This copy is for personal use only. To order printed copies, contact reprints@rsna.org I n P r e s s 2 Key Points 1. The positive rates of RT-PCR assay and chest CT imaging in our cohort were 59% (601/1014), and 88% (888/1014) for the diagnosis of suspected patients with COVID-19, respectively. 2.With RT-PCR as a reference, the sensitivity of chest CT imaging for COVID-19 was 97% (580/601). In patients with negative RT-PCR results but positive chest CT scans (n=308 patients), 48% (147/308) of patients were re-considered as highly likely cases, with 33% (103/308) as probable cases by a comprehensive evaluation. 3.With analysis of serial RT-PCR assays and CT scans, 60% to 93% of patients had initial positive chest CT consistent with COVID-19 before the initial positive RT-PCR results. 42% of patients showed improvement of follow-up chest CT scans before the RT-PCR results turning negative. Summary StatementChest CT had higher sensitivity for diagnosis of COVID-19 as compared with initial reverse-transcription polymerase chain reaction (RT-PCR) from swab samples in the epidemic area of China. Abbreviations RT-PCR = reverse transcription polymerase chain reaction NCP = novel coronavirus pneumonia PPV = positive predictive value NPV = negative predictive value I n P r e s s 3 Abstract Background: Chest CT is used for diagnosis of 2019 novel coronavirus disease (COVID-19), as an important complement to the reverse-transcription polymerase chain reaction (RT-PCR) tests. Purpose: To investigate the diagnostic value and consistency of chest CT as compared with comparison to RT-PCR assay in COVID-19. underwent both chest CT and RT-PCR tests were included. With RT-PCR as reference standard, the performance of chest CT in diagnosing COVID-19 was assessed. Besides, for patients with multiple RT-PCR assays, the dynamic conversion of RT-PCR results (negative to positive, positive to negative, respectively) was analyzed as compared with serial chest CT scans for those with time-interval of 4 days or more. Results: Of 1014 patients, 59% (601/1014) had positive RT-PCR results, and 88% (888/1014) had positive chest CT scans. The sensitivity of chest CT in suggesting COVID-19 was 97% (95%CI, 95-98%, 580/601 patients) based on positive RT-PCRresults. In patients with negative RT-PCR results, 75% (308/413) had positive chest CT findings; of 308, 48% were considered as highly likely cases, with 33% as probable cases. By analysis of serial RT-PCR assays and CT scans, the mean interval time between the initial negative to positive RT-PCR results was 5.1 ± 1.5 days; the initial positive to subsequent negative RT-PCR result was 6.9 ± 2.3 days). 60% to 93% of cases had initial positive CT consistent with COVID-19 prior (or parallel) to the initial positive RT-PCR results. 42% (24/57) cases showed improvement in follow-up chest CT scans before the RT-PCR results turning negative. Conclusion:Chest CT has a high sensitivity for diagnosis of COVID-19. Chest CT may be considered as a primary tool for the current COVID-19 detection in epidemic ar...

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The incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (<50 bp) and 27,622 SVs (≥50 bp) per genome. We also discover 156 inversions per genome and 58 of the inversions intersect with the critical regions of recurrent microdeletion and microduplication syndromes. Taken together, our SV callsets represent a three to sevenfold increase in SV detection compared to most standard high-throughput sequencing studies, including those from the 1000 Genomes Project. The methods and the dataset presented serve as a gold standard for the scientific community allowing us to make recommendations for maximizing structural variation sensitivity for future genome sequencing studies.

Age-related declines in hematopoietic stem cell (HSC) function may contribute to anemia, poor response to vaccination, and tumorigenesis. Here, we show that mammalian target of rapamycin (mTOR) activity is increased in HSCs from old mice compared to those from young mice. mTOR activation through conditional deletion of Tsc1 in the HSC of young mice mimicked the phenotype of HSC from aged mice in various ways. These included increased abundance of the mRNA encoding the CDK inhibitors p16Ink4a, p19Arf, and p21Cip1, a relative decrease in lymphopoiesis, and impaired capacity to reconstitute the hematopoietic system. In the old mice, rapamycin increased the life span, restored the self renewal and hematopoiesis of HSC, and enabled effective vaccination against a lethal challenge with influenza virus. Together, our data implicate mTOR signaling in HSC aging and demonstrate the potential of mTOR inhibitors for restoring hematopoiesis in the elderly.

A long-standing but poorly understood observation in stem cell biology is that the quiescence of the adult stem cells associates with their longterm functions ( 1 -6 ). The molecular pathway that keeps them in quiescence is largely obscure, although recent studies have implicated stem cell niches ( 4 ) and cell-intrinsic functions of p21 ( 5 ) and Pten ( 6 ) in this process. The signifi cance of quiescence in stem cell function is bolstered as genetic disruption of its quiescence almost invariably inactivates the hematopoietic stem cell (HSC) function ( 4 -6 ). Nevertheless, it is largely unclear how an active metabolism is incompatible with a normal HSC function.In addition to cell-intrinsic factors, accumulating data demonstrated that residence of adult HSCs in the BM niches is essential for their quiescence and long-term functions ( 7 -9 ). Because exposure to high levels of oxygen damages the functions of HSCs ( 10 -15 ), it has been proposed that hypoxia is important for HSC functions. However, the underlying molecular mechanism of how hypoxia maintains the stemness is unknown.In Drosophila and in vitro -cultured mammalian cells, hypoxia activates tuberous sclerosis complex (TSC), which can inhibit the target of rapamycin (TOR), through REDD1 and AMP-activated protein kinase ( 16 -20 ). Whether this pathway operates in the HSCs has yet to be tested.The mammalian TOR (mTOR) pathway has emerged as a key regulator for cellular metabolism. Accumulating data have demonstrated that mTOR regulates several important cellular functions, including protein synthesis, autophagy, endocytosis and nutrient uptake ( 21 ). An increased mTOR activity results in increased cellular growth and nonmalignant growth of cells in solid organs ( 22,23 The tuberous sclerosis complex (TSC) -mammalian target of rapamycin (mTOR) pathway is a key regulator of cellular metabolism. We used conditional deletion of Tsc1 to address how quiescence is associated with the function of hematopoietic stem cells (HSCs). We demonstrate that Tsc1 deletion in the HSCs drives them from quiescence into rapid cycling, with increased mitochondrial biogenesis and elevated levels of reactive oxygen species (ROS). Importantly, this deletion dramatically reduced both hematopoiesis and self-renewal of HSCs, as revealed by serial and competitive bone marrow transplantation. In vivo treatment with an ROS antagonist restored HSC numbers and functions. These data demonstrated that the TSC -mTOR pathway maintains the quiescence and function of HSCs by repressing ROS production. The detrimental effect of up-regulated ROS in metabolically active HSCs may explain the well-documented association between quiescence and the " stemness " of HSCs.