Publications by authors named "David A Johnson"

226 Publications

The Variation in the Standard Entropies of Aqueous Tripositive Lanthanide Ions.

Inorg Chem 2020 Aug 20;59(15):10756-10767. Epub 2020 Jul 20.

Department of Chemistry, University of Hull, Hull HU6 7RX, England.

Previous published entropies of solid lanthanide trichloride hydrates are reviewed and revised by taking account of the Kramers degeneracy of ground states with half-integral values of . The revised values necessitate corrections to the standard entropies of the aqueous tripositive lanthanide ions which display an irregular variation with both atomic number and ionic radius. These irregularities can be smoothed out by taking account of contributions from the electronic or magnetic entropy, from structural changes in the coordination that have been revealed by EXAFS and XANES measurements and X-ray crystallography, and from an increasing intrusion of eight coordination across the series. When these contributions are removed, the entropies of the aqueous ions refer to a hypothetical nine-coordinate state in trigonal triprismatic coordination. Within experimental error, they then vary uniformly across the lanthanide series and there is a good linear correlation with the reciprocal of the metal-oxygen distance in the nine-coordinate aqua complexes.
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http://dx.doi.org/10.1021/acs.inorgchem.0c01117DOI Listing
August 2020

Attenuation of Oxidative Injury With Targeted Expression of NADPH Oxidase 2 Short Hairpin RNA Prevents Onset and Maintenance of Electrical Remodeling in the Canine Atrium: A Novel Gene Therapy Approach to Atrial Fibrillation.

Circulation 2020 Sep 20;142(13):1261-1278. Epub 2020 Jul 20.

Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL (S.Y., A.P., J.H., W.Z., J.N., A.B., D.A.J., G.G., T.W., S.B., B.B., B.P.K., R.P., J.A.W., R.A.).

Background: Atrial fibrillation (AF) is the most common heart rhythm disorder in adults and a major cause of stroke. Unfortunately, current treatments of AF are suboptimal because they are not targeted to the molecular mechanisms underlying AF. Using a highly novel gene therapy approach in a canine, rapid atrial pacing model of AF, we demonstrate that NADPH oxidase 2 (NOX2) generated oxidative injury causes upregulation of a constitutively active form of acetylcholine-dependent K current (), called ; this is an important mechanism underlying not only the genesis, but also the perpetuation of electric remodeling in the intact, fibrillating atrium.

Methods: To understand the mechanism by which oxidative injury promotes the genesis and maintenance of AF, we performed targeted injection of NOX2 short hairpin RNA (followed by electroporation to facilitate gene delivery) in atria of healthy dogs followed by rapid atrial pacing. We used in vivo high-density electric mapping, isolation of atrial myocytes, whole-cell patch clamping, in vitro tachypacing of atrial myocytes, lucigenin chemiluminescence assay, immunoblotting, real-time polymerase chain reaction, immunohistochemistry, and Masson trichrome staining.

Results: First, we demonstrate that generation of oxidative injury in atrial myocytes is a frequency-dependent process, with rapid pacing in canine atrial myocytes inducing oxidative injury through the induction of NOX2 and the generation of mitochondrial reactive oxygen species. We show that oxidative injury likely contributes to electric remodeling in AF by upregulating by a mechanism involving frequency-dependent activation of PKC (protein kinase C epsilon). The time to onset of nonsustained AF increased by >5-fold in NOX2 short hairpin RNA-treated dogs. Furthermore, animals treated with NOX2 short hairpin RNA did not develop sustained AF for up to 12 weeks. The electrophysiological mechanism underlying AF prevention was prolongation of atrial effective refractory periods, at least in part attributable to the attenuation of . Attenuated membrane translocation of PKC appeared to be a likely molecular mechanism underlying this beneficial electrophysiological remodeling.

Conclusions: NOX2 oxidative injury (1) underlies the onset, and the maintenance of electric remodeling in AF, as well, and (2) can be successfully prevented with a novel, gene-based approach. Future optimization of this approach may lead to a novel, mechanism-guided therapy for AF.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044127DOI Listing
September 2020

The importance of colonoscopy bowel preparation for the detection of colorectal lesions and colorectal cancer prevention.

Endosc Int Open 2020 May 17;8(5):E673-E683. Epub 2020 Apr 17.

University of Texas Health Science Center, Houston, Texas, United States.

