Artificial Intelligence-Augmented Pediatric Lung POCUS: A Pilot Study of Novice Learners.

OBJECTIVE: Respiratory symptoms are among the most common chief complaints of pediatric patients in the emergency department (ED). Point-of-care ultrasound (POCUS) outperforms conventional chest X-ray and is user-dependent, which can be challenging to novice ultrasound (US) users. We introduce a novel concept using artificial intelligence (AI)-enhanced pleural sweep to generate complete panoramic views of the lungs, and then assess its accuracy among novice learners (NLs) to identify pneumonia. METHODS: Previously healthy 0- to 17-year-old patients presenting to a pediatric ED with cardiopulmonary chief complaint were recruited. NLs received a 1-hour training on traditional lung POCUS and the AI-assisted software. Two POCUS-trained experts interpreted the images, which served as the criterion standard. Both expert and learner groups were blinded to each other's interpretation, patient data, and outcomes. Kappa was used to determine agreement between POCUS expert interpretations. RESULTS: Seven NLs, with limited to no prior POCUS experience, completed examinations on 32 patients. The average patient age was 5.53 years (±1.07). The median scan time of 7 minutes (minimum-maximum 3-43; interquartile 8). Three (8.8%) patients were diagnosed with pneumonia by criterion standard. Sensitivity, specificity, and accuracy for NLs AI-augmented interpretation were 66.7% (confidence interval [CI] 9.4-99.1%), 96.5% (CI 82.2-99.9%), and 93.7% (CI 79.1-99.2%). The average image quality rating was 2.94 (±0.16) out of 5 across all lung fields. Interrater reliability between expert sonographers was high with a kappa coefficient of 0.8. CONCLUSION: This study shows that AI-augmented lung US for diagnosing pneumonia has the potential to increase accuracy and efficiency.

The tumor suppressor CDKN3 controls mitosis.

Mitosis is controlled by a network of kinases and phosphatases. We screened a library of small interfering RNAs against a genome-wide set of phosphatases to comprehensively evaluate the role of human phosphatases in mitosis. We found four candidate spindle checkpoint phosphatases, including the tumor suppressor CDKN3. We show that CDKN3 is essential for normal mitosis and G1/S transition. We demonstrate that subcellular localization of CDKN3 changes throughout the cell cycle. We show that CDKN3 dephosphorylates threonine-161 of CDC2 during mitotic exit and we visualize CDC2(pThr-161) at kinetochores and centrosomes in early mitosis. We performed a phosphokinome-wide mass spectrometry screen to find effectors of the CDKN3-CDC2 signaling axis. We found that one of the identified downstream phosphotargets, CKß phosphorylated at serine 209, localizes to mitotic centrosomes and controls the spindle checkpoint. Finally, we show that CDKN3 protein is down-regulated in brain tumors. Our findings indicate that CDKN3 controls mitosis through the CDC2 signaling axis. These results have implications for targeted anticancer therapeutics.

Pharmacogenetic predictors of nausea and vomiting of pregnancy severity and response to antiemetic therapy: a pilot study.

BACKGROUND: Nausea and vomiting of pregnancy (NVP) is a common condition. The objective of this study was to evaluate the association between response to antiemetics in the treatment of NVP and genetic polymorphisms in the serotonin receptor subunit genes HTR3A and HTR3B. METHODS: Pregnant women ≥18 years of age with NVP starting antiemetic therapy with promethazine, prochlorperazine, metoclopramide, or ondansetron at ≤ 16 weeks gestational age were eligible. The study recruited 29 women with complete data and sampling who returned for their one week follow-up and were genotyped for HTR3A and HTR3B polymorphisms. Severity of NVP was captured (using Pregnancy Unique Quantification of Emesis (PUQE) and Quality of Life (QOL) tools) upon enrollment and after one week of antiemetic therapy. These measures were correlated with pharmacogenetic variability. RESULTS: Subjects with genotype associated with high serotonin affinity of the 5-HT3B receptor (rs1176744, CC) required more antiemetic medications (p < 0.001) than other subjects. Those with genotypes associated with increased expression of the 5-HT3A receptor subunit (rs1062613, CT or TT) had worse final PUQE scores (p = 0.01) than other subjects while rs3782025 variants carriers had significantly better initial (p = 0.02) and final (p = 0.02) PUQE scores than other subjects. CONCLUSIONS: HTR3B and HTR3A gene variants may contribute to variability in response to antiemetic therapy for NVP.

The impact of glucocorticoid polymorphisms on markers of neonatal respiratory disease after antenatal betamethasone administration.

