Publications by authors named "Kevin Johnson"

597 Publications

Optimizing trajectory ordering for fast radial ultra-short TE (UTE) acquisitions.

J Magn Reson 2021 Apr 2;327:106977. Epub 2021 Apr 2.

UC Berkeley-UCSF Graduate Program in Bioengineering, University of California, San Francisco and University of California, Berkeley, CA, United States; Radiology and Biomedical Imaging, University of California, San Francisco, CA, United States. Electronic address:

Purpose: Additional spoiler gradients are required in 3D UTE sequences with random view ordering to suppress magnetization refocusing. By leveraging the encoding gradient induced spoiling effect, the spoiler gradients could potentially be reduced or removed to shorten the TR and increase encoding efficiency. An analysis framework is built that models the gradient spoiling effects and a new ordering scheme is proposed for fast 3D UTE acquisition.

Theory And Methods: UTE signal evolution and spatial encoding gradient induced spoiling effect are derived from the Bloch equations. And the concept is validated in 2D radial UTE simulation. Then an optimized ordering scheme, named reordered 2D golden angle (r2DGA) scheme, for 3D UTE acquisition is proposed. The r2DGA scheme is compared to the sequential and 3D golden angle schemes in both phantom and volunteer studies.

Results: The proposed r2DGA ordering scheme was applied to two applications, single breath-holding and free breathing 3D lung MRI. With r2DGA ordering scheme, breath-holding lung MRI scan increased 60% scan efficiency by removing the spoiler gradients and the free breathing scan reduced 20% scan time compared to the 3D golden angle scheme by reducing the spoiler gradients.

Conclusions: The proposed r2DGA ordering scheme UTE acquisition reduces the need of spoiler gradients and increases the encoding efficiency, and shows improvements in both breath-holding and free breathing lung MRI applications.
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http://dx.doi.org/10.1016/j.jmr.2021.106977DOI Listing
April 2021

Phenotyping coronavirus disease 2019 during a global health pandemic: lessons learned from the characterization of an early cohort.

J Biomed Inform 2021 Apr 7:103777. Epub 2021 Apr 7.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN2525 West End Ave, Suite 1475 Nashville, TN USA 37203.

From the start of the coronavirus disease 2019 (COVID-19) pandemic, researchers have looked to electronic health record (EHR) data as a way to study possible risk factors and outcomes. To ensure the validity and accuracy of research using these data, investigators need to be confident that the phenotypes they construct are reliable and accurate, reflecting the healthcare settings from which they are ascertained. We developed a COVID-19 registry at a single academic medical center and used data from March 1 to June 5, 2020 to assess differences in population-level characteristics in pandemic and non-pandemic years respectively. Median EHR length, previously shown to impact phenotype performance in type 2 diabetes, was significantly shorter in the SARS-CoV-2 positive group relative to a 2019 influenza tested group (median 3.1 years vs 8.7; Wilcoxon rank sum P=1.3e-52). Using three phenotyping methods of increasing complexity (billing codes alone and domain-specific algorithms provided by an EHR vendor and clinical experts), common medical comorbidities were abstracted from COVID-19 EHRs, defined by the presence of a positive laboratory test (positive predictive value 100%, recall 93%). After combining performance data across phenotyping methods, we observed significantly lower false negative rates for those records billed for a comprehensive care visit (p=4e-11) and those with complete demographics data recorded (p=7e-5). In an early COVID-19 cohort, we found that phenotyping performance of nine common comorbidities was influenced by median EHR length, consistent with previous studies, as well as by data density, which can be measured using portable metrics including CPT codes. Here we present those challenges and potential solutions to creating deeply phenotyped, acute COVID-19 cohorts.
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http://dx.doi.org/10.1016/j.jbi.2021.103777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026248PMC
April 2021

Transcriptomic signatures of temperature adaptation in the eastern oyster Crassostrea virginica.

J Evol Biol 2021 Apr 10. Epub 2021 Apr 10.

Department of Biological Sciences, Louisiana State University, Baton Rouge, LA, 70803, USA.

The large geographic distribution of the eastern oyster, Crassostrea virginica makes it an ideal species to test how populations have adapted to latitudinal gradients in temperature. Despite inhabiting distinct thermal regimes, populations of C. virginica near the species' southern and northern geographic range show no population differences in their physiological response to temperature. In this study, we used comparative transcriptomics to understand how oysters from either end of the species' range maintain enantiostasis across three acclimation temperatures (10, 20, and 30˚C). With this approach, we identified genes that were differentially expressed in response to temperature between individuals of C. virginica collected from New Brunswick, Canada and Louisiana, USA. We observed a core set of genes whose expression responded to temperature in both populations, but also an even larger set of genes with expression patterns that were unique to each population. Intriguingly the genes with population-specific responses to temperature had elevated F and Ka/Ks ratios compared to the genome-wide average. In contrast, genes showing only a response to temperature were found to only have elevated F values suggesting that divergent F may be due to selection on linked regulatory regions rather than positive selection on protein coding regions Taken together our results suggest that, despite coarse-scale physiological similarities, natural selection has shaped divergent gene expression responses to temperature in geographically separated populations of this broadly eurythermal marine invertebrate.
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http://dx.doi.org/10.1111/jeb.13789DOI Listing
April 2021

Extensive genome-wide duplications in the eastern oyster ().

Philos Trans R Soc Lond B Biol Sci 2021 May 5;376(1825):20200164. Epub 2021 Apr 5.

Department of Biological Sciences, University of Rhode Island, 120 Flagg Road, Kingston, RI 02881, USA.

Genomic structural variation is an important source of genetic and phenotypic diversity, playing a critical role in evolution. The recent availability of a high-quality reference genome for the eastern oyster, , and whole-genome sequence data of samples from across the species range in the USA, provides an opportunity to explore structural variation across the genome of this species. Our analysis shows significantly greater individual-level duplications of regions across the genome than that of most model vertebrate species. Duplications are widespread across all ten chromosomes with variation in frequency per chromosome. The eastern oyster shows a large interindividual variation in duplications as well as particular chromosomal regions with a higher density of duplications. A high percentage of duplications seen in lie completely within genes and exons, suggesting the potential for impacts on gene function. These results support the hypothesis that structural changes may play a significant role in standing genetic variation in , and potentially have a role in their adaptive and evolutionary success. Altogether, these results suggest that copy number variation plays an important role in the genomic variation of . This article is part of the Theo Murphy meeting issue 'Molluscan genomics: broad insights and future directions for a neglected phylum'.
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http://dx.doi.org/10.1098/rstb.2020.0164DOI Listing
May 2021

Ultrasound-guided pediatric inguinal hernia repair.