Colonoscopy for colorectal cancer (CRC) screening has reduced CRC incidence and mortality and improved prognosis. Optimal bowel preparation and high-quality endoscopic technique facilitate early CRC detection. This review provides a narrative on the clinical importance of bowel preparation for colonoscopy and highlights available bowel preparations. A PubMed search was conducted through June 2019 to identify studies evaluating clinical outcomes, efficacy, safety, and tolerability associated with bowel preparation for CRC screening-related colonoscopy. Selecting the optimal bowel preparation regimen is based on considerations of efficacy, safety, and tolerability, in conjunction with individual patient characteristics and preferences. Available bowel preparations include high-volume (4 L) and low-volume (2 L and 1 L), polyethylene glycol (PEG) solutions, sodium sulfate, sodium picosulfate/magnesium oxide plus anhydrous citric acid, sodium phosphate tablets, and the over-the-counter preparations magnesium citrate and PEG-3350. These preparations may be administered as a single dose on the same day or evening before, or as two doses administered the same day or evening before/morning of colonoscopy. Ingesting at least half the bowel preparation on the day of colonoscopy (split-dosing) is associated with higher adequate bowel preparation quality versus evening-before dosing (odds ratio [OR], 2.5; 95 % confidence interval [CI], 1.9-3.4). High-quality bowel preparation is integral for optimal CRC screening/surveillance by colonoscopy. Over the last 30 years, patients and providers have gained more options for bowel preparation, including low-volume agents with enhanced tolerability and cleansing quality that are equivalent to 4 L preparations. Split-dosing is preferred for achieving a high-quality preparation.
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http://dx.doi.org/10.1055/a-1127-3144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165013PMC
May 2020

Niche differentiation and plasticity in soil phosphorus acquisition among co-occurring plants.

Nat Plants 2020 04 23;6(4):349-354. Epub 2020 Mar 23.

Department of Animal and Plant Sciences, University of Sheffield, Sheffield, UK.

How species coexist despite competing for the same resources that are in limited supply is central to our understanding of the controls on biodiversity. Resource partitioning may facilitate coexistence, as co-occurring species use different sources of the same limiting resource. In plant communities, however, direct evidence for partitioning of the commonly limiting nutrient, phosphorus (P), has remained scarce due to the challenges of quantifying P acquisition from its different chemical forms present in soil. To address this, we used P to directly trace P uptake from DNA, orthophosphate and calcium phosphate into monocultures and mixed communities of plants growing in grassland soil. We show that co-occurring plants acquire P from these important organic and mineral sources in different proportions, and that differences in P source use are consistent with the species' root adaptations for P acquisition. Furthermore, the net benefit arising from niche plasticity (the gain in P uptake for a species in a mixed community compared to monoculture) correlates with species abundance in the wild, suggesting that niche plasticity for P is a driver of community structure. This evidence for P resource partitioning and niche plasticity may explain the high levels of biodiversity frequently found in P-limited ecosystems worldwide.
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http://dx.doi.org/10.1038/s41477-020-0624-4DOI Listing
April 2020

Optimization of 8-oxoadenines with toll-like-receptor 7 and 8 activity.

Bioorg Med Chem Lett 2020 03 22;30(6):126984. Epub 2020 Jan 22.

Center for Translational Medicine, University of Montana, Missoula, MT 59812, United States; Division of Biological Sciences, University of Montana, Missoula, MT 59812, United States; GSK Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, United States.

Toll-like receptors 7 and 8 (TLR7/8) agonists are potent immunostimulants that are attracting considerable interest as vaccine adjuvants. We recently reported the synthesis of a new series of 2-O-butyl-8-oxoadenines substituted at the 9-position with various linkers and N-heterocycles, and showed that TLR7/8 selectivity, potency and cytokine induction could be modulated by varying the alkyl linker length and the N-heterocyclic ring. In the present study, we further optimized the oxoadenine scaffold by investigating the effect of different substituents at the 2-position of the oxoadenine on TLR7/8 potency/selectivity, cytokine induction and DC maturation in human PBMCs. The results show that introducing a 1-(S)-methylbutoxy group at the 2-position of the oxoadenine significantly increased potency for TLR7/8 activity, cytokine induction and DC maturation.
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http://dx.doi.org/10.1016/j.bmcl.2020.126984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050994PMC
March 2020

Dedicated MRI in the emergency department to expedite diagnostic management of hip fracture.

Emerg Radiol 2020 Feb 15;27(1):41-44. Epub 2019 Oct 15.

Department of Emergency Medicine, Brown University, Providence, RI, USA.

Purpose: To determine the effect on time to diagnosis of making MRI imaging for hip fractures available directly in the emergency department (ED).

Methods: We conducted a retrospective observational study of patients with MRI imaging of the hip for suspected occult fracture, comparing time to diagnosis and time to disposition of populations imaged in the year preceding and the year following installation of an MRI scanner in the ED.

Results: Time to diagnosis of hip fractures was 709 min before installation of a dedicated ED MRI scanner and 280 min after, a 60% reduction. Including the MRI in the diagnostic workup did not increase ED throughput time, and we were able to save 48% of the patients who had an ED-based MRI from an admission to the hospital.

Conclusion: Implementation of an MRI scanner for dedicated emergency department use enables faster hip fracture diagnosis and surgical consultation, or definitive disposition without increasing ED throughput time.
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http://dx.doi.org/10.1007/s10140-019-01729-5DOI Listing
February 2020

Synthetic Toll-like Receptors 7 and 8 Agonists: Structure-Activity Relationship in the Oxoadenine Series.

