Coupling metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and human traits.

Genetic studies of the metabolome can uncover enzymatic and transport processes shaping human metabolism. Using rare variant aggregation testing based on whole-exome sequencing data to detect genes associated with levels of 1,294 plasma and 1,396 urine metabolites, we discovered 235 gene-metabolite associations, many previously unreported. Complementary approaches (genetic, computational (in silico gene knockouts in whole-body models of human metabolism) and one experimental proof of principle) provided orthogonal evidence that studies of rare, damaging variants in the heterozygous state permit inferences concordant with those from inborn errors of metabolism.

On brain stimulation in epilepsy.

Brain stimulation has, for many decades, been considered as a potential solution for the unmet needs of the many people living with drug-resistant epilepsy. Clinically, there are several different approaches in use, including vagus nerve stimulation (VNS), deep brain stimulation of the thalamus, and responsive neurostimulation (RNS). Across populations of patients, all deliver reductions in seizure load and SUDEP risk, yet do so variably, and the improvements seem incremental rather than transformative.

Efficacy of parenteral bronchodilators on ventilatory outcomes in pediatric critical asthma: a national cohort study.

To evaluate the association of parenteral epinephrine and terbutaline use on ventilatory support in children admitted to the intensive care unit (ICU) with critical asthma in the United States. Data were obtained from the Pediatric Health Information System data base for children ages 2 to 18 years admitted to the ICU with a diagnosis of asthma exacerbation from January 1, 2016, to December 31, 2023. The primary outcomes included noninvasive ventilation (NIV) and/or invasive mechanical ventilation (IMV) use after receipt of terbutaline and/or epinephrine.