J Pediatr Surg 2021 Mar 11. Epub 2021 Mar 11.

Section of Pediatric Surgery, Department of Surgery, Michigan Medicine, C.S. Mott Children's and Von Voigtlander Women's Hospital, Ann Arbor, MI, USA 48109; Department of Interventional Radiology, Michigan Medicine, Ann Arbor MI USA 48109. Electronic address:

Purpose: Inguinal hernias are amongst the most common surgical conditions in children. Typically, these repairs are performed through an open or laparoscopic approach, using a high ligation of the hernia sac. The use of ultrasound has been described in identifying and evaluating hernia contents in children. Our goal was to determine if ultrasound guidance could be used to perform a high ligation of the hernia sac in pediatric patients.

Methods: Following IRB approval, a retrospective review of all female patients at a single center undergoing ultrasound guided inguinal hernia repair between 2017 and 2018 was performed. Pre-operative characteristics, intra-operative outcomes, and post-operative outcomes were all evaluated. Laparoscopy was used to evaluate the repair and evaluate for a contralateral hernia. Male patients did not undergo ultrasound inguinal hernia repair to avoid damage to the vas deferens and vessels.

Results: A total of 10 patients with 13 hernias total were found during the study period. A total of one patient was converted to a laparoscopic repair. No patients were found to have an inappropriate repair or a missed contralateral hernia, and there were no vascular injuries or injuries to surrounding structures. No patients had a hernia recurrence during the study period.

Conclusion: This study demonstrates the safety and feasibility of ultrasound guided inguinal hernia repairs in female pediatric patients. Further study is needed to compare these repairs to existing techniques, evaluate for recurrences over time, and evaluate if these repairs can be performed without general anesthetic in some patients.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.02.053DOI Listing
March 2021

Interstrand Cross-Link Formation Involving Reaction of a Mispaired Cytosine Residue with an Abasic Site in Duplex DNA.

Chem Res Toxicol 2021 Apr 30;34(4):1124-1132. Epub 2021 Mar 30.

Department of Chemistry, University of Missouri, 125 Chemistry Building, Columbia, Missouri 65211, United States.

The formation of interstrand cross-links in duplex DNA is important in biology, medicine, and biotechnology. Interstrand cross-links arising from the reaction of the aldehyde residue of an abasic (apurinic or AP) site with the exocyclic amino groups of guanine or adenine residues on the opposing strand of duplex DNA have previously been characterized. The canonical nucleobase cytosine has an exocyclic amino group but its ability to form interstrand cross-links by reaction with an AP site has not been characterized before now. Here it is shown that substantial yields of interstrand cross-links are generated in sequences having a mispaired cytosine residue located one nucleotide to the 3'-side of the AP site on the opposing strand (e.g., 5'XA/5'CA, where X = AP). Formation of the dC-AP cross-link is pH-dependent, with significantly higher yields at pH 5 than pH 7. Once formed, the dC-AP cross-link is quite stable, showing less than 5% dissociation over the course of 96 h at pH 7 and 37 °C. No significant yields of cross-link are observed when the cytosine residue is paired with its Watson-Crick partner guanine. It was also shown that a single AP site can engage with multiple nucleobase cross-linking partners in some sequences. Specifically, the dG-AP and dC-AP cross-links coexist in dynamic equilibrium in the sequence 5'CXA/5'CAG (X = AP). In this sequence, the dC-AP cross-link dominates. However, in the presence of NaBHCN, irreversible reduction of small amounts of the dG-AP cross-link present in the mixture shifts the equilibria away from the dC-AP cross-link toward good yields of the dG-AP cross-link.
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http://dx.doi.org/10.1021/acs.chemrestox.1c00004DOI Listing
April 2021

ConceptWAS: A high-throughput method for early identification of COVID-19 presenting symptoms and characteristics from clinical notes.

J Biomed Inform 2021 Mar 25;117:103748. Epub 2021 Mar 25.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address:

Objective: Identifying symptoms and characteristics highly specific to coronavirus disease 2019 (COVID-19) would improve the clinical and public health response to this pandemic challenge. Here, we describe a high-throughput approach - Concept-Wide Association Study (ConceptWAS) - that systematically scans a disease's clinical manifestations from clinical notes. We used this method to identify symptoms specific to COVID-19 early in the course of the pandemic.

Methods: We created a natural language processing pipeline to extract concepts from clinical notes in a local ER corresponding to the PCR testing date for patients who had a COVID-19 test and evaluated these concepts as predictors for developing COVID-19. We identified predictors from Firth's logistic regression adjusted by age, gender, and race. We also performed ConceptWAS using cumulative data every two weeks to identify the timeline for recognition of early COVID-19-specific symptoms.

Results: We processed 87,753 notes from 19,692 patients subjected to COVID-19 PCR testing between March 8, 2020, and May 27, 2020 (1,483 COVID-19-positive). We found 68 concepts significantly associated with a positive COVID-19 test. We identified symptoms associated with increasing risk of COVID-19, including "anosmia" (odds ratio [OR] = 4.97, 95% confidence interval [CI] = 3.21-7.50), "fever" (OR = 1.43, 95% CI = 1.28-1.59), "cough with fever" (OR = 2.29, 95% CI = 1.75-2.96), and "ageusia" (OR = 5.18, 95% CI = 3.02-8.58). Using ConceptWAS, we were able to detect loss of smell and loss of taste three weeks prior to their inclusion as symptoms of the disease by the Centers for Disease Control and Prevention (CDC).

Conclusion: ConceptWAS, a high-throughput approach for exploring specific symptoms and characteristics of a disease like COVID-19, offers a promise for enabling EHR-powered early disease manifestations identification.
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http://dx.doi.org/10.1016/j.jbi.2021.103748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992296PMC
March 2021

Tetrahydrofuran-Based Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonists: Ligand-Based Discovery, Activity in a Rodent Asthma Model, and Mechanism-of-Action via Cryogenic Electron Microscopy.

J Med Chem 2021 Apr 22;64(7):3843-3869. Epub 2021 Mar 22.

Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.

Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium-permeable ion channel highly expressed in the primary sensory neurons functioning as a polymodal sensor for exogenous and endogenous stimuli and has generated widespread interest as a target for inhibition due to its implication in neuropathic pain and respiratory disease. Herein, we describe the optimization of a series of potent, selective, and orally bioavailable TRPA1 small molecule antagonists, leading to the discovery of a novel tetrahydrofuran-based linker. Given the balance of physicochemical properties and strong target engagement in a rat AITC-induced pain assay, compound was progressed into a guinea pig ovalbumin asthma model where it exhibited significant dose-dependent reduction of inflammatory response. Furthermore, the structure of the TRPA1 channel bound to compound was determined via cryogenic electron microscopy to a resolution of 3 Å, revealing the binding site and mechanism of action for this class of antagonists.
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http://dx.doi.org/10.1021/acs.jmedchem.0c02023DOI Listing
April 2021

Rapid high-resolution volumetric T mapping using a highly accelerated stack-of-stars Look Locker technique.

Magn Reson Imaging 2021 Mar 17;79:28-37. Epub 2021 Mar 17.

Department of Medical Imaging, the University of Arizona, Tucson, AZ 85724, USA; Department of Biomedical Engineering, the University of Arizona, Tucson, AZ 85721, USA. Electronic address:

Purpose: To develop a fast volumetric T mapping technique.

Materials And Methods: A stack-of-stars (SOS) Look Locker technique based on the acquisition of undersampled radial data (>30× relative to Nyquist) and an efficient multi-slab excitation scheme is presented. A principal-component based reconstruction is used to reconstruct T maps. Computer simulations were performed to determine the best choice of partitions per slab and degree of undersampling. The technique was validated in phantoms against reference T values measured with a 2D Cartesian inversion-recovery spin-echo technique. The SOS Look Locker technique was tested in brain (n = 4) and prostate (n = 5). Brain T mapping was carried out with and without k acceleration and results between the two approaches were compared. Prostate T mapping was compared to standard techniques. A reproducibility study was conducted in brain and prostate. Statistical analyses were performed using linear regression and Bland Altman analysis.

Results: Phantom T values showed excellent correlations between SOS Look Locker and the inversion-recovery spin-echo reference (r = 0.9965; p < 0.0001) and between SOS Look Locker with slab-selective and non-slab selective inversion pulses (r = 0.9999; p < 0.0001). In vivo results showed that full brain T mapping (1 mm) with k acceleration is achieved in 4 min 21 s. Full prostate T mapping (0.9 × 0.9 × 4 mm) is achieved in 2 min 43 s. T values for brain and prostate were in agreement with literature values. A reproducibility study showed coefficients of variation in the range of 0.18-0.2% (brain) and 0.15-0.18% (prostate).

Conclusion: A rapid volumetric T mapping technique was developed. The technique enables high-resolution T mapping with adequate anatomical coverage in a clinically acceptable time.
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http://dx.doi.org/10.1016/j.mri.2021.03.003DOI Listing
March 2021

Rapid high-resolution volumetric T mapping using a highly accelerated stack-of-stars Look Locker technique.

Magn Reson Imaging 2021 Mar 17;79:28-37. Epub 2021 Mar 17.

Department of Medical Imaging, the University of Arizona, Tucson, AZ 85724, USA; Department of Biomedical Engineering, the University of Arizona, Tucson, AZ 85721, USA. Electronic address:

Purpose: To develop a fast volumetric T mapping technique.

Materials And Methods: A stack-of-stars (SOS) Look Locker technique based on the acquisition of undersampled radial data (>30× relative to Nyquist) and an efficient multi-slab excitation scheme is presented. A principal-component based reconstruction is used to reconstruct T maps. Computer simulations were performed to determine the best choice of partitions per slab and degree of undersampling. The technique was validated in phantoms against reference T values measured with a 2D Cartesian inversion-recovery spin-echo technique. The SOS Look Locker technique was tested in brain (n = 4) and prostate (n = 5). Brain T mapping was carried out with and without k acceleration and results between the two approaches were compared. Prostate T mapping was compared to standard techniques. A reproducibility study was conducted in brain and prostate. Statistical analyses were performed using linear regression and Bland Altman analysis.

Results: Phantom T values showed excellent correlations between SOS Look Locker and the inversion-recovery spin-echo reference (r = 0.9965; p < 0.0001) and between SOS Look Locker with slab-selective and non-slab selective inversion pulses (r = 0.9999; p < 0.0001). In vivo results showed that full brain T mapping (1 mm) with k acceleration is achieved in 4 min 21 s. Full prostate T mapping (0.9 × 0.9 × 4 mm) is achieved in 2 min 43 s. T values for brain and prostate were in agreement with literature values. A reproducibility study showed coefficients of variation in the range of 0.18-0.2% (brain) and 0.15-0.18% (prostate).

Conclusion: A rapid volumetric T mapping technique was developed. The technique enables high-resolution T mapping with adequate anatomical coverage in a clinically acceptable time.
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http://dx.doi.org/10.1016/j.mri.2021.03.003DOI Listing
March 2021

Pseudo-Enhancement in Intracranial Aneurysms on Black-Blood MRI: Effects of Flow Rate, Spatial Resolution, and Additional Flow Suppression.

J Magn Reson Imaging 2021 Mar 10. Epub 2021 Mar 10.

Department of Radiology and Neuroradiology, University Medical Center Schleswig-Holstein, Kiel, Germany.

Background: Vessel-wall enhancement (VWE) on black-blood MRI (BB MRI) has been proposed as an imaging marker for a higher risk of rupture and associated with wall inflammation. Whether VWE is causally linked to inflammation or rather induced by flow phenomena has been a subject of debate.

Purpose: To study the effects of slow flow, spatial resolution, and motion-sensitized driven equilibrium (MSDE) preparation on signal intensities in BB MRI of patient-specific aneurysm flow models.

Study Type: Prospective.

Subjects/flow Aneurysm Model/virtual Vessels: Aneurysm flow models based on 3D rotational angiography datasets of three patients with intracranial aneurysms were 3D printed and perfused at two different flow rates, with and without Gd-containing contrast agent.

Field Strength/sequence: Variable refocusing flip angle 3D fast-spin echo sequence at 3 T with and without MSDE with three voxel sizes ((0.5 mm) , (0.7 mm) , and (0.9 mm) ); time-resolved with phase-contrast velocity-encoding 3D spoiled gradient echo sequence (4D flow MRI).

Assessment: Three independent observers performed a qualitative visual assessment of flow patterns and signal enhancement. Quantitative analysis included voxel-wise evaluation of signal intensities and magnitude velocity distributions in the aneurysm.