ACS Omega 2019 Sep 10;4(13):15665-15677. Epub 2019 Sep 10.

GSK Vaccines, 553 Old Corvallis Road, Hamilton, Montana 59840, United States.

Toll-like receptors 7 and 8 (TLR7/8) are broadly expressed on antigen-presenting cells, making TLR7/8 agonists likely candidates for the development of new vaccine adjuvants. We previously reported the synthesis of a new series of 8-oxoadenines substituted at the 9-position with a 4-piperidinylalkyl moiety and demonstrated that TLR7/8 selectivity and potency could be modulated by varying the length of the alkyl linker. In the present study, we broadened our initial structure-activity relationship study to further evaluate the effects of N-heterocycle ring size, chirality, and substitution on TLR7/8 potency, receptor selectivity, and cytokine (IFNα and TNFα) induction from human peripheral blood mononuclear cells (PBMCs). TLR7/8 activity correlated primarily to linker length and to a lesser extent to ring size, while ring chirality had little effect on TLR7/8 potency or selectivity. Substitution of the heterocyclic ring with an aminoalkyl or hydroxyalkyl group for subsequent conjugation to phospholipids or antigens was well tolerated with the retention of both TLR7/8 activity and cytokine induction from human PBMCs.
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http://dx.doi.org/10.1021/acsomega.9b02138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761749PMC
September 2019

Region-specific parasympathetic nerve remodeling in the left atrium contributes to creation of a vulnerable substrate for atrial fibrillation.

JCI Insight 2019 10 17;4(20). Epub 2019 Oct 17.

Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Atrial fibrillation (AF) is the most common heart rhythm disorder and a major cause of stroke. Unfortunately, current therapies for AF are suboptimal, largely because the molecular mechanisms underlying AF are poorly understood. Since the autonomic nervous system is thought to increase vulnerability to AF, we used a rapid atrial pacing (RAP) canine model to investigate the anatomic and electrophysiological characteristics of autonomic remodeling in different regions of the left atrium. RAP led to marked hypertrophy of parent nerve bundles in the posterior left atrium (PLA), resulting in a global increase in parasympathetic and sympathetic innervation throughout the left atrium. Parasympathetic fibers were more heterogeneously distributed in the PLA when compared with other left atrial regions; this led to greater fractionation and disorganization of AF electrograms in the PLA. Computational modeling revealed that heterogeneously distributed parasympathetic activity exacerbates sympathetic substrate for wave break and reentry. We further discovered that levels of nerve growth factor (NGF) were greatest in the left atrial appendage (LAA), where AF was most organized. Preferential NGF release by the LAA - likely a direct function of frequency and regularity of atrial stimulation - may have important implications for creation of a vulnerable AF substrate.
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http://dx.doi.org/10.1172/jci.insight.130532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824299PMC
October 2019

Shear stress regulation of miR-93 and miR-484 maturation through nucleolin.

Proc Natl Acad Sci U S A 2019 06 10;116(26):12974-12979. Epub 2019 Jun 10.

Department of Medicine, University of California, San Diego, CA 92093;

Pulsatile shear (PS) and oscillatory shear (OS) elicit distinct mechanotransduction signals that maintain endothelial homeostasis or induce endothelial dysfunction, respectively. A subset of microRNAs (miRs) in vascular endothelial cells (ECs) are differentially regulated by PS and OS, but the regulation of the miR processing and its implications in EC biology by shear stress are poorly understood. From a systematic in silico analysis for RNA binding proteins that regulate miR processing, we found that nucleolin (NCL) is a major regulator of miR processing in response to OS and essential for the maturation of miR-93 and miR-484 that target mRNAs encoding Krüppel-like factor 2 (KLF2) and endothelial nitric oxide synthase (eNOS). Additionally, anti-miR-93 and anti-miR-484 restore KLF2 and eNOS expression and NO bioavailability in ECs under OS. Analysis of posttranslational modifications of NCL identified that serine 328 (S328) phosphorylation by AMP-activated protein kinase (AMPK) was a major PS-activated event. AMPK phosphorylation of NCL sequesters it in the nucleus, thereby inhibiting miR-93 and miR-484 processing and their subsequent targeting of KLF2 and eNOS mRNA. Elevated levels of miR-93 and miR-484 were found in sera collected from individuals afflicted with coronary artery disease in two cohorts. These findings provide translational relevance of the AMPK-NCL-miR-93/miR-484 axis in miRNA processing in EC health and coronary artery disease.
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http://dx.doi.org/10.1073/pnas.1902844116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600934PMC
June 2019

Response of photosynthesis, growth and water relations of a savannah-adapted tree and grass grown across high to low CO2.

Ann Bot 2019 08;124(1):77-90

Department of Animal and Plant Sciences, University of Sheffield, Sheffield, UK.

