Publications by authors named "Ran Dai"

15 Publications

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COVID-19 in Solid Organ Transplantation: Results of the National COVID Cohort Collaborative.

Transplant Direct 2021 Nov 6;7(11):e775. Epub 2021 Oct 6.

Division of Nephology, Department of Medicine, University of Nebraska Medical Center, Omaha, NE.

Coronavirus disease 2019 (COVID-19) has resulted in significant morbidity and mortality in solid organ transplant (SOT) recipients. The National COVID Cohort Collaborative was developed to facilitate analysis of patient-level data for those tested for COVID-19 across the United States.

Methods: In this study, we identified a cohort of SOT recipients testing positive or negative for COVID-19 (COVID+ and COVID-, respectively) between January 1, 2020, and November 20, 2020. Univariable and multivariable logistic regression were used to determine predictors of a positive result among those tested. Outcomes following COVID-19 diagnosis were also explored.

Results: Of 18 121 SOT patients tested, 1925 were positive (10.6%). COVID+ SOT patients were more likely to have a kidney transplant and be non-White race. Comorbidities were common in all SOT patients but significantly more common in those who were COVID+. Of COVID+ SOT, 42.9% required hospital admission. COVID+ status was the strongest predictor of acute kidney injury (AKI), rejection, and graft failure in the 90 d after testing. A total of 40.9% of COVID+ SOT experienced a major adverse renal or cardiac event, 16.3% experienced a major adverse cardiac event, 35.3% experienced AKI, and 1.5% experienced graft loss.

Conclusions: In the largest US cohort of COVID+ SOT recipients to date, we identified patient factors associated with the diagnosis of COVID-19 and outcomes following infection, including a high incidence of major adverse renal or cardiac event and AKI.
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http://dx.doi.org/10.1097/TXD.0000000000001234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500600PMC
November 2021

Sex and Organ-Specific Risk of Major Adverse Renal or Cardiac Events in Solid Organ Transplant Recipients with COVID-19.

Am J Transplant 2021 Oct 12. Epub 2021 Oct 12.

Division of Nephology, Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA.

While older males are at highest risk for poor COVID-19 outcomes, it is not known if this applies to the immunosuppressed recipient of a solid organ transplant (SOT), nor how the type of allograft transplanted may impact outcomes. In a cohort study of adult (>18 years) patients testing positive for COVID-19 (Jan 01, 2020-June 21, 2021) from 56 sites across the United States identified using the National COVID Cohort Collaborative (N3C) Enclave, we used multivariable Cox proportional hazards models to assess time to MARCE after COVID-19 diagnosis in those with and without SOT. We examined the exposure of age-stratified recipient sex overall and separately in kidney, liver, lung, and heart transplant recipients. 3,996 (36.4%) SOT and 91,646 (4.8%) non-SOT patients developed MARCE. Risk of post-COVID outcomes differed by transplant allograft type with heart and kidney recipients at highest risk. Males with SOT were at increased risk of MARCE, but to a lesser degree than the non-SOT cohort (HR 0.89, 95% CI 0.81-0.98 for SOT and HR 0.61, 95% CI 0.60-0.62 for non-SOT (females versus males)). This represents the largest COVID-19 SOT cohort to date and the first-time sex-age stratified and allograft-specific COVID-19 outcomes have been explored in those with SOT.
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http://dx.doi.org/10.1111/ajt.16865DOI Listing
October 2021

The bias of isotonic regression.

Electron J Stat 2020 5;14(1):801-834. Epub 2020 Feb 5.

Department of statistics, University of Wisconsin-Madison, USA.

We study the bias of the isotonic regression estimator. While there is extensive work characterizing the mean squared error of the isotonic regression estimator, relatively little is known about the bias. In this paper, we provide a sharp characterization, proving that the bias scales as ( ) up to log factors, where 1 ≤ ≤ 2 is the exponent corresponding to Hölder smoothness of the underlying mean. Importantly, this result only requires a strictly monotone mean and that the noise distribution has subexponential tails, without relying on symmetric noise or other restrictive assumptions.
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http://dx.doi.org/10.1214/20-ejs1677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266167PMC
February 2020

Causal inference in randomized clinical trials.

Bone Marrow Transplant 2020 01 26;55(1):4-8. Epub 2019 Mar 26.

Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, USA.

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http://dx.doi.org/10.1038/s41409-018-0424-xDOI Listing
January 2020

Structure-Based Optimization of Pyridoxal 5'-Phosphate-Dependent Transaminase Enzyme (BioA) Inhibitors that Target Biotin Biosynthesis in Mycobacterium tuberculosis.

J Med Chem 2017 07 22;60(13):5507-5520. Epub 2017 Jun 22.

Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.

The pyridoxal 5'-phosphate (PLP)-dependent transaminase BioA catalyzes the second step in the biosynthesis of biotin in Mycobacterium tuberculosis (Mtb) and is an essential enzyme for bacterial survival and persistence in vivo. A promising BioA inhibitor 6 containing an N-aryl, N'-benzoylpiperazine scaffold was previously identified by target-based whole-cell screening. Here, we explore the structure-activity relationships (SAR) through the design, synthesis, and biological evaluation of a systematic series of analogues of the original hit using a structure-based drug design strategy, which was enabled by cocrystallization of several analogues with BioA. To confirm target engagement and discern analogues with off-target activity, each compound was evaluated against wild-type (WT) Mtb in biotin-free and -containing medium as well as BioA under- and overexpressing Mtb strains. Conformationally constrained derivative 36 emerged as the most potent analogue with a K of 76 nM against BioA and a minimum inhibitory concentration of 1.7 μM (0.6 μg/mL) against Mtb in biotin-free medium.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5590679PMC
July 2017

Instrumental variable with competing risk model.

Stat Med 2017 04 8;36(8):1240-1255. Epub 2017 Jan 8.

Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, U.S.A.

In this paper, we discuss causal inference on the efficacy of a treatment or medication on a time-to-event outcome with competing risks. Although the treatment group can be randomized, there can be confoundings between the compliance and the outcome. Unmeasured confoundings may exist even after adjustment for measured covariates. Instrumental variable methods are commonly used to yield consistent estimations of causal parameters in the presence of unmeasured confoundings. On the basis of a semiparametric additive hazard model for the subdistribution hazard, we propose an instrumental variable estimator to yield consistent estimation of efficacy in the presence of unmeasured confoundings for competing risk settings. We derived the asymptotic properties for the proposed estimator. The estimator is shown to be well performed under finite sample size according to simulation results. We applied our method to a real transplant data example and showed that the unmeasured confoundings lead to significant bias in the estimation of the effect (about 50% attenuated). Copyright © 2017 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/sim.7205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479873PMC
April 2017

HDRsEf1 Protects the Intestinal Epithelium and Attenuates ETEC-Induced IL-8 Secretion in Enterocytes.

Mediators Inflamm 2016 7;2016:7474306. Epub 2016 Nov 7.

State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture, Huazhong Agricultural University, Wuhan, Hubei 430070, China.

The probiotic HDRsEf1 (Ef1) has been shown to have positive effects on piglet diarrhoea, but the mechanism has not yet been elucidated. In this study, using the IPEC-J2 cell line to mimic intestinal epithelial cells and enterotoxigenic (ETEC) K88ac as a representative intestinal pathogen, the mechanism underlying Ef1 protection against an enteropathogen was investigated. The results demonstrated that Ef1 was effective in displacing K88ac from the IPEC-J2 cell layer. Moreover, Ef1 and its cell-free supernatant (S-Ef1) modulate IL-8 released by IPEC-J2 cells. Ef1 and its cell-free supernatant showed the potential to protect enterocytes from an acute inflammatory response. In addition, Ef1 and its cell-free supernatant increased the transepithelial electrical resistance (TEER) of the enterocyte monolayer, thus strengthening the intestinal barrier against ETEC. These results may contribute to the development of therapeutic interventions using Ef1 in intestinal disorders of piglets.
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http://dx.doi.org/10.1155/2016/7474306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116501PMC
May 2017

Labor Epidural Intolerance Due to a Congenitally Narrowed Spinal Canal.

Reg Anesth Pain Med 2016 Nov/Dec;41(6):776-779

From the *Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL; and †Ochsner Health System, New Orleans, LA.

Reports exist of severe upper back pain of unknown etiology after administration of large volumes into the epidural space. We present a case of an otherwise healthy parturient who developed severe upper back and neck pain after receiving only a small volume of epidural medication. Magnetic resonance imaging revealed a congenitally narrowed spinal canal because of short pedicle syndrome. Epidural injectate occupies and compresses a percentage of the spinal canal and its neuronal contents. This may result in pain and epidural intolerance when continued injectate reaches a critical point, a threshold that is lower with shortened pedicles or congenital spinal stenosis. We believe a similar mechanism may explain the pain that patients sometimes experience after administration of large epidural volumes.
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http://dx.doi.org/10.1097/AAP.0000000000000493DOI Listing
April 2018

Fragment-based exploration of binding site flexibility in Mycobacterium tuberculosis BioA.

J Med Chem 2015 Jul 24;58(13):5208-17. Epub 2015 Jun 24.

†Department of Medicinal Chemistry, University of Minnesota, 8-101 Weaver-Densford, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States.

