CT Use Reduction In Ostensive Ureteral Stone (CURIOUS).

INTRODUCTION: Computed tomography (CT) is performed in over 90% of patients diagnosed with ureteral stones, but only 10% of patients presenting to the emergency department (ED) with acute flank pain are hospitalized for a clinically important stone or non-stone diagnosis. Hydronephrosis can be accurately detected using point-of-care ultrasound and is a key predictor of ureteral stone and risk of subsequent complications. The absence of hydronephrosis is insufficient to exclude a stone. We created a sensitive clinical decision rule to predict clinically important ureteral stones. We hypothesized that this rule could identify patients at low risk for this outcome. METHODS: We conducted a retrospective cohort study in a random sample of 4000 adults who presented to one of 21 Kaiser Permanente Northern California EDs and underwent a CT for suspected ureteral stone from 1/1/2016 to 12/31/2020. The primary outcome was clinically important stone, defined as stone resulting in hospitalization or urologic procedure within 60 days. We used recursive partition analysis to generate a clinical decision rule predicting the outcome. We estimated the C-statistic (area under the curve), plotted the receiver operating characteristic (ROC) curve for the model, and calculated sensitivity, specificity, and predictive values of the model based on a risk threshold of 2%. RESULTS: Among 4000 patients, 354 (8.9%) had a clinically important stone. Our partition model resulted in four terminal nodes with risks ranging from 0.4% to 21.8%. The area under the ROC curve was 0.81 (95% CI 0.80, 0.83). Using a 2% risk cut point, a clinical decision tree including hydronephrosis, hematuria, and a history of prior stones predicted complicated stones with sensitivity 95.5% (95% CI 92.8%-97.4%), specificity 59.9% (95% CI 58.3%-61.5%), positive predictive value 18.8% (95% CI 18.1%-19.5%), and negative predictive value 99.3% (95% CI 98.8%-99.6%). CONCLUSIONS: Application of this clinical decision rule to imaging decisions would have led to 63% fewer CT scans with a miss rate of 0.4%. A limitation was the application of our decision rule only to patients who underwent CT for suspected ureteral stone. Thus, this rule would not apply to patients who were thought to have ureteral colic but did not receive a CT because ultrasound or history were sufficient for diagnosis. These results could inform future prospective validation studies.

SLC22 Transporters in the Fly Renal System Regulate Response to Oxidative Stress In Vivo.

Several SLC22 transporters in the human kidney and other tissues are thought to regulate endogenous small antioxidant molecules such as uric acid, ergothioneine, carnitine, and carnitine derivatives. These transporters include those from the organic anion transporter (OAT), OCTN/OCTN-related, and organic cation transporter (OCT) subgroups. In mammals, it has been difficult to show a clear in vivo role for these transporters during oxidative stress. Ubiquitous knockdowns of related Drosophila SLC22s-including transporters homologous to those previously identified by us in mammals such as the "Fly-Like Putative Transporters" FLIPT1 (SLC22A15) and FLIPT2 (SLC22A16)-have shown modest protection against oxidative stress. However, these fly transporters tend to be broadly expressed, and it is unclear if there is an organ in which their expression is critical. Using two tissue-selective knockdown strategies, we were able to demonstrate much greater and longer protection from oxidative stress compared to previous whole fly knockdowns as well as both parent and WT strains (CG6126: p < 0.001, CG4630: p < 0.01, CG16727: p < 0.0001 and CG6006: p < 0.01). Expression in the Malpighian tubule and likely other tissues as well (e.g., gut, fat body, nervous system) appear critical for managing oxidative stress. These four Drosophila SLC22 genes are similar to human SLC22 transporters (CG6126: SLC22A16, CG16727: SLC22A7, CG4630: SLC22A3, and CG6006: SLC22A1, SLC22A2, SLC22A3, SLC22A6, SLC22A7, SLC22A8, SLC22A11, SLC22A12 (URAT1), SLC22A13, SLC22A14)-many of which are highly expressed in the kidney. Consistent with the Remote Sensing and Signaling Theory, this indicates an important in vivo role in the oxidative stress response for multiple SLC22 transporters within the fly renal system, perhaps through interaction with SLC22 counterparts in non-renal tissues. We also note that many of the human relatives are well-known drug transporters. Our work not only indicates the importance of SLC22 transporters in the fly renal system but also sets the stage for in vivo studies by examining their role in mammalian oxidative stress and organ crosstalk.