Background And Aims: By the year 2100, atmospheric CO2 concentration ([CO2]a) could reach 800 ppm, having risen from ~200 ppm since the Neogene, beginning ~24 Myr ago. Changing [CO2]a affects plant carbon-water balance, with implications for growth, drought tolerance and vegetation shifts. The evolution of C4 photosynthesis improved plant hydraulic function under low [CO2]a and preluded the establishment of savannahs, characterized by rapid transitions between open C4-dominated grassland with scattered trees and closed forest. Understanding directional vegetation trends in response to environmental change will require modelling. But models are often parameterized with characteristics observed in plants under current climatic conditions, necessitating experimental quantification of the mechanistic underpinnings of plant acclimation to [CO2]a.

Methods: We measured growth, photosynthesis and plant-water relations, within wetting-drying cycles, of a C3 tree (Vachellia karroo, an acacia) and a C4 grass (Eragrostis curvula) grown at 200, 400 or 800 ppm [CO2]a. We investigated the mechanistic linkages between trait responses to [CO2]a under moderate soil drying, and photosynthetic characteristics.

Key Results: For V. karroo, higher [CO2]a increased assimilation, foliar carbon:nitrogen, biomass and leaf starch, but decreased stomatal conductance and root starch. For Eragrostis, higher [CO2]a decreased C:N, did not affect assimilation, biomass or starch, and markedly decreased stomatal conductance. Together, this meant that C4 advantages in efficient water-use over the tree were maintained with rising [CO2]a.

Conclusions: Acacia and Eragrostis acclimated differently to [CO2]a, with implications for their respective responses to water limitation and environmental change. Our findings question the carbon-centric focus on factors limiting assimilation with changing [CO2]a, how they are predicted and their role in determining productivity. We emphasize the continuing importance of water-conserving strategies in the assimilation response of savannah plants to rising [CO2]a.
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http://dx.doi.org/10.1093/aob/mcz048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676382PMC
August 2019

Translational Gastroenterology: The Future Is Now!

Authors:
David A Johnson

Am J Gastroenterol 2019 05;114(5):697-699

Eastern Virginia Medical School, Norfolk, Virginia.

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http://dx.doi.org/10.14309/ajg.0000000000000214DOI Listing
May 2019

The Gestation and Growth of the Periodic Table.

Chimia (Aarau) 2019 Mar;73(3):144-151

Department of Inorganic and Analytical Chemistry, University of Geneva, 30 quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland;, Email:

The development of ideas of chemical periodicity from Lavoisier to Mendeleyev's first periodic table of 1869 is surveyed. Although his first periodic table contained a number of errors and weaknesses, his remarkable predictions of the properties of several then unknown elements, together with his capacity to adapt the table to new discoveries, slowly led to its general acceptance. The theory of atomic structure slowly developed to a point where it could rationalise the structure of the table which had, however, been established solely on the basis of experimental observations. Chemistry has played the central role, up to and including the final modification of Seaborg to introduce the actinides - although this had been foreseen by Alfred Werner! Finally we discuss the many physical forms in which the table has been presented.
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http://dx.doi.org/10.2533/chimia.2019.144DOI Listing
March 2019

Stereoselective One-Pot Deconjugation, Aldol, and Stabilized Peterson Olefination of α-Trialkylsilyl-β-alkyl-α,β-Unsaturated Esters.

Org Lett 2019 03 20;21(5):1379-1383. Epub 2019 Feb 20.

Department of Chemistry and Biochemistry , The University of Alabama , Tuscaloosa , Alabama 35487-0336 , United States.

A stereoselective reaction process including a one-pot deconjugation, aldol, and stabilized Peterson olefination of α-trialkylsilyl-β-alkyl-α,β-unsaturated esters coupled with aliphatic aldehydes is described. This sequential procedure afforded tri-and disubstituted conjugated diene ester products with dr values of 12-20:1 for the newly established alkene moieties in modest to good isolated yields.
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http://dx.doi.org/10.1021/acs.orglett.9b00069DOI Listing
March 2019

Bowel preparation for colonoscopy: what is best and necessary for quality?

Curr Opin Gastroenterol 2019 01;35(1):51-57

Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, Virginia, USA.

Purpose Of Review: Colonoscopy is recognizably, the best colon cancer prevention test, provided the quality of the preparation is adequate for detection of precancerous polyps but also allowing for accurate identification of margins, thereby facilitating complete endoscopic resection. As there are many aspects effecting colon prep outcomes, it is timely to review new standards for optimizing outcomes, including product selection based on patient demographics.

Recent Findings: New national guidelines have set a minimum quality threshold for adequacy and also defined a split day delivery for oral options as the "standard of care". Several new prep options have been recently released and these data are discussed.

Summary: Optimizing the quality of colon preps has major implications for clinical practice. Clinicians must recognize new targets for standard of care, providing the best approach for each individual patient, considering variable factors which may otherwise compromise success.
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http://dx.doi.org/10.1097/MOG.0000000000000494DOI Listing
January 2019

The Role and Value of Public Members in Health Care Regulatory Governance.