Statistical Tests: Kruskal-Wallis test, potential regressions.

Results: A hyperintense signal in the lumen and adjacent to the aneurysm walls on BB MRI was colocalized with slow flow. Signal intensities increased by a factor of 2.56 ± 0.68 (P < 0.01) after administering Gd contrast. After Gd contrast administration, the signal was suppressed most in conjunction with high flows and with MSDE (2.41 ± 2.07 for slow flow without MSDE, and 0.87 ± 0.99 for high flow with MSDE). A clear result was not achieved by modifying the spatial resolution .

Data Conclusions: Slow-flow phenomena contribute substantially to aneurysm enhancement and vary with MRI parameters. This should be considered in the clinical setting when assessing VWE in patients with an unruptured aneurysm.

Evidence Level: 2 TECHNICAL EFFICACY: Stage 2.
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http://dx.doi.org/10.1002/jmri.27587DOI Listing
March 2021

Letter to the editor: Oral vancomycin versus no therapy for pediatric primary sclerosing cholangitis.

Hepatology 2021 Feb 26. Epub 2021 Feb 26.

Department of Gastroenterology, Lady Cilento Children's Hospital, and Children's Medical Research Institute, University of Queensland, Brisbane, Qld, Australia.

In their recent study addressing efficacy of oral vancomycin (OVT) and ursodeoxycholic acid (UDCA) compared to no therapy in pediatric primary sclerosing cholangitis (PSC), Deneau et al. state: "OVT and UDCA are not effective treatments for PSC in children" [1]. Their study shows that the null hypothesis of no effect has not been rejected; a real effect might have been present but missed. Complications take up to 10 years to develop, but their median follow-up was just 4.2 years. The subsequent editorial [2] noted the limitations of a retrospective, propensity-matched study and argues cogently for the need to replace empiric practice with data from well-planned randomized controlled trials (RCTs).
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http://dx.doi.org/10.1002/hep.31764DOI Listing
February 2021

Enzymatic bypass of an N-deoxyadenosine DNA-ethylene dibromide-peptide crosslink by translesion DNA polymerases.

J Biol Chem 2021 Feb 19:100444. Epub 2021 Feb 19.

Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA. Electronic address:

Unrepaired DNA-protein crosslinks, due to their bulky nature, can stall replication forks and result in genome instability. Large DNA-protein crosslinks can be cleaved into DNA-peptide crosslinks, but the extent to which these smaller fragments disrupt normal replication is not clear. Ethylene dibromide (1,2-dibromoethane) is a known carcinogen that can crosslink the repair protein O-alkylguanine-DNA alkyltransferase (AGT) to the N6 position of deoxyadenosine (dA) in DNA, as well as four other positions in DNA. We investigated the effect of a 15-mer peptide from the active site of AGT, crosslinked to the N6 position of dA, on DNA replication by human translesion synthesis DNA polymerases (Pols) η, ⍳, and κ. The peptide-DNA crosslink was bypassed by the three polymerases at different rates. In steady-state kinetics, the specificity constant (k/K) for incorporation of the correct nucleotide opposite to the adduct decreased by 220-fold with Pol κ, 10-fold with pol η, and not at all with Pol ⍳. Pol η incorporated all four nucleotides across from the lesion, with the preference dT > dC > dA > dG, while Pol ⍳ and κ only incorporated the correct nucleotide. However, LC-MS/MS analysis of the primer-template extension product revealed error-free bypass of the crosslinked 15-mer peptide by Pol η. We conclude that a bulky 15-mer peptide cross-linked to the N6 position of dA can retard polymerization and cause miscoding but that overall fidelity is not compromised because only correct pairs are extended.
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http://dx.doi.org/10.1016/j.jbc.2021.100444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024977PMC
February 2021

Spatial dependency and the role of local susceptibility for velocity selective arterial spin labeling (VS-ASL) relative tagging efficiency using accelerated 3D radial sampling with a BIR-8 preparation.

Magn Reson Med 2021 Jul 21;86(1):293-307. Epub 2021 Feb 21.

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

Purpose: Velocity selective arterial spin labeling (VS-ASL) is a promising approach for non-contrast perfusion imaging that provides robustness to vascular geometry and transit times; however, VS-ASL assumes spatially uniform tagging efficiency. This work presents a mapping approach to investigate VS-ASL relative tagging efficiency including the impact of local susceptibility effects on a BIR-8 preparation.

Methods: Numerical simulations of tagging efficiency were performed to evaluate sensitivity to regionally varying local susceptibility gradients and blood velocity. Tagging efficiency mapping was performed in susceptibility phantoms and healthy human subjects (N = 7) using a VS-ASL preparation module followed by a short, high spatial resolution 3D radial-based image acquisition. Tagging efficiency maps were compared to 4D-flow, B , and B maps acquired in the same imaging session for six of the seven subjects.

Results: Numerical simulations were found to predict reduced tagging efficiency with the combination of high blood velocity and local gradient fields. Phantom experiments corroborated numerical results. Relative efficiency mapping in normal volunteers showed unique efficiency patterns depending on individual subject anatomy and physiology. Uniform tagging efficiency was generally observed in vivo, but reduced efficiency was noted in regions of high blood velocity and local susceptibility gradients.

Conclusion: We demonstrate an approach to map the relative tagging efficiency and show application of this methodology to a novel BIR-8 preparation recently proposed in the literature. We present results showing rapid flow in the presence of local susceptibility gradients can lead to complicated signal modulations in both tag and control images and reduced tagging efficiency.
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http://dx.doi.org/10.1002/mrm.28726DOI Listing
July 2021

Sentiment analysis of user feedback on the HSE's Covid-19 contact tracing app.

Ir J Med Sci 2021 Feb 18. Epub 2021 Feb 18.

Lero - The Irish Software Research Centre, Tierney Building, University of Limerick, Limerick, Ireland.

Background: Digital Contact Tracing is seen as a key tool in reducing the propagation of Covid-19. But it requires high uptake and continued participation across the population to be effective. To achieve sufficient uptake/participation, health authorities should address, and thus be aware of, user concerns.

Aim: This work manually analyzes user reviews of the Irish Heath Service Executive's (HSE) Contact Tracker app, to identify user concerns and to lay the foundations for subsequent, large-scale, automated analyses of reviews. While this might seem tightly scoped to the Irish context, the HSE app provides the basis for apps in many jurisdictions in the USA and Europe.