Drosophila SLC22 Orthologs Related to OATs, OCTs, and OCTNs Regulate Development and Responsiveness to Oxidative Stress.

The SLC22 family of transporters is widely expressed, evolutionarily conserved, and plays a major role in regulating homeostasis by transporting small organic molecules such as metabolites, signaling molecules, and antioxidants. Analysis of transporters in fruit flies provides a simple yet orthologous platform to study the endogenous function of drug transporters in vivo. Evolutionary analysis of Drosophila melanogaster putative SLC22 orthologs reveals that, while many of the 25 SLC22 fruit fly orthologs do not fall within previously established SLC22 subclades, at least four members appear orthologous to mammalian SLC22 members (SLC22A16:CG6356, SLC22A15:CG7458, CG7442 and SLC22A18:CG3168). We functionally evaluated the role of SLC22 transporters in Drosophila melanogaster by knocking down 14 of these genes. Three putative SLC22 ortholog knockdowns-CG3168, CG6356, and CG7442/SLC22A-did not undergo eclosion and were lethal at the pupa stage, indicating the developmental importance of these genes. Additionally, knocking down four SLC22 members increased resistance to oxidative stress via paraquat testing (CG4630: p < 0.05, CG6006: p < 0.05, CG6126: p < 0.01 and CG16727: p < 0.05). Consistent with recent evidence that SLC22 is central to a Remote Sensing and Signaling Network (RSSN) involved in signaling and metabolism, these phenotypes support a key role for SLC22 in handling reactive oxygen species.

Systems Biology Analysis Reveals Eight SLC22 Transporter Subgroups, Including OATs, OCTs, and OCTNs.

The SLC22 family of OATs, OCTs, and OCTNs is emerging as a central hub of endogenous physiology. Despite often being referred to as "drug" transporters, they facilitate the movement of metabolites and key signaling molecules. An in-depth reanalysis supports a reassignment of these proteins into eight functional subgroups, with four new subgroups arising from the previously defined OAT subclade: OATS1 (SLC22A6, SLC22A8, and SLC22A20), OATS2 (SLC22A7), OATS3 (SLC22A11, SLC22A12, and Slc22a22), and OATS4 (SLC22A9, SLC22A10, SLC22A24, and SLC22A25). We propose merging the OCTN (SLC22A4, SLC22A5, and Slc22a21) and OCT-related (SLC22A15 and SLC22A16) subclades into the OCTN/OCTN-related subgroup. Using data from GWAS, in vivo models, and in vitro assays, we developed an SLC22 transporter-metabolite network and similar subgroup networks, which suggest how multiple SLC22 transporters with mono-, oligo-, and multi-specific substrate specificity interact to regulate metabolites. Subgroup associations include: OATS1 with signaling molecules, uremic toxins, and odorants, OATS2 with cyclic nucleotides, OATS3 with uric acid, OATS4 with conjugated sex hormones, particularly etiocholanolone glucuronide, OCT with neurotransmitters, and OCTN/OCTN-related with ergothioneine and carnitine derivatives. Our data suggest that the SLC22 family can work among itself, as well as with other ADME genes, to optimize levels of numerous metabolites and signaling molecules, involved in organ crosstalk and inter-organismal communication, as proposed by the remote sensing and signaling theory.

Accuracy of Medical Student Measurements of CT Right-to-Left Ventricular Diameter in Patients with Acute Pulmonary Embolism.