Acad Med 2019 02;94(2):182-186

D.A. Johnson is senior vice president of assessment services, Federation of State Medical Boards, Euless, Texas. K.L. Arnhart is senior research analyst, Federation of State Medical Boards, Euless, Texas. H.J. Chaudhry is president and CEO, Federation of State Medical Boards, Euless, Texas, and clinical associate professor of internal medicine, University of Texas Southwestern Medical School, Dallas, Texas. D.H. Johnson is Donald W. Seldin Distinguished Chair in Internal Medicine and professor and chairman, University of Texas Southwestern Medical School, Dallas, Texas. G.T. McMahon is president and CEO, Accreditation Council for Continuing Medical Education, Chicago, Illinois.

American medicine has progressively embraced transparency and accountability in professional self-regulation. While public members serving on health care regulatory boards involved with the accreditation, assessment, certification, education, and licensing of physicians provide formal opportunities for voicing public interests, their presence has not been deeply explored. Using 2016 survey and interview data from health care organizations and public members, the authors explore the value and challenges of public members. Public members were often defined as individuals who did not have a background in health care and provided a patient perspective, but in some instances prior health care experience did not automatically exclude these individuals from serving as public members. Public members served on the majority of national health care regulatory boards and constituted an average 9% to 15% of board composition, depending on how rigidly the organizations defined "public member." Public members were valued for their commitment to the priorities and interests of the public, ability to help boards maintain that public focus, and various professional skills they offer to boards. A main challenge that public members faced was their lack of familiarity with and knowledge of the health care field. The authors suggest several considerations for improved public member integration into health care regulatory organizations: clearly defined roles of public members, including evaluating whether or not previous health care experience either contributes or hinders their role within the organization; greater visibility of opportunities for the public to serve on these boards; and potentially a more intensive orientation for public members.
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http://dx.doi.org/10.1097/ACM.0000000000002481DOI Listing
February 2019

Pilot, Randomized, Blinded, Placebo-Controlled Trial Investigating the Correlation Between Acid Control and Heartburn Relief with 14 Days of Esomeprazole Treatment.

Adv Ther 2018 11 25;35(11):2024-2040. Epub 2018 Sep 25.

Global R&D, Pfizer Consumer Healthcare, Madison, NJ, USA.

Introduction: Reflux symptoms are frequently associated with esophageal acid exposure. However, other potential causes unrelated to acid secretion are possible, and the relationship between acid control and symptomatic improvement remains unclear. This study investigated the correlation between individual intragastric pH control and heartburn relief among subjects with frequent heartburn who are likely to self-treat with over-the-counter (OTC) medications. We hypothesized that improved acid control would provide greater symptomatic improvement among individuals representative of an OTC population.

Methods: This phase 4, single-center, randomized, double-blind, placebo-controlled study was conducted in subjects without diagnosed gastroesophageal reflux disease or other gastrointestinal conditions who were experiencing frequent heartburn (≥ 3 episodes/week; ≥ 2 nighttime episodes/week over past 30 days) that was responsive to treatment. Subjects entered a 7-day run-in phase, received placebo BID (before breakfast and dinner), and completed symptom diaries. During the treatment phase, subjects received esomeprazole 20 mg BID, esomeprazole 20 mg then placebo, or placebo BID. Subjects underwent 24-h intragastric pH monitoring at baseline and day 14 and completed daily symptom diaries.

Results: In the per-protocol population (n = 39), mean (SD) change from baseline in percentage of time with intragastric pH > 4 was 58.7% (± 26.4%) versus 41.0% (± 30.4%) for those who did and did not achieve 24-h heartburn relief. Significant correlations were observed between change in percentage of time with intragastric pH > 4 and 24-h heartburn relief (OR 1.028; 95% CI 1.001, 1.055; P = 0.0442) and complete resolution (OR 1.034; 95% CI 1.003, 1.065; P = 0.0301).

Conclusions: Individuals with greater improvements in duration of intragastric acid suppression had an increased likelihood of achieving heartburn relief and resolution. These results indicate that individuals not adequately controlling their intragastric pH may require an escalation in dose of their acid-suppressive therapy, assessment with 24-h pH monitoring, or a change in treatment regimen to address non-reflux-related etiologies of their heartburn.

Trial Registration: ClinicalTrials.gov identifier: NCT02708355.

Funding: Pfizer Consumer Healthcare, Madison, NJ, USA. Plain language summary available for this article.
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http://dx.doi.org/10.1007/s12325-018-0792-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224004PMC
November 2018

Tandem Copper-Catalyzed Conjugate Addition-Diastereoselective Protonation of ( E)-α-Trialkylsilyl-β-Alkyl(Aryl)-α,β-Unsaturated Esters.

Org Lett 2018 10 14;20(19):6099-6103. Epub 2018 Sep 14.

Department of Chemistry and Biochemistry , The University of Alabama , Tuscaloosa , Alabama 35487-0336 , United States.