The PLP-dependent transaminase (BioA) of Mycobacterium tuberculosis and other pathogens that catalyzes the second step of biotin biosynthesis is a now well-validated target for antibacterial development. Fragment screening by differential scanning fluorimetry has been performed to discover new chemical scaffolds and promote optimization of existing inhibitors. Calorimetry confirms binding of six molecules with high ligand efficiency. Thermodynamic data identifies which molecules bind with the enthalpy driven stabilization preferred in compounds that represent attractive starting points for future optimization. Crystallographic characterization of complexes with these molecules reveals the dynamic nature of the BioA active site. Different side chain conformational states are stabilized in response to binding by different molecules. A detailed analysis of conformational diversity in available BioA structures is presented, resulting in the identification of two states that might be targeted with molecular scaffolds incorporating well-defined conformational attributes. This new structural data can be used as part of a scaffold hopping strategy to further optimize existing inhibitors or create new small molecules with improved therapeutic potential.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4687966PMC
July 2015

Target-based identification of whole-cell active inhibitors of biotin biosynthesis in Mycobacterium tuberculosis.

Chem Biol 2015 Jan 31;22(1):76-86. Epub 2014 Dec 31.

Center for Drug Design, University of Minnesota, Minneapolis, MN 55455, USA; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address:

Biotin biosynthesis is essential for survival and persistence of Mycobacterium tuberculosis (Mtb) in vivo. The aminotransferase BioA, which catalyzes the antepenultimate step in the biotin pathway, has been established as a promising target due to its vulnerability to chemical inhibition. We performed high-throughput screening (HTS) employing a fluorescence displacement assay and identified a diverse set of potent inhibitors including many diversity-oriented synthesis (DOS) scaffolds. To efficiently select only hits targeting biotin biosynthesis, we then deployed a whole-cell counterscreen in biotin-free and biotin-containing medium against wild-type Mtb and in parallel with isogenic bioA Mtb strains that possess differential levels of BioA expression. This counterscreen proved crucial to filter out compounds whose whole-cell activity was off target as well as identify hits with weak, but measurable whole-cell activity in BioA-depleted strains. Several of the most promising hits were cocrystallized with BioA to provide a framework for future structure-based drug design efforts.
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http://dx.doi.org/10.1016/j.chembiol.2014.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4305006PMC
January 2015

Inhibition of Mycobacterium tuberculosis transaminase BioA by aryl hydrazines and hydrazides.

Chembiochem 2014 Mar 31;15(4):575-86. Epub 2014 Jan 31.

Department of Medicinal Chemistry, University of Minnesota, 308 Harvard St. SE, Minneapolis, MN 55455 (USA).

7,8-Diaminopelargonic acid synthase (BioA) of Mycobacterium tuberculosis is a recently validated target for therapeutic intervention in the treatment of tuberculosis (TB). Using biophysical fragment screening and structural characterization of compounds, we have identified a potent aryl hydrazine inhibitor of BioA that reversibly modifies the pyridoxal-5'-phosphate (PLP) cofactor, forming a stable quinonoid. Analogous hydrazides also form covalent adducts that can be observed crystallographically but are incapable of inactivating the enzyme. In the X-ray crystal structures, small molecules induce unexpected conformational remodeling in the substrate binding site. We compared these conformational changes to those induced upon binding of the substrate (7-keto-8-aminopelargonic acid), and characterized the inhibition kinetics and the X-ray crystal structures of BioA with the hydrazine compound and analogues to unveil the mechanism of this reversible covalent modification.
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http://dx.doi.org/10.1002/cbic.201300748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020011PMC
March 2014

Isoflurane does not affect brain cell death, hippocampal neurogenesis, or long-term neurocognitive outcome in aged rats.

Anesthesiology 2010 Feb;112(2):305-15

Department of Anesthesia, University of California-San Francisco, 513 Parnassus Ave., San Francisco, California 94143, USA.

Background: Roughly, 10% of elderly patients develop postoperative cognitive dysfunction. General anesthesia impairs spatial memory in aged rats, but the mechanism is not known. Hippocampal neurogenesis affects spatial learning and memory in rats, and isoflurane affects neurogenesis in neonatal and young adult rats. We tested the hypothesis that isoflurane impairs neurogenesis and hippocampal function in aged rats.

Methods: Isoflurane was administered to 16-month-old rats at one minimum alveolar concentration for 4 h. FluoroJade staining was performed to assess brain cell death 16 h after isoflurane administration. Dentate gyrus progenitor proliferation was assessed by bromodeoxyuridine injection 4 days after anesthesia and quantification of bromodeoxyuridine+ cells 12 h later. Neuronal differentiation was studied by determining colocalization of bromodeoxyuridine with the immature neuronal marker NeuroD 5 days after anesthesia. New neuronal survival was assessed by quantifying cells coexpressing bromodeoxyuridine and the mature neuronal marker NeuN 5 weeks after anesthesia. Four months after anesthesia, associative learning was assessed by fear conditioning. Spatial reference memory acquisition and retention was tested in the Morris Water Maze.

