusevimab group compared with 44 (10.7%) in the placebo group, with an estimated 79% reduction in events (P < 0.001). This reduction was similar between participants with 5 or less and more than 5 days of symptoms at study entry. Grade 3 or higher treatment-emergent adverse events through day 28 were seen less frequently among participants randomly assigned to amubarvimab plus romlusevimab (7.3%) than placebo (16.1%) (P < 0.001), with no severe infusion reactions or drug-related serious adverse events.

Limitation

The study population was mostly unvaccinated against COVID-19 and enrolled before the spread of Omicron variants and subvariants.

Conclusion

Amubarvimab plus romlusevimab was safe and significantly reduced the risk for hospitalization and/or death among nonhospitalized adults with mild to moderate SARS-CoV-2 infection at high risk for progression to severe disease.

Primary funding source

National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

Background

It is unknown if early COVID-19 monoclonal antibody (mAb) therapy can reduce risk of Long COVID. The mAbs amubarvimab/romlusevimab were previously demonstrated to reduce risk of hospitalization/death by 79%. This study assessed the impact of amubarvimab/romlusevimab on late outcomes, including Long COVID.

Methods

Non-hospitalized high-risk adults within 10 days of COVID-19 symptom onset enrolled in a randomized, double-blind, placebo-controlled phase 2/3 trial of amubarvimab/romlusevimab for COVID-19 treatment. Late symptoms, assessed using a participant-completed symptom diary, were a pre-specified exploratory endpoint. The primary outcome for this analysis was the composite of Long COVID by participant self-report (presence of COVID-19 symptoms as recorded in the diary at week 36) or hospitalization or death by week 36. Inverse probability weighting (IPW) was used to address incomplete outcome ascertainment, giving weighted risk ratios (wRR) comparing amubarvimab/romlusevimab to placebo.

Findings

Participants received amubarvimab/romlusevimab (n = 390) or placebo (n = 390) between January and July 2021. Median age was 49 years, 52% were female, 18% Black/African American, 49% Hispanic/Latino, and 9% COVID-19-vaccinated at entry. At week 36, 103 (13%) had incomplete outcome ascertainment, and 66 (17%) on amubarvimab/romlusevimab and 92 (24%) on placebo met the primary outcome (wRR = 0.70, 95% confidence interval (CI) 0.53-0.93). The difference was driven by fewer hospitalizations/deaths with amubarvimab/romlusevimab (4%) than placebo (13%). Among 652 participants with available diary responses, 53 (16%) on amubarvimab/romlusevimab and 44 (14%) on placebo reported presence of Long COVID.

Interpretation

Amubarvimab/romlusevimab treatment, while highly effective in preventing hospitalizations/deaths, did not reduce risk of Long COVID. Additional interventions are needed to prevent Long COVID.

Funding

National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Amubarvimab and romlusevimab supplied by Brii Biosciences.