Diagnostic delays among COVID-19 patients with a second concurrent diagnosis.

BACKGROUND: Little is known about the effect of a new pandemic on diagnostic errors. OBJECTIVE: We aimed to identify delayed second diagnoses among patients presenting to the emergency department (ED) with COVID-19. DESIGNS: An observational cohort Study. SETTINGS AND PARTICIPANTS: Consecutive hospitalized adult patients presenting to the ED of a tertiary referral center with COVID-19 during the Delta and Omicron variant surges. Included patients had evidence of a second diagnosis during their ED stay. MAIN OUTCOME AND MEASURES: The primary outcome was delayed diagnosis (without documentation or treatment in the ED). Contributing factors were assessed using two logistic regression models. RESULTS: Among 1249 hospitalized COVID-19 patients, 216 (17%) had evidence of a second diagnosis in the ED. The second diagnosis of 73 patients (34%) was delayed, with a mean (SD) delay of 1.5 (0.8) days. Medical treatment was deferred in 63 patients (86%) and interventional therapy in 26 (36%). The probability of an ED diagnosis was the lowest for Infection-related diagnoses (56%) and highest for surgical-related diagnoses (89%). Evidence for the second diagnosis by physical examination (adjusted odds ratios [AOR] 2.35, 95% confidence interval [CI] 1.20-4.68) or by imaging (AOR 2.10, 95% CI 1.16-3.79) were predictors for ED diagnosis. Low oxygen saturation (AOR 0.38, 95% CI 0.18-0.79) and cough or dyspnea (AOR 0.48, 95% CI 0.25-0.94) in the ED were predictors of a delayed second diagnosis.

Kinetic and equilibrium properties of regulatory Ca(2+)-binding domains in sodium-calcium exchangers 2 and 3.

In mammals, three sodium-calcium exchanger (NCX) protein isoforms (NCX1, NCX2, and NCX3) mediate Ca(2+) fluxes across the membrane to maintain cellular Ca(2+) homeostasis. NCX isoforms and their splice variants are expressed in a tissue-specific manner to meet physiological demands. NCX1 is ubiquitously expressed, NCX2 is expressed in the brain and spinal cord, and NCX3 is expressed in the brain and skeletal muscle. Eukaryotic NCXs contain two cytosolic regulatory Ca(2+)-binding domains, CBD1 and CBD2, which form a two-domain tandem (CBD12) through a short linker. Ca(2+) binding to the CBDs underlies allosteric regulation of NCX. Previous structural and functional studies in NCX1 have shown that the CBDs synergistically interact, where their interactions are modulated in a splice variant-specific manner by splicing segment at CBD2. Here, we analyze the equilibrium and kinetic properties of Ca(2+) binding to purified preparations of CBD1, CBD2, and CBD12 from NCX2 and from NCX3 splice variants. We show that CBD1 interacts with CBD2 in the context of the CBD12 tandem in all NCX isoforms, where these interactions specifically modulate Ca(2+) sensing at the primary sensor of CBD1 to meet the physiological requirements. For example, the rate-limiting slow dissociation of "occluded" Ca(2+) from the primary allosteric sensor of variants expressed in skeletal muscle is ∼10-fold slower than that of variants expressed in the brain. Notably, these kinetic differences between NCX variants occur while maintaining a similar Ca(2+) affinity of the primary sensor, since the resting [Ca(2+)]i levels are similar among different cell types.