Objectives: Acute pulmonary embolism (PE) is a common disease, necessitating risk stratification to determine management. A right ventricle (RV) to left ventricle (LV) diameter ratio ≥1.0 on computed tomography pulmonary angiography (CTPA) suggests RV strain, which may indicate a worse prognosis. Two prior studies showed that residents with brief training by a radiologist could accurately measure RV/LV ratio. We assessed whether medical students could accurately measure RV dilatation. Methods: We conducted a post hoc analysis of a retrospective cohort study of adults undergoing management for acute PE at 21 community emergency departments across Kaiser Permanente Northern California from 2013 to 2015. We created a sample, stratified to contain an equal number of patients from each of the 5 PE Severity Index classes. Four medical students measured RV and LV diameter on CTPA after training from an emergency medicine physician and an interventional radiologist. We used Cohen's kappa statistics, Bland-Altman plots, and Pearson correlation coefficients to assess interrater reliability. Results: Of the 108 CTPAs reviewed, 79 (73%) showed RV dilatation and 29 (27%) did not. The kappa statistic for the presence of RV dilatation of the medical students compared to the radiologist showed moderate agreement for 3 medical students (kappa (95% CI): 0.46 (0.21-0.70), 0.49 (0.31-0.68), 0.50 (0.32-0.68)) and fair agreement for 1 medical student (kappa (95% CI): 0.29 (0.10-0.47)). The average interrater differences in RV/LV ratio between a radiologist and each of the 4 medical students were -0.04, -0.05, 0.04, and 0.24. Pearson correlation coefficients were 0.87, 0.80, 0.74, and 0.78, respectively, indicating moderate correlation (P < .001 for all). Conclusion: Medical students were able to identify RV dilatation on CTPA in moderate agreement with that of a radiologist. Further study is needed to determine whether medical student accuracy could improve with additional training.

Reevaluate how to evaluate: Systemic assessment biases affect students' confidence in college upper-division biology laboratory courses.

Grades influence students' confidence and decisions to complete STEM degrees and pursue relevant careers. What affects students' confidence and performance in college upper-division biology laboratory courses and how relevant are evaluation methods to career success? STEM laboratory courses are an excellent model to address these issues because of the hybrid environment, combining traditional lecture course format and the practical application of knowledge. We surveyed 567 students in two upper-division laboratory molecular biology courses at a major research university to compare course-content self-assessment, students' predicted grades, and actual grades received. By analyzing students' confidence and correlating them to grades assigned by the instructor, we identified biases including student and Instructor Assistant (IA) gender, IA experience, and academic quarter. Considering the systemic effect of identified biases, a correlation (R2  = 0.37, p < 0.01) between predicted and actual grades, and weak but statistically significant correlation (R2  = 0.10, p < 0.01) between students' comprehensive course-content self-assessment and their predicted grade are not surprising. Our analysis suggests that students' quantifiable self-assessment, a relatively simple and data-rich resource, helps identify evaluation bias. If administered periodically throughout the course, these assessments can help mitigate biases, improve student learning, evaluation, and retention in STEM fields.

Presyncope Is Associated with Intensive Care Unit Admission in Emergency Department Patients with Acute Pulmonary Embolism.

INTRODUCTION: Syncope is common among emergency department (ED) patients with acute pulmonary embolism (PE) and indicates a higher acuity and worse prognosis than in patients without syncope. Whether presyncope carries the same prognostic implications has not been established. We compared incidence of intensive care unit (ICU) admission in three groups of ED PE patients: those with presyncope; syncope; and neither. METHODS: This retrospective cohort study included all adults with acute, objectively confirmed PE in 21 community EDs from January 2013-April 2015. We combined electronic health record extraction with manual chart abstraction. We used chi-square test for univariate comparisons and performed multivariate analysis to evaluate associations between presyncope or syncope and ICU admission from the ED, reported as adjusted odds ratios (aOR) with 95% confidence intervals (CI). RESULTS: Among 2996 PE patients, 82 (2.7%) had presyncope and 109 (3.6%) had syncope. ICU admission was similar between groups (presyncope 18.3% vs syncope 25.7%) and different than their non-syncope counterparts (either 22.5% vs neither 4.7%; p<0.0001). On multivariate analysis, both presyncope and syncope were independently associated with ICU admission, controlling for demographics, higher-risk PE Severity Index (PESI) class, ventilatory support, proximal clot location, and submassive and massive PE classification: presyncope, aOR 2.79 (95% CI, 1.40, 5.56); syncope, aOR 4.44 (95% CI 2.52, 7.80). These associations were only minimally affected when excluding massive PE from the model. There was no significant interaction between either syncope or presyncope and PESI, submassive or massive classification in predicting ICU admission. CONCLUSION: Presyncope appears to carry similar strength of association with ICU admission as syncope in ED patients with acute PE. If this is confirmed, clinicians evaluating patients with acute PE may benefit from including presyncope in their calculus of risk assessment and site-of-care decision-making.