Methods: Manual analysis of (1287) user reviews from the Google/Apple playstores was performed, to identify the aspects of the app that users focused on, and the positive/negative sentiment expressed.

Results: The findings suggest a largely positive sentiment towards the app, and that users thought it handled data protection and transparency aspects well. But feedback suggests that users would appreciate more targeted feedback on the incidence of the virus, and facilities for more proactive engagement, like notifications that prompt users to submit their health status daily. Finally, the analysis suggests that the "android battery" issue and the backward-compatibility issue with iPhones seriously impacted retention/uptake of the app respectively.

Conclusion: The HSE have responded to the public's desire for targeted feedback in newer versions, but should consider increasing the app's proactive engagement. The results suggest they should also raise the backward compatibility issue, regarding older iPhones, with Apple.
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http://dx.doi.org/10.1007/s11845-021-02529-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891483PMC
February 2021

The assembled and annotated genome of the pigeon louse Columbicola columbae, a model ectoparasite.

G3 (Bethesda) 2021 Feb;11(2)

School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA.

The pigeon louse Columbicola columbae is a longstanding and important model for studies of ectoparasitism and host-parasite coevolution. However, a deeper understanding of its evolution and capacity for rapid adaptation is limited by a lack of genomic resources. Here, we present a high-quality draft assembly of the C. columbae genome, produced using a combination of Oxford Nanopore, Illumina, and Hi-C technologies. The final assembly is 208 Mb in length, with 12 chromosome-size scaffolds representing 98.1% of the assembly. For gene model prediction, we used a novel clustering method (wavy_choose) for Oxford Nanopore RNA-seq reads to feed into the MAKER annotation pipeline. High recovery of conserved single-copy orthologs (BUSCOs) suggests that our assembly and annotation are both highly complete and highly accurate. Consistent with the results of the only other assembled louse genome, Pediculus humanus, we find that C. columbae has a relatively low density of repetitive elements, the majority of which are DNA transposons. Also similar to P. humanus, we find a reduced number of genes encoding opsins, G protein-coupled receptors, odorant receptors, insulin signaling pathway components, and detoxification proteins in the C. columbae genome, relative to other insects. We propose that such losses might characterize the genomes of obligate, permanent ectoparasites with predictable habitats, limited foraging complexity, and simple dietary regimes. The sequencing and analysis for this genome were relatively low cost, and took advantage of a new clustering technique for Oxford Nanopore RNAseq reads that will be useful to future genome projects.
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http://dx.doi.org/10.1093/g3journal/jkab009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022949PMC
February 2021

A phantom study comparing radial trajectories for accelerated cardiac 4D flow MRI against a particle imaging velocimetry reference.

Magn Reson Med 2021 Jul 5;86(1):363-371. Epub 2021 Feb 5.

Departments of Medical Physics and Radiology, University of Wisconsin-Madison, Madison, Wisconsin, USA.

Purpose: Radial sampling is one method to accelerate 4D flow MRI acquisition, making feasible dual-velocity encoding (Venc) assessment of slow flow in the left ventricle (LV). Here, two radial trajectories are compared in vitro for this application: 3D radial (phase-contrast vastly undersampled isotropic projection, PC-VIPR) versus stack of stars (phase-contrast stack of stars, PC-SOS), with benchtop particle imaging velocimetry (PIV) serving as a reference standard.

Methods: The study contained three steps: (1) Construction of an MRI- and PIV-compatible LV model from a healthy adult's CT images. (2) In vitro PIV using a pulsatile flow pump. (3) In vitro dual-Venc 4D flow MRI using PC-VIPR and PC-SOS (two repeat experiments). Each MR image set was retrospectively undersampled to five effective scan durations and compared with the PIV reference. The root-mean-square velocity vector difference (RMSE) between MRI and PIV images was compared, along with kinetic energy (KE) and wall shear stress (WSS).

Results: RMSE increased as scan time decreased for both MR acquisitions. RMSE was 3% lower in PC-SOS images than PC-VIPR images in 30-min scans (3.8 vs. 3.9 cm/s) but 98% higher in 2.5-min scans (9.5 vs. 4.8 cm/s). PIV intrasession repeatability showed a RMSE of 4.4 cm/s, reflecting beat-to-beat flow variation, while MRI had intersession RMSEs of 3.8/3.5 cm/s for VIPR/SOS, respectively. Speed, KE, and WSS were overestimated voxel-wise in 30-min MRI scans relative to PIV by 0.4/0.3 cm/s, 0.2/0.1 μJ/mL, and 36/43 mPa, respectively, for VIPR/SOS.

Conclusions: PIV is feasible for application-specific 4D flow MRI protocol optimization. PC-VIPR is better-suited to dual-Venc LV imaging with short scan times.
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http://dx.doi.org/10.1002/mrm.28698DOI Listing
July 2021

Daikenchuto increases blood flow in the superior mesenteric artery in humans: A comparison study between four-dimensional phase-contrast vastly undersampled isotropic projection reconstruction magnetic resonance imaging and Doppler ultrasound.

PLoS One 2021 27;16(1):e0245878. Epub 2021 Jan 27.

Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.

Respiratory-gated four-dimensional phase-contrast vastly undersampled isotropic projection reconstruction (4D PC-VIPR) is magnetic resonance (MR) imaging technique that enables analysis of vascular morphology and hemodynamics in a single examination using cardiac phase resolved 3D phase-contrast magnetic resonance imaging. The present study aimed to assess the usefulness of 4D PC-VIPR for the superior mesenteric artery (SMA) flowmetry before and after flow increase was induced by the herbal medicine Daikenchuto (TJ-100) by comparing it with Doppler ultrasound (DUS) as a current standard. Twenty healthy volunteers were enrolled in this prospective single-arm study. The peak cross-sectionally averaged velocity was measured by 4D PC-VIPR, peak velocity was measured by DUS, and flow volume (FV) of SMA and aorta were measured by 4D PC-VIPR and DUS 25 min before and after the peroral administration of TJ-100. The peak cross-sectionally averaged velocity, peak velocity, and FV of SMA measured by 4D PC-VIPR and DUS significantly increased after administration of TJ-100 (4D PC-VIPR: the peak cross-sectionally averaged velocity; p = 0.004, FV; p = 0.035, DUS: the peak velocity; p = 0.003, FV; p = 0.010). Furthermore, 4D PC-VIPR can analyze multiple blood vessels simultaneously. The ratio of the SMA FV to the aorta, before and after oral administration on the 4D PC-VIPR test also increased (p = 0.015). The rate of change assessed by 4D PC-VIPR and DUS were significantly correlated (the peak cross-sectionally averaged velocity and peak velocity: r = 0.650; p = 0.005, FV: r = 0.659; p = 0.004). Retrospective 4D PC-VIPR was a useful modality for morphological and hemodynamic analysis of SMA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245878PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840032PMC
January 2021

Switching to centrifugal pumps may decrease hemolysis rates among pediatric ECMO patients.

