ABSTRACT
Approximately half of U.S. women giving birth annually receive Pitocin, the synthetic form of oxytocin (OXT), yet its effective dose can vary significantly. This variability presents safety concerns due to unpredictable responses, which may lead to adverse outcomes for both mother and baby. To address the need for improved dosing, we developed a data-driven mathematical model to predict OXT receptor (OXTR) binding. Our study focuses on five prevalent OXTR variants (V45L, P108A, L206V, V281M, and E339K) and their impact on OXT-OXTR binding dynamics in two distinct cell types: human embryonic kidney cells (HEK293T), commonly used in experimental systems, and human myometrial smooth muscle cells, containing endogenous OXTR. We parameterized the model with cell-specific OXTR surface localization measurements. To strengthen the robustness of our study, we conducted a comprehensive meta-analysis of OXT- OXTR binding, enabling parameterization of our model with cell-specific OXT-OXTR binding kinetics (myometrial OXT-OXTR K d = 1.6 nM, kon = 6.8 × 10 5 M -1 min -1 , and koff = 0.0011 min -1 ). Our meta-analysis revealed significant homogeneity in OXT-OXTR affinity across experiments and species with a K d = 0.52 - 9.32 nM and mean K d = 1.48 ± 0.36 nM. Our model achieves several valuable insights into designing dosage strategies. First, we predicted that the OXTR complex reaches maximum occupancy at 10 nM OXT in myometrial cells and at 1 µM in HEK293T cells. This information is pivotal for guiding experimental design and data interpretation when working with these distinct cell types, emphasizing the need to consider effects for specific cell types when choosing OXTR-transfected cell lines. Second, our model recapitulated the significant effects of genetic variants for both experimental and physiologically relevant systems, with V281M and E339K substantially compromising OXT-OXTR binding capacity. These findings suggest the need for personalized oxytocin dosing based on individual genetic profiles to enhance therapeutic efficacy and reduce risks, especially in the context of labor and delivery. Third, we demonstrated the potential for rescuing the attenuated cell response observed in V281M and E339K variants by increasing the OXT dosage at specific, early time points. Cellular responses to OXT, including Ca 2+ release, manifest within minutes. Our model indicates that providing V281M- and E339K-expressing cells with doubled OXT dose during the initial minute of binding can elevate OXT-OXTR complex formation to levels comparable to wild-type OXTR. In summary, our study provides a computational framework for precision oxytocin dosing strategies, paving the way for personalized medicine.
ABSTRACT
OBJECTIVE: Despite strong evidence for its utility in clinical management and diagnosis of intracranial hemorrhage (ICH), the use of neonatal cranial point-of-care ultrasound (POCUS) has not been standardized in neonatal intensive care units (NICUs) in the United States. The primary aim of this study was to evaluate the feasibility of training NICU providers to perform cranial POCUS by tracking the quality of image acquisition following training. METHODS: Observational single-center cohort study of cranial POCUS images obtained by trained neonatal practitioners (attendings, fellows, and advanced practice providers) using a protocol developed by a radiologist and neonatologist. Exams were performed on infants born ≤1250 g and/or ≤30 weeks gestation within the first 3 days after birth. A survey to assess attitudes regarding cranial POCUS was given before each of three training sessions. Demographic and clinical data collection were portrayed with descriptive statistics. Metrics of image quality were assessed by a radiologist and sonographer independently. Analysis of trends in quality of POCUS images over time was performed using a multinomial Cochran-Armitage test. RESULTS: Eighty-two cranial POCUS scans were performed over a 2-year period. Infant median age at exam was 14 hours (IQR 7-22 hours). Metrics of image quality depicted quarterly demonstrated a significant improvement in depth (P = .01), gain (P = .048), and quality of anatomy images captured (P < .001) over time. Providers perceived increased utility and safety of cranial POCUS over time. CONCLUSION: Cranial POCUS image acquisition improved significantly following care team training, which may enable providers to diagnose ICH at the bedside.