Results: Cell death was sporadic and not different between groups. We did not detect any differences in hippocampal progenitor proliferation, neuronal differentiation, new neuronal survival, or in any of the tests of long-term hippocampal function.

Conclusion: In aged rats, isoflurane does not affect brain cell death, hippocampal neurogenesis, or long-term neurocognitive outcome.
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http://dx.doi.org/10.1097/ALN.0b013e3181ca33a1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5214622PMC
February 2010

Isoflurane differentially affects neurogenesis and long-term neurocognitive function in 60-day-old and 7-day-old rats.

Anesthesiology 2009 Apr;110(4):834-48

Department of Anesthesia and Perioperative Care, University of California, San Francisco 94143, USA.

Background: Anesthetic agents cause cell death in the developing rodent brain and long-term, mostly hippocampal-dependent, neurocognitive dysfunction. However, a causal link between these findings has not been shown. Postnatal hippocampal neurogenesis affects hippocampal function into adulthood; therefore, the authors tested the hypothesis that isoflurane affects long-term neurocognitive function via an effect on dentate gyrus neurogenesis.

Methods: The S-phase marker 5-bromodeoxyuridine was administered at various times before, during, and after 4 h of isoflurane given to postnatal day (P)60 and P7 rats to assess dentate gyrus progenitor proliferation, early neuronal lineage selection, and long-term survival of new granule cell neurons. Fear conditioning and spatial reference memory was tested at various intervals from 2 weeks until 8 months after anesthesia.

Results: In P60 rats, isoflurane increased early neuronal differentiation as assessed by BrdU/NeuroD costaining, decreased progenitor proliferation for 1 day, and subsequently increased progenitor proliferation 5-10 days after anesthesia. In P7 rats, isoflurane did not induce neuronal lineage selection but decreased progenitor proliferation until at least 5 days after anesthesia. Isoflurane improved spatial reference memory of P60 rats long-term, but it caused a delayed-onset, progressive, persistent hippocampal deficit in P7 rats in fear conditioning and spatial reference memory tasks.

Conclusion: The authors conclude that isoflurane differentially affects both neurogenesis and long-term neurocognitive function in P60 and P7 rats. Neurogenesis might mediate the long-term neurocognitive outcome after isoflurane at different ages.
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http://dx.doi.org/10.1097/ALN.0b013e31819c463dDOI Listing
April 2009

Effect of hypercarbia and isoflurane on brain cell death and neurocognitive dysfunction in 7-day-old rats.

Anesthesiology 2009 Apr;110(4):849-61

Department of Anesthesia and Perioperative Car, University of California, San Francisco, California 94143, USA.

Background: Millions of neonates undergo anesthesia each year. Certain anesthetic agents cause brain cell death and long-term neurocognitive dysfunction in postnatal day (P)7 rats. Despite its intuitive appeal, a causal link between cell death and neurocognitive decline after anesthesia has not been established. If one existed, the degree of cell death would be expected to correlate with the degree of neurocognitive dysfunction caused by anesthesia. The authors therefore tested if cell death caused by various durations of isoflurane at 1 minimum alveolar concentration causes duration-dependent long-term neurocognitive dysfunction.

Methods: Isoflurane was administered to P7 rats at 1 minimum alveolar concentration for 0, 1, 2, or 4 h. To control for the respiratory depressant effects of anesthesia, a group of rats was treated with 4 h of carbon dioxide. Cell death was assessed by FluoroJade staining 12 h after the end of each intervention, and neurocognitive outcome was assessed 8 weeks later by using fear conditioning, spatial reference memory, and spatial working memory tasks.

Results: Widespread brain cell death was caused by 2 h and 4 h of isoflurane and by 4 h of carbon dioxide. The degree and distribution of thalamic cell death was similar in 4 h isoflurane-treated and 4-h carbon dioxide-treated rats. Only 4 h of isoflurane caused a long-term neurocognitive deficit affecting both spatial reference memory and spatial working memory. Working memory was improved in carbon dioxide-treated rats.

Conclusion: Isoflurane-induced brain cell death may be partly caused by hypercarbia. The inconsistencies between cell death and neurocognitive outcome suggest that additional or alternative mechanisms may mediate anesthesia-induced long-term neurocognitive dysfunction.
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http://dx.doi.org/10.1097/ALN.0b013e31819c7140DOI Listing
April 2009
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