Perfusion 2021 Jan 18:267659120982572. Epub 2021 Jan 18.

Division of Pediatric Surgery, Mott Children's Hospital, Ann Arbor, MI, USA.

Recent advances in ECLS technology have led to the adoption of centrifugal pumps for the majority of patients worldwide. Despite several advantages of centrifugal pumps, they remain controversial because a number of studies have shown increased rates of hemolysis. The aim of this study was to assess the impact of transitioning from roller to centrifugal pumps on hemolysis rates at our center. A retrospective analysis of all pediatric ECMO patients at a single center between 2005 and 2017 was undertaken. Hemolysis was defined as a plasma free hemoglobin >50 mg/dL. Multivariable logistic regression was performed correcting for several factors to determine risk factors for hemolysis and analyze outcomes among patients with hemolysis. Significant findings were those with  < 0.05. A total of 590 patients were identified during the study period. Multivariable logistic regression for risk factors for hemolysis showed roller pumps (OR 1.92, CI 1.11-3.33) and ECMO duration (OR 1.002 per hour, CI 1.00-1.01) to be significant factors. Rates of hemolysis significantly improved following conversion from roller to centrifugal pumps, with significantly lower rates of hemolysis in 2012, 2015, 2016, and 2017 when compared to the historical average with roller pumps from 2005 to 2009 (34.7%). Additionally, hemolysis was associated with an increased risk of death (OR 3.59, CI 2.05-6.29) when correcting for other factors. These data suggest decreasing rates of hemolysis with centrifugal pumps compared to roller pumps. Since hemolysis was also associated with increased risk of death, these data support the switch from roller to centrifugal pumps at ECMO centers.
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http://dx.doi.org/10.1177/0267659120982572DOI Listing
January 2021

Does Use of a Feeding Protocol Change Outcomes in Gastroschisis? A Report from the Midwest Pediatric Surgery Consortium.

Eur J Pediatr Surg 2020 Dec 27. Epub 2020 Dec 27.

Department of Surgery, Center for Prospective Trials, Children's Mercy Hospital, Kansas City, Missouri, United States.

Introduction:  Gastroschisis feeding practices vary. Standardized neonatal feeding protocols have been demonstrated to improve nutritional outcomes. We report outcomes of infants with gastroschisis that were fed with and without a protocol.

Materials And Methods:  A retrospective study of neonates with uncomplicated gastroschisis at 11 children's hospitals from 2013 to 2016 was performed.Outcomes of infants fed via institutional-specific protocols were compared with those fed without a protocol. Subgroup analyses of protocol use with immediate versus delayed closure and with sutured versus sutureless closure were conducted.

Results:  Among 315 neonates, protocol-based feeding was utilized in 204 (65%) while no feeding protocol was used in 111 (35%). There were less surgical site infections (SSI) in those fed with a protocol (7 vs. 16%,  = 0.019). There were no differences in TPN duration, time to initial oral intake, time to goal feeds, ventilator use, peripherally inserted central catheter line deep venous thromboses, or length of stay. Of those fed via protocol, less SSIs occurred in those who underwent sutured closure (9 vs. 19%,  = 0.026). Further analyses based on closure timing or closure method did not demonstrate any significant differences.

Conclusion:  Across this multi-institutional cohort of infants with uncomplicated gastroschisis, there were more SSIs in those fed without an institutional-based feeding protocol but no differences in other outcomes.
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http://dx.doi.org/10.1055/s-0040-1721074DOI Listing
December 2020

Electronic health records and clinician burnout: A story of three eras.

J Am Med Inform Assoc 2020 Dec 22. Epub 2020 Dec 22.

Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

Objective: The study sought to provide physicians, informaticians, and institutional policymakers with an introductory tutorial about the history of medical documentation, sources of clinician burnout, and opportunities to improve electronic health records (EHRs). We now have unprecedented opportunities in health care, with the promise of new cures, improved equity, greater sensitivity to social and behavioral determinants of health, and data-driven precision medicine all on the horizon. EHRs have succeeded in making many aspects of care safer and more reliable. Unfortunately, current limitations in EHR usability and problems with clinician burnout distract from these successes. A complex interplay of technology, policy, and healthcare delivery has contributed to our current frustrations with EHRs. Fortunately, there are opportunities to improve the EHR and health system. A stronger emphasis on improving the clinician's experience through close collaboration by informaticians, clinicians, and vendors can combine with specific policy changes to address the causes of burnout.

Target Audience: This tutorial is intended for clinicians, informaticians, policymakers, and regulators, who are essential participants in discussions focused on improving clinician burnout. Learners in biomedicine, regardless of clinical discipline, also may benefit from this primer and review.

Scope: We include (1) an overview of medical documentation from a historical perspective; (2) a summary of the forces converging over the past 20 years to develop and disseminate the modern EHR; and (3) future opportunities to improve EHR structure, function, user base, and time required to collect and extract information.
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http://dx.doi.org/10.1093/jamia/ocaa274DOI Listing
December 2020

Protein Residues and a Novel Motif Involved in the Cellular Localization of CheZ in ORS571.

Front Microbiol 2020 7;11:585140. Epub 2020 Dec 7.

Key Laboratory of Coastal Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai, China.

Chemotaxis is essential for the competitiveness of motile bacteria in complex and harsh environments. The localization of chemotactic proteins in the cell is critical for coordinating a maximal response to chemotactic signals. One chemotaxis protein with a well-defined subcellular localization is the phosphatase CheZ. CheZ localizes to cell poles by binding with CheA in and other enteric bacteria, or binding with a poorly understood protein called ChePep in epsilon-. In alpha-, CheZ lacks CheA-binding sites, and its cellular localization remains unknown. We therefore determined the localization of CheZ in the alpha- ORS571. CheZ, also termed as CheZ was found to be located to cell poles independently of CheA, and we suspect that either the N-terminal helix or the four-helix bundle of CheZ is sufficient to locate to cell poles. We also found a novel motif, AXXFQ, which is adjacent to the phosphatase active motif DXXXQ, which effects the monopolar localization of CheZ. This novel motif consisting of AXXFQ is conserved in CheZ and widely distributed among . Finally, we found that the substitution of phosphatase active site affects the polar localization of CheZ. In total, this work characterized the localization pattern of CheZ containing a novel motif, and we mapped the regions of CheZ that are critical for its polar localization.
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http://dx.doi.org/10.3389/fmicb.2020.585140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750401PMC
December 2020

A retrospective approach to evaluating potential adverse outcomes associated with delay of procedures for cardiovascular and cancer-related diagnoses in the context of COVID-19.