A tandem Cu(I)-catalyzed conjugate addition of Kharasch reagents/diastereoselective protonation of ( E)-α-trialkylsilyl-β-alkyl(aryl)-α,β-unsaturated esters afforded the saturated products with d.r. values of >20:1 favoring the anti-diastereomer in modest to excellent isolated yields.
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http://dx.doi.org/10.1021/acs.orglett.8b02527DOI Listing
October 2018

Diastereoselective Syntheses of ( E)-α-Trialkylsilyl α,β-Unsaturated Esters, α-Silane-Substituted Conjugated Silyl Ketene Acetals, and α,γ-Substituted Allylsilanes.

J Org Chem 2018 09 6;83(17):9914-9928. Epub 2018 Aug 6.

Department of Chemistry , The University of Alabama , 250 Hackberry Lane, Tuscaloosa , Alabama 35487-0336 , United States.

The vicinal functionalization of propiolate esters via a catalytic carbocupration/silicon group migration sequence has been further investigated to include the syntheses of a wide variety of β-alkyl- and β-aryl-substituted ( E)-α-silyl α,β-unsaturated esters. The ester substrates were transformed into their β,γ-unsaturated isomers by means of an LDA-mediated γ-deprotonation, extended silyl ketene acetal formation, and final α-protonation sequence. The silyl ketene acetal intermediates were also isolated, and their stereochemistries were established by NOE. The isolation of the intermediate extended silyl ketene acetals afforded further understanding of the lithium-extended dienolate structure and furnished additional support for Snieckus's proposed cyclic eight-membered transition state in the deprotonation of ( Z)-α,β-unsaturated carbonyls with metallodialkylamides.
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http://dx.doi.org/10.1021/acs.joc.8b01209DOI Listing
September 2018

Bioinformatics Approach to Identify Novel AMPK Targets.

Methods Mol Biol 2018 ;1732:99-109

Department of Medicine, University of California, San Diego, La Jolla, CA, USA.

In silico analysis of Big Data is a useful tool to identify putative kinase targets as well as nodes of signaling cascades that are difficult to discover by traditional single molecule experimentation. System approaches that use a multi-tiered investigational methodology have been instrumental in advancing our understanding of cellular mechanisms that result in phenotypic changes. Here, we present a bioinformatics approach to identify AMP-activated protein kinase (AMPK) target proteins on a proteome-wide scale and an in vitro method for preliminary validation of these targets. This approach offers an initial screening for the identification of AMPK targets that can be further validated using mutagenesis and molecular biology techniques.
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http://dx.doi.org/10.1007/978-1-4939-7598-3_7DOI Listing
January 2019

The Effect of Melatonin Upon Postacute Withdrawal Among Males in a Residential Treatment Program (M-PAWS): A Randomized, Double-blind, Placebo-controlled Trial.

J Addict Med 2018 May/Jun;12(3):201-206

Division of Pharmaceutical, Social, and Administrative Sciences, Mylan School of Pharmacy, Duquesne University, Pittsburgh, PA (CDB, KMK, DAJ, PAW-E, VJG).

Objective: Assess the effect of melatonin (5 mg) compared with placebo as an adjuvant treatment along with current behavioral and pharmacotherapy for 28 days on weekly self-reported severity of anxiety, depression, stress, and sleep complaints, and also how sleep is affecting daily life in males 18 years of age and older in recovery from substance use at a residential program in south-western Pennsylvania.

Background: Individuals in recovery experience a variety of symptoms including, but are not limited to, anxiety, depression, sleep difficulties, and stress. In the U.S., melatonin is a readily available nutraceutical that is used to alleviate sleep difficulties. Studies also suggest that melatonin may also have anxiolytic and antidepressive actions alone, as well as in those with co-morbid insomnia. Observation of clinicians treating individuals during and/or post drug cessation indicated that melatonin is commonly provided specifically to alleviate sleep difficulties with little evidence regarding efficacy in this population. The paucity of evidence as well as observation of clinical practices provided the rationale for this randomized clinical trial.

Methods: A single-center, randomized, double-blind, placebo-controlled, parallel-group trial was conducted. Seventy individuals were enrolled, block-randomized with an allocation ratio of 1:1. Intention-to-treat analysis was performed for all primary outcome measures. Primary outcome measures were assessed with the Generalized Anxiety Disorder Scale (GAD-7), Personal Health Questionnaire Depression Scale (PHQ-8), Perceived Stress Scale (PSS-14), and Pittsburgh Sleep Symptom Questionnaire-Insomnia (PSSQ-1). Secondary outcome measures were to acquire participant characteristics, determine adherence, and document adverse events.

Results: No statistically significant between-group differences were detected for baseline characteristics. Even though the proportion of individuals reporting an adverse event between groups was not significantly different, the frequency of reported adverse events was greater in the melatonin group. Intention-to-treat analysis for all the measured outcomes revealed no statistically significant between-group differences for same day comparisons.

