This copy is for personal use only. To order printed copies, contact reprints@rsna.org I n P r e s s Abbreviations: AUC = area under the receiver operating characteristic curve CI = confidence interval COVID-19 = coronavirus disease 2019 COVNet = COVID-19 detection neural network CAP = community acquired pneumonia DICOM = digital imaging and communications in medicine Key Results:A deep learning method was able to identify COVID-19 on chest CT exams (area under the receiver operating characteristic curve, 0.96).A deep learning method to identify community acquired pneumonia on chest CT exams (area under the receiver operating characteristic curve, 0.95).There is overlap in the chest CT imaging findings of all viral pneumonias with other chest diseases that encourages a multidisciplinary approach to the final diagnosis used for patient treatment. Summary Statement:Deep learning detects coronavirus disease 2019 (COVID-19) and distinguish it from community acquired pneumonia and other non-pneumonic lung diseases using chest CT. I n P r e s s Abstract:Background: Coronavirus disease has widely spread all over the world since the beginning of 2020. It is desirable to develop automatic and accurate detection of COVID-19 using chest CT.Purpose: To develop a fully automatic framework to detect COVID-19 using chest CT and evaluate its performances. Materials and Methods:In this retrospective and multi-center study, a deep learning model, COVID-19 detection neural network (COVNet), was developed to extract visual features from volumetric chest CT exams for the detection of COVID-19. Community acquired pneumonia (CAP) and other non-pneumonia CT exams were included to test the robustness of the model. The datasets were collected from 6 hospitals between August 2016 and February 2020. Diagnostic performance was assessed by the area under the receiver operating characteristic curve (AUC), sensitivity and specificity. Results:The collected dataset consisted of 4356 chest CT exams from 3,322 patients. The average age is 49±15 years and there were slightly more male patients than female (1838 vs 1484; p-value=0.29). The per-exam sensitivity and specificity for detecting COVID-19 in the independent test set was 114 of 127 (90% [95% CI: 83%, 94%]) and 294 of 307 (96% [95% CI: 93%, 98%]), respectively, with an AUC of 0.96 (p-value<0.001). The per-exam sensitivity and specificity for detecting CAP in the independent test set was 87% (152 of 175) and 92% (239 of 259), respectively, with an AUC of 0.95 (95% CI: 0.93, 0.97). Conclusions:A deep learning model can accurately detect COVID-19 and differentiate it from community acquired pneumonia and other lung diseases.

Trimethlyamine-N-oxide (TMAO) was recently identified as a promoter of atherosclerosis. Patients with CKD exhibit accelerated development of atherosclerosis; however, no studies have explored the relationship between TMAO and atherosclerosis formation in this group. This study measured serum concentrations and urinary excretion of TMAO in a CKD cohort (n=104), identified the effect of renal transplant on serum TMAO concentration in a subset of these patients (n=6), and explored the cross-sectional relationship between serum TMAO and coronary atherosclerosis burden in a separate CKD cohort (n=220) undergoing coronary angiography. Additional exploratory analyses examined the relationship between baseline serum TMAO and long-term survival after coronary angiography. Serum TMAO concentrations demonstrated a strong inverse association with eGFR (r 2 =0.31, P,0.001). TMAO concentrations were markedly higher in patients receiving dialysis (median [interquartile range], 94.4 mM [54.8-133.0 mM] for dialysis-dependent patients versus 3.3 mM [3.1-6.0 mM] for healthy controls; P,0.001); whereas renal transplantation resulted in substantial reductions in TMAO concentrations (median [min-max] 71.2 mM [29.2-189.7 mM] pretransplant versus 11.4 mM [8.9-20.2 mM] posttransplant; P=0.03). TMAO concentration was an independent predictor for coronary atherosclerosis burden (P=0.02) and predicted long-term mortality independent of traditional cardiac risk factors (hazard ratio, 1.26 per 10 mM increment in TMAO concentration; 95% confidence interval, 1.13 to 1.40; P,0.001). In conclusion, serum TMAO concentrations substantially increase with decrements in kidney function, and this effect is reversed by renal transplantation. Increased TMAO concentrations correlate with coronary atherosclerosis burden and may associate with long-term mortality in patients with CKD undergoing coronary angiography. Patients with CKD have a high prevalence of cardiovascular comorbidities, which primarily contributes to the exceedingly high mortality in this group. 