J Biomed Inform 2021 01 10;113:103657. Epub 2020 Dec 10.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address:

Objective: During the COVID-19 pandemic, health systems postponed non-essential medical procedures to accommodate surge of critically-ill patients. The long-term consequences of delaying procedures in response to COVID-19 remains unknown. We developed a high-throughput approach to understand the impact of delaying procedures on patient health outcomes using electronic health record (EHR) data.

Materials And Methods: We used EHR data from Vanderbilt University Medical Center's (VUMC) Research and Synthetic Derivatives. Elective procedures and non-urgent visits were suspended at VUMC between March 18, 2020 and April 24, 2020. Surgical procedure data from this period were compared to a similar timeframe in 2019. Potential adverse impact of delay in cardiovascular and cancer-related procedures was evaluated using EHR data collected from January 1, 1993 to March 17, 2020. For surgical procedure delay, outcomes included length of hospitalization (days), mortality during hospitalization, and readmission within six months. For screening procedure delay, outcomes included 5-year survival and cancer stage at diagnosis.

Results: We identified 416 surgical procedures that were negatively impacted during the COVID-19 pandemic compared to the same timeframe in 2019. Using retrospective data, we found 27 significant associations between procedure delay and adverse patient outcomes. Clinician review indicated that 88.9% of the significant associations were plausible and potentially clinically significant. Analytic pipelines for this study are available online.

Conclusion: Our approach enables health systems to identify medical procedures affected by the COVID-19 pandemic and evaluate the effect of delay, enabling them to communicate effectively with patients and prioritize rescheduling to minimize adverse patient outcomes.
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http://dx.doi.org/10.1016/j.jbi.2020.103657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728428PMC
January 2021

Comparison of data-driven and general temporal constraints on compressed sensing for breast DCE MRI.

Magn Reson Med 2021 Jun 11;85(6):3071-3084. Epub 2020 Dec 11.

Department of Radiology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.

Purpose: Current breast DCE-MRI strategies provide high sensitivity for cancer detection but are known to be insufficient in fully capturing rapidly changing contrast kinetics at high spatial resolution across both breasts. Advanced acquisition and reconstruction strategies aim to improve spatial and temporal resolution and increase specificity for disease characterization. In this work, we evaluate the spatial and temporal fidelity of a modified data-driven low-rank-based model (known as MOCCO, model consistency condition) compressed-sensing (CS) reconstruction compared to CS with temporal total variation with radial acquisition for high spatial-temporal breast DCE MRI.

Methods: Reconstruction performance was characterized using numerical simulations of a golden-angle stack-of-stars breast DCE-MRI acquisition at 5-second temporal resolution. Specifically, MOCCO was compared with CS total variation and conventional SENSE reconstructions. The temporal model for MOCCO was prelearned over the source data, whereas CS total variation was performed using a first-order temporal gradient sparsity transform.

Results: The MOCCO reconstruction was able to capture rapid lesion kinetics while providing high image quality across a range of optimal regularization values. It also recovered kinetics in small lesions (1.5 mm) in line-profile analysis and error images, whereas g-factor maps showed relatively low and constant values with no significant artifacts. The CS-TV method demonstrated either recovery of high spatial resolution with reduced temporal accuracy using large regularization values, or recovery of rapid lesion kinetics with reduced image quality using low regularization values.

Conclusion: Simulations demonstrated that MOCCO with radial acquisition provides a robust imaging technique for improving temporal fidelity, while maintaining high spatial resolution and image quality in the setting of bilateral breast DCE MRI.
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http://dx.doi.org/10.1002/mrm.28628DOI Listing
June 2021

Use of electronic health records to support a public health response to the COVID-19 pandemic in the United States: a perspective from 15 academic medical centers.

J Am Med Inform Assoc 2021 02;28(2):393-401

Department of Biomedical Informatics, University of California San Diego Health, La Jolla, California, USA.

Our goal is to summarize the collective experience of 15 organizations in dealing with uncoordinated efforts that result in unnecessary delays in understanding, predicting, preparing for, containing, and mitigating the COVID-19 pandemic in the US. Response efforts involve the collection and analysis of data corresponding to healthcare organizations, public health departments, socioeconomic indicators, as well as additional signals collected directly from individuals and communities. We focused on electronic health record (EHR) data, since EHRs can be leveraged and scaled to improve clinical care, research, and to inform public health decision-making. We outline the current challenges in the data ecosystem and the technology infrastructure that are relevant to COVID-19, as witnessed in our 15 institutions. The infrastructure includes registries and clinical data networks to support population-level analyses. We propose a specific set of strategic next steps to increase interoperability, overall organization, and efficiencies.
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http://dx.doi.org/10.1093/jamia/ocaa287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665546PMC
February 2021

Successful response of primary sclerosing cholangitis and associated ulcerative colitis to oral vancomycin may depend on brand and personalized dose: report in an adolescent.

Clin J Gastroenterol 2021 Apr 24;14(2):684-689. Epub 2020 Nov 24.

Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford University, Palo Alto, CA, USA.

Primary sclerosing cholangitis (PSC) is a rare, progressive liver disease characterized by cholestasis and bile duct fibrosis that has no accepted therapy known to delay or arrest its progression. We report a 23-year-old female patient who at age 14 was diagnosed with moderate pancolonic ulcerative colitis (UC) and at age 15 with small-duct PSC unresponsive to conventional therapy. The patient began single drug therapy with the antibiotic oral vancomycin (OVT) and achieved normalization of liver enzymes and resolution of UC symptoms with colonic mucosal healing. These improvements have persisted over 8 years. There has been no colon dysplasia, liver fibrosis or failure, bile duct stricture, or cancer. Of note, the patient's response was dependent on the brand of oral vancomycin capsule, as well as dose. This raised the questions of possible differences in bioequivalence of different commercial versions of the drug and whether this factor might play into the variability of efficacy seen in published trials. Evidence suggests that oral vancomycin both alters the intestinal microbiome and has immunomodulatory effects. Its striking effectiveness in this and other patients supports further investigation in randomized trials, with careful attention to its bioavailability profile in the gut.
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http://dx.doi.org/10.1007/s12328-020-01296-0DOI Listing
April 2021

Structure, gene order, and nucleotide composition of mitochondrial genomes in parasitic lice from Amblycera.