Conclusions: The diversity of medication regimens, and also the services provided by the residential treatment site add to the complexity of assessing the efficacy of melatonin on the measured outcomes. Given these limitations, there exists insufficient evidence to suggest that the effect of melatonin and placebo on the outcomes were significantly different.
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http://dx.doi.org/10.1097/ADM.0000000000000386DOI Listing
October 2019

The Effects of Sleep on the Commensal Microbiota: Eyes Wide Open?

J Clin Gastroenterol 2018 03;52(3):204-209

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA.

Sleep dysfunction is an epidemic, the implications of which have a profound impact on a variety of gastrointestinal disease. Recent data suggests a relationship between sleep dysfunction and intestinal dysbiosis, a known proinflammatory driver. This article evaluates the interplay between sleep dysfunction and gastrointestinal health and disease, with a focus on the impact of circadian rhythm disruption on the commensal microbiota.
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http://dx.doi.org/10.1097/MCG.0000000000000965DOI Listing
March 2018

Wake-up Call to Clinicians: The Impact of Sleep Dysfunction on Gastrointestinal Health and Disease.

J Clin Gastroenterol 2018 03;52(3):194-203

Department of Internal Medicine, Division of Gastroenterology and Hepatology, Carilion Clinic, Roanoke.

Sleep dysfunction is an epidemic affecting a large portion of the adult population. Recent studies have linked sleep dysfunction with an upregulation of proinflammatory cytokines (eg, tumor necrosis factor-α, interleukin-1 and interleukin-6), the implications of which can have a profound impact on a variety of gastrointestinal disease. In particular, sleep dysfunction seems to accelerate disease states characterized by inflammation (eg, gastroesophageal reflux disease, irritable bowel syndrome and functional dyspepsia, chronic liver disease, inflammatory bowel disease, and colorectal cancer). This article evaluates the complex interplay between sleep dysfunction and gastrointestinal health and disease.
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http://dx.doi.org/10.1097/MCG.0000000000000963DOI Listing
March 2018

Critical appraisal of pathology transmission in the α-synuclein fibril model of Lewy body disorders.

Exp Neurol 2018 01 19;299(Pt A):172-196. Epub 2017 Oct 19.

Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, United States. Electronic address:

Lewy body disorders are characterized by the emergence of α-synucleinopathy in many parts of the central and peripheral nervous systems, including in the telencephalon. Dense α-synuclein pathology appears in regio inferior of the hippocampus in both Parkinson's disease and dementia with Lewy bodies and may disturb cognitive function. The preformed α-synuclein fibril model of Parkinson's disease is growing in use, given its potential for seeding the self-propagating spread of α-synucleinopathy throughout the mammalian brain. Although it is often assumed that the spread occurs through neuroanatomical connections, this is generally not examined vis-à-vis the uptake and transport of tract-tracers infused at precisely the same stereotaxic coordinates. As the neuronal connections of the hippocampus are historically well defined, we examined the first-order spread of α-synucleinopathy three months following fibril infusions centered in the mouse regio inferior (CA2+CA3), and contrasted this to retrograde and anterograde transport of the established tract-tracers FluoroGold and biotinylated dextran amines (BDA). Massive hippocampal α-synucleinopathy was insufficient to elicit memory deficits or loss of cells and synaptic markers in this model of early disease processes. However, dense α-synuclein inclusions in the fascia dentata were negatively correlated with memory capacity. A modest compensatory increase in synaptophysin was evident in the stratum radiatum of cornu Ammonis in fibril-infused animals, and synaptophysin expression correlated inversely with memory function in fibril but not PBS-infused mice. No changes in synapsin I/II expression were observed. The spread of α-synucleinopathy was somewhat, but not entirely consistent with FluoroGold and BDA axonal transport, suggesting that variables other than innervation density also contribute to the materialization of α-synucleinopathy. For example, layer II entorhinal neurons of the perforant pathway exhibited somal α-synuclein inclusions as well as retrogradely labeled FluoroGold somata. However, some afferent brain regions displayed dense retrograde FluoroGold label and no α-synuclein inclusions (e.g. medial septum/diagonal band), supporting the selective vulnerability hypothesis. The pattern of inclusions on the contralateral side was consistent with specific spread through commissural connections (e.g. stratum pyramidale of CA3), but again, not all commissural projections exhibited α-synucleinopathy (e.g. hilar mossy cells). The topographical extent of inclusions is displayed here in high-resolution images that afford viewers a rich opportunity to dissect the potential spread of pathology through neural circuitry. Finally, the results of this expository study were leveraged to highlight the challenges and limitations of working with preformed α-synuclein fibrils.
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http://dx.doi.org/10.1016/j.expneurol.2017.10.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736319PMC
January 2018

Increased detection of Barrett's esophagus-associated neoplasia using wide-area trans-epithelial sampling: a multicenter, prospective, randomized trial.

Gastrointest Endosc 2018 02 27;87(2):348-355. Epub 2017 Jul 27.