1,2 For example, the 5-year survival for ESRD patients receiving dialysis is approximately 35%, with .50% of the mortality in this group resulting directly from cardiovascular causes. 1 It is well established that CKD patients exhibit a disproportionate burden of atherosclerosis as compared with individuals having normal kidney function. [2][3][4][5] Furthermore, a higher prevalence of traditional risk factors for the development of atherosclerosis, such as hypertension, diabetes and hyperlipidemia, only partially accounts for the accelerated atherosclerosis in CKD patients, leading to the hypothesis that unique risk factors must be present in this population. 6,7

We examined the osteoblast/osteocyte expression and function of polycystin-1 (PC1), a transmembrane protein that is a component of the polycystin-2 (PC2)-ciliary mechano-sensor complex in renal epithelial cells. We found that MC3T3-E1 osteoblasts and MLO-Y4 osteocytes express transcripts for PC1, PC2, and the ciliary proteins Tg737 and Kif3a. Immunohistochemical analysis detected cilia-like structures in MC3T3-E1 osteoblastic and MLO-Y4 osteocyte-like cell lines as well as primary osteocytes and osteoblasts from calvaria. Pkd1 m1Bei mice have inactivating missense mutations of Pkd1 gene that encode PC1. Pkd1 m1Bei homozygous mutant mice demonstrated delayed endochondral and intramembranous bone formation, whereas heterozygous Pkd1 m1Bei mutant mice had osteopenia caused by reduced osteoblastic function. Heterozygous and homozygous Pkd1 m1Bei mutant mice displayed a gene dose-dependent decrease in the expression of Runx2 and osteoblastrelated genes. In addition, overexpression of constitutively active PC1 C-terminal constructs in MC3T3-E1 osteoblasts resulted in an increase in Runx2 P1 promoter activity and endogenous Runx2 expression as well as an increase in osteoblast differentiation markers. Conversely, osteoblasts derived from Pkd1 m1Bei homozygous mutant mice had significant reductions in endogenous Runx2 expression, osteoblastic markers, and differentiation capacity ex vivo. Co-expression of constitutively active PC1 C-terminal construct into Pkd1 m1Bei homozygous osteoblasts was sufficient to normalize Runx2 P1 promoter activity. These findings are consistent with a possible functional role of cilia and PC1 in anabolic signaling in osteoblasts/osteocytes.

PC1 (polycystin-1) is a highly conserved, receptor-like multidomain membrane protein widely expressed in various cell types and tissues (1, 2). Mutations of human PKD1 (polycystic kidney disease gene 1) cause autosomal dominant polycystic kidney disease (ADPKD) 2 (3, 4). The genetics of ADPKD is complex, because it is widely held that inactivation of the normal copy of the PKD1 gene by a second somatic mutation in conjunction with the inherited mutation of the other allele is required for renal cyst formation, which occurs in only a subset of the dually affected tubules (5). Although primarily affecting the kidney, ADPKD is also a multisystem disorder (6, 7). Extrarenal manifestations include intracranial and aortic aneurysms and cystic disease of liver and pancreas (8 -11). The biological functions of PC1 are poorly defined in some tissues that express PKD1 transcripts, such as bone. Indeed, the absence of clinically demonstrable skeletal abnormalities in patients with ADPKD initially delayed the investigation of PKD1 function in bone. The apparent lack of abnormalities in other tissues expressing PC1 may arise because of differences in the frequency of a second hit somatic mutation, the presence of other modifying factors that may compensate for lack of PC1 function in other organs (12), or failure to detect more subtle phenotypes. For example, lung was not thought to be affected by PKD1 mutations until computed tomography scans of lungs of ADPKD patients showed a 3-fold increase in the prevalence of bronchiectasis compared with controls (13).Pkd1 is highly