Gene 2021 Feb 18;768:145312. Epub 2020 Nov 18.

Department of Entomology, Purdue University, West Lafayette, IN, USA.

Parasitic lice have unique mitochondrial (mt) genomes characterized by rearranged gene orders, variable genome structures, and less AT content compared to most other insects. However, relatively little is known about the mt genomes of Amblycera, the suborder sister to all other parasitic lice. Comparing among nine different genera (including representative of all seven families), we show that Amblycera have variable and highly rearranged mt genomes. Some genera have fragmented genomes that vary considerably in length, whereas others have a single mt chromosome. Notably, these genomes are more AT-biased than most other lice. We also recover genus-level phylogenetic relationships among Amblycera that are consistent with those reported from large nuclear datasets, indicating that mt sequences are reliable for reconstructing evolutionary relationships in Amblycera. However, gene order data cannot reliably recover these same relationships. Overall, our results suggest that the mt genomes of lice, already know to be distinctive, are even more variable than previously thought.
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http://dx.doi.org/10.1016/j.gene.2020.145312DOI Listing
February 2021

ConceptWAS: a high-throughput method for early identification of COVID-19 presenting symptoms.

medRxiv 2020 Nov 10. Epub 2020 Nov 10.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN.

Objective: Identifying symptoms highly specific to COVID-19 would improve the clinical and public health response to infectious outbreaks. Here, we describe a high-throughput approach - Concept-Wide Association Study (ConceptWAS) that systematically scans a disease's clinical manifestations from clinical notes. We used this method to identify symptoms specific to COVID-19 early in the course of the pandemic.

Methods: Using the Vanderbilt University Medical Center (VUMC) EHR, we parsed clinical notes through a natural language processing pipeline to extract clinical concepts. We examined the difference in concepts derived from the notes of COVID-19-positive and COVID-19-negative patients on the PCR testing date. We performed ConceptWAS using the cumulative data every two weeks for early identifying specific COVID-19 symptoms.

Results: We processed 87,753 notes 19,692 patients (1,483 COVID-19-positive) subjected to COVID-19 PCR testing between March 8, 2020, and May 27, 2020. We found 68 clinical concepts significantly associated with COVID-19. We identified symptoms associated with increasing risk of COVID-19, including "absent sense of smell" (odds ratio [OR] = 4.97, 95% confidence interval [CI] = 3.21-7.50), "fever" (OR = 1.43, 95% CI = 1.28-1.59), "with cough fever" (OR = 2.29, 95% CI = 1.75-2.96), and "ageusia" (OR = 5.18, 95% CI = 3.02-8.58). Using ConceptWAS, we were able to detect loss sense of smell or taste three weeks prior to their inclusion as symptoms of the disease by the Centers for Disease Control and Prevention (CDC).

Conclusion: ConceptWAS is a high-throughput approach for exploring specific symptoms of a disease like COVID-19, with a promise for enabling EHR-powered early disease manifestations identification.
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http://dx.doi.org/10.1101/2020.11.06.20227165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668764PMC
November 2020

Homodimerization and heterodimerization requirements of SOS response coregulators UmuDAb and DdrR revealed by two-hybrid analyses.

Can J Microbiol 2020 Nov 12:1-14. Epub 2020 Nov 12.

Department of Biology and Chemistry, Morehead State University, Morehead, KY 40351, USA.

The multidrug-resistant pathogen displays unusual control of its SOS mutagenesis genes, as it does not encode a LexA repressor, but instead employs the UmuDAb repressor and a small protein, DdrR, that is uniquely found in species. We used bacterial adenylate cyclase two-hybrid analyses to determine if UmuDAb and DdrR coregulation might involve physical interactions. Neither quantitative nor qualitative assays showed UmuDAb interaction with DdrR. DdrR hybrid proteins, however, demonstrated modest head-to-tail interactions in a qualitative assay. The similarity of UmuDAb to the homodimer-forming polymerase manager UmuD and LexA repressor proteins suggested that it may form dimers, which we observed. UmuDAb homodimerization required a free C terminus, and either small truncations or addition of a histidine tag at the C terminus abolished this homodimerization. The amino acid N100, crucial for UmuD dimer formation, was dispensable if both C termini were free to interact. However, mutation of the amino acid G124, necessary for LexA dimerization, yielded significantly less UmuDAb dimerization, even if both C termini were free. This suggests that UmuDAb forms dimers like LexA does, but may not coregulate gene expression involving a physical association with DdrR. The homodimerization of these coregulators provides insight into a LexA-independent, coregulatory process of controlling a conserved bacterial action such as the mutagenic DNA damage response.
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http://dx.doi.org/10.1139/cjm-2020-0219DOI Listing
November 2020

A Non-covalent Ligand Reveals Biased Agonism of the TRPA1 Ion Channel.

Neuron 2021 01 4;109(2):273-284.e4. Epub 2020 Nov 4.

Department of Biochemical Cellular Pharmacology, Genentech, 103 DNA Way, South San Francisco, CA 94080, USA. Electronic address:

The TRPA1 ion channel is activated by electrophilic compounds through the covalent modification of intracellular cysteine residues. How non-covalent agonists activate the channel and whether covalent and non-covalent agonists elicit the same physiological responses are not understood. Here, we report the discovery of a non-covalent agonist, GNE551, and determine a cryo-EM structure of the TRPA1-GNE551 complex, revealing a distinct binding pocket and ligand-interaction mechanism. Unlike the covalent agonist allyl isothiocyanate, which elicits channel desensitization, tachyphylaxis, and transient pain, GNE551 activates TRPA1 into a distinct conducting state without desensitization and induces persistent pain. Furthermore, GNE551-evoked pain is relatively insensitive to antagonist treatment. Thus, we demonstrate the biased agonism of TRPA1, a finding that has important implications for the discovery of effective drugs tailored to different disease etiologies.
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http://dx.doi.org/10.1016/j.neuron.2020.10.014DOI Listing
January 2021