OBJECTIVE: We previously demonstrated that maternal and fetal genotypes are associated independently with neonatal respiratory distress syndrome. The objective of the current study was to determine the impact of maternal and fetal single-nucleotide polymorphisms (SNPs) in key betamethasone pathways on respiratory outcomes that serve as markers for severity of disease. STUDY DESIGN: DNA was obtained from women who were given betamethasone and from their infants. Samples were genotyped for 73 exploratory drug metabolism and glucocorticoid pathway SNPs. Clinical variables and neonatal outcomes were obtained. Logistic regression analysis that controlled for relevant clinical variables to determine SNP impact on bronchopulmonary dysplasia (BPD), the need for respiratory support, and surfactant therapy use was performed. RESULTS: Data from 109 women who delivered 117 infants were analyzed: 14.5% of the infants experienced BPD; 70.8% of the infants needed some respiratory support after birth, and 27.5% of the infants needed surfactant therapy. In a multivariable regression analysis, gestational age at delivery was associated with most neonatal respiratory outcomes (P ≤ .01), and chorioamnionitis was associated with BPD (P < .03). The following genotypes were associated with respiratory severity outcomes: BPD-fetal Importin 13 gene (IPO13; rs4448553; odds ratio [OR], 0.01; 95% confidence interval [CI], 0.00-0.92); surfactant use-maternal IPO13 (rs2428953 and 2486014; OR, 13.8; 95% CI, 1.80-105.5; and OR, 35.5; 95% CI, 1.71-736.6, respectively). CONCLUSION: Several discrete maternal and fetal SNPs in the IPO13 family may be associated with neonatal respiratory outcomes after maternal antenatal corticosteroid treatment for anticipated preterm birth.

The impact of drug metabolizing enzyme polymorphisms on outcomes after antenatal corticosteroid use.

OBJECTIVE: To determine the impact of maternal and fetal single nucleotide polymorphisms in key betamethasone pathways on neonatal outcomes. STUDY DESIGN: DNA was obtained from women given betamethasone and their infants. Samples were genotyped for 73 exploratory drug metabolism and glucocorticoid pathway single nucleotide polymorphisms. Clinical variables and neonatal outcomes were obtained. Logistic regression analysis using relevant clinical variables and genotypes to model for associations with neonatal respiratory distress syndrome was performed. RESULTS: One hundred nine women delivering 117 infants were analyzed. Sixty-four infants (49%) developed respiratory distress syndrome. Multivariable analysis revealed that respiratory distress syndrome was associated with maternal single nucleotide polymorphisms in CYP3A5 (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.16-2.30) and the glucocorticoid resistance (OR, 0.28; 95% CI, 0.08-0.95) and fetal single nucleotide polymorphisms in ADCY9 (OR, 0.17; 95% CI, 0.03-0.80) and CYP3A7*1E (rs28451617; OR, 23.68; 95% CI, 1.33-420.6). CONCLUSION: Maternal and fetal genotypes are independently associated with neonatal respiratory distress syndrome after treatment with betamethasone for preterm labor.

Collection of human genomic DNA from neonates: a comparison between umbilical cord blood and buccal swabs.

OBJECTIVE: To compare DNA yield from neonatal umbilical cord blood and buccal swab specimens. STUDY DESIGN: Umbilical cord blood was obtained at birth in a cohort of women enrolled in a preterm labor study. If cord blood was not obtained, neonatal buccal samples were obtained using the Oragene saliva kits. DNA was extracted from all samples using the QIAamp extraction kits. DNA concentration and yield were compared between umbilical cord blood and buccal swabs. RESULTS: DNA concentrations from umbilical cord blood (n = 35) was greater than that obtained from buccal swabs (n = 20) (total sample: 209.0 ± 110.7 ng/µL vs 6.9 ± 6.7 ng/µL respectively, P < .001; partial sample: n = 30 cord blood vs n = 11 buccal, 70.0 ± 51.4 ng/µL vs 11.3 ± 6.7 ng/µL, respectively, P < .001) and produced more total DNA (total sample: 116.5 ± 70.8 µg vs 4.2 ± 4.0 µg, P < .001; partial:14.0 ± 10.3 µg vs 1.1 ± 0.7 µg, respectively, P < .001). CONCLUSION: Buccal swabs yield less neonatal DNA than umbilical cord blood specimens.

Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia.

BACKGROUND: This study evaluates the relationship between cytochrome P450 (CYP) 3A5 genotype and vincristine-induced peripheral neuropathy (VIPN) in children with precursor B cell acute lymphoblastic leukemia (preB ALL). We have shown in vitro that vincristine is metabolized significantly more efficiently by CYP3A5 than by CYP3A4. We also found that vincristine neurotoxicity is less common in African-Americans (70% express CYP3A5) than in Caucasians. We test the hypothesis that CYP3A5 expressers experience less vincristine neuropathy than do CYP3A5 non-expressers. PROCEDURE: This study of pharmacogenetics of vincristine neuropathy in children with preB ALL was completed at Indiana University Simon Cancer Center. Whole blood for DNA extraction and genotyping was collected as well as plasma from a single time-point for analysis of vincristine and primary metabolite (M1) concentrations. Vincristine neuropathy was captured via chart review and graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. RESULTS: Eighty-nine percent of CYP3A5 expressers experienced neurotoxicity versus 100% of non-expressers (P = 0.03). The proportion of treatment months with neurotoxicity was significantly different between the expressers and non-expressers (16% vs. 27%, P = 0.0007). Limited pharmacokinetic data suggest different rates of vincristine metabolism between CYP3A5 genotype groups with higher primary metabolite (M1) plasma concentrations (P = 0.0004) and lower metabolic ratios ([vincristine]/[M1]) (P = 0.036) in the CYP3A5 expressers compared to the CYP3A5 non-expressers. M1 concentration was also inversely related to severity of neuropathy (P = 0.0316). CONCLUSIONS: In children with preB ALL, CYP3A5 expressers experience less VIPN, produce more M1, and have lower metabolic ratios compared to CYP3A5 non-expressers.