expressed in bone, and several mouse models with inactivating mutations of Pkd1 have skeletal abnormalities in the setting of polycystic kidney disease and embryonic lethality (6, 7, 14 -16). Most recently, however, the heterozygous Pkd1 m1Bei mouse, which has an inactivating mutation of Pkd1 and survives to adulthood without polycystic kidney disease, has been shown to develop osteopenia and impaired osteoblastic differentiation (17,18), suggesting that Pkd1 may function in bone. Because homozygous PKD1/Pkd1 mutations in humans and mice are lethal, and most of the existing models are globally Pkd1-deficient, the significance of inactivation of Pkd1 in osteoblasts remains uncertain, and the bone changes might reflect an indirect effect due to loss of PKD1, in the kidney or other tissues.In the current study, to determine if PKD1 in osteoblasts has a direct function in regulating postnatal skeletal functions, we used mouse genetic approaches to conditionally delete Pkd1 in osteoblasts. We demonstrate that conditional deletion of Pkd1 from osteoblasts using Oc-Cre results defective osteoblast function in vivo and in vitro, and osteopenia, indicating that PKD1 has a direct role to regulate osteoblast function and skeletal homeostasis. EXPERIMENTAL PROCEDURES

MJ. FGF23 directly impairs endothelium-dependent vasorelaxation by increasing superoxide levels and reducing nitric oxide bioavailability. Am J Physiol Endocrinol Metab 307: E426 -E436, 2014. First published July 15, 2014 doi:10.1152/ajpendo.00264.2014.-Fibroblast growth factor 23 (FGF23) is secreted primarily by osteocytes and regulates phosphate and vitamin D metabolism. Elevated levels of FGF23 are clinically associated with endothelial dysfunction and arterial stiffness in chronic kidney disease (CKD) patients; however, the direct effects of FGF23 on endothelial function are unknown. We hypothesized that FGF23 directly impairs endothelial vasorelaxation by hindering nitric oxide (NO) bioavailability. We detected expression of all four subtypes of FGF receptors (Fgfr1-4) in male mouse aortas. Exogenous FGF23 (90 -9,000 pg/ml) did not induce contraction of aortic rings and did not relax rings precontracted with PGF 2␣. However, preincubation with FGF23 (9,000 pg/ml) caused a ϳ36% inhibition of endothelium-dependent relaxation elicited by acetylcholine (ACh) in precontracted aortic rings, which was prevented by the FGFR antagonist PD166866 (50 nM). Furthermore, in FGF23-pretreated (9,000 pg/ml) aortic rings, we found reductions in NO levels. We also investigated an animal model of CKD (Col4a3 Ϫ/Ϫ mice) that displays highly elevated serum FGF23 levels and found they had impaired endothelium-dependent vascular relaxation and reduced nitrate production compared with age-matched wild types. To elucidate a mechanism for the FGF23-induced impairment, we measured superoxide levels in endothelial cells and aortic rings and found that they were increased following FGF23 treatment. Crucially, treatment with the superoxide scavenger tiron reduced superoxide levels and also restored aortic relaxation to ACh. Therefore, our data suggest that FGF23 increases superoxide, inhibits NO bioavailability, and causes endothelial dysfunction in mouse aorta. Together, these data provide evidence that high levels of FGF23 contribute to cardiovascular dysfunction. fibroblast growth factor 23; chronic kidney disease; nitric oxide; superoxide; and cardiovascular disease IT IS WELL KNOWN THAT PATIENTS with chronic kidney disease (CKD) have an increased risk of cardiovascular disease (CVD). Modification of the traditional risk factors for CVD (e.g., dyslipidemia, hypertension, anemia, and hyperhomocysteinemia) does not improve cardiovascular function in patients with CKD (32), suggesting that other factors may be responsible. Fibroblast growth factor 23 (FGF23) is a hormone secreted by osteocytes that serves as an important regulator of serum phosphate and vitamin D via direct actions on the kidney and parathyroid (6,8). Recently, high circulating levels of FGF23 have been clinically associated with the development of CVD (3,9,33,47,55,72) especially during CKD where serum FGF23 is substantially increased 10-to 1,000-fold (30, 37). Nevertheless, despite these clinical associations, there have been relatively few studies to determine whethe...