Department of Gastroenterology and Hepatology, Veterans Affairs Medical Center, Kansas City, Missouri, USA; Department of Gastroenterology, University of Kansas School of Medicine, Kansas City, Kansas, USA. Electronic address:

Background And Aims: Wide-area transepithelial sampling (WATS) with computer-assisted 3-dimensional analysis is a sampling technique that combines abrasive brushing of the Barrett's esophagus (BE) mucosa followed by neural network analysis to highlight abnormal-appearing cells.

Methods: We performed a randomized trial of referred BE patients undergoing surveillance at 16 medical centers. Subjects received either biopsy sampling followed by WATS or WATS followed by biopsy sampling. The primary outcome was rate of detection of high-grade dysplasia/esophageal adenocarcinoma (HGD/EAC) using WATS in conjunction with biopsy sampling compared with biopsy sampling alone using standard histopathologic criteria. Secondary aims included evaluating neoplasia detection rates based on the procedure order (WATS vs biopsy sampling first), of each procedure separately, and the additional time required for WATS.

Results: One hundred sixty patients (mean age, 63.4 years; 76% men; 95% white) completed the trial. The median circumferential and maximal BE extents were 1.0 cm (interquartile range: .0-5.0) and 4.0 cm (interquartile range, 2.0-8.0), respectively. The diagnostic yield for biopsy sampling alone was as follows: HGD/EAC, 7 (4.4%); low-grade dysplasia (LGD), 28 (17.5%); nondysplastic BE (NDBE), 106 (66.25%); and no BE, 19 (11.9%). The addition of WATS to biopsy sampling yielded an additional 23 cases of HGD/EAC (absolute increase, 14.4%; 95% confidence interval, 7.5%-21.2%). Among these 23 patients, 11 were classified by biopsy sampling as NDBE and 12 as LGD/indefinite for dysplasia (IND); 14 received biopsy sampling first and 9 WATS first (not significant) and most (n = 21; 91.7%) had a prior dysplasia history. WATS added an average of 4.5 minutes to the procedure.

Conclusion: Results of this multicenter, prospective, randomized trial demonstrate that the use of WATS in a referral BE population increases the detection of HGD/EAC. (Clinical trial registration number: NCT03008980.).
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http://dx.doi.org/10.1016/j.gie.2017.07.039DOI Listing
February 2018

Colorectal Cancer Screening: Recommendations for Physicians and Patients From the U.S. Multi-Society Task Force on Colorectal Cancer.

Gastroenterology 2017 07 9;153(1):307-323. Epub 2017 Jun 9.

VA Medical Center, White River Junction, Vermont, and Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.

This document updates the colorectal cancer (CRC) screening recommendations of the U.S. Multi-Society Task Force of Colorectal Cancer (MSTF), which represents the American College of Gastroenterology, the American Gastroenterological Association, and The American Society for Gastrointestinal Endoscopy. CRC screening tests are ranked in 3 tiers based on performance features, costs, and practical considerations. The first-tier tests are colonoscopy every 10 years and annual fecal immunochemical test (FIT). Colonoscopy and FIT are recommended as the cornerstones of screening regardless of how screening is offered. Thus, in a sequential approach based on colonoscopy offered first, FIT should be offered to patients who decline colonoscopy. Colonoscopy and FIT are recommended as tests of choice when multiple options are presented as alternatives. A risk-stratified approach is also appropriate, with FIT screening in populations with an estimated low prevalence of advanced neoplasia and colonoscopy screening in high prevalence populations. The second-tier tests include CT colonography every 5 years, the FIT-fecal DNA test every 3 years, and flexible sigmoidoscopy every 5 to 10 years. These tests are appropriate screening tests, but each has disadvantages relative to the tier 1 tests. Because of limited evidence and current obstacles to use, capsule colonoscopy every 5 years is a third-tier test. We suggest that the Septin9 serum assay (Epigenomics, Seattle, Wash) not be used for screening. Screening should begin at age 50 years in average-risk persons, except in African Americans in whom limited evidence supports screening at 45 years. CRC incidence is rising in persons under age 50, and thorough diagnostic evaluation of young persons with suspected colorectal bleeding is recommended. Discontinuation of screening should be considered when persons up to date with screening, who have prior negative screening (particularly colonoscopy), reach age 75 or have <10 years of life expectancy. Persons without prior screening should be considered for screening up to age 85, depending on age and comorbidities. Persons with a family history of CRC or a documented advanced adenoma in a first-degree relative age <60 years or 2 first-degree relatives with these findings at any age are recommended to undergo screening by colonoscopy every 5 years, beginning 10 years before the age at diagnosis of the youngest affected relative or age 40, whichever is earlier. Persons with a single first-degree relative diagnosed at ≥60 years with CRC or an advanced adenoma can be offered average-risk screening options beginning at age 40 years.
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http://dx.doi.org/10.1053/j.gastro.2017.05.013DOI Listing
July 2017

Colorectal cancer screening: Recommendations for physicians and patients from the U.S. Multi-Society Task Force on Colorectal Cancer.

Gastrointest Endosc 2017 07 6;86(1):18-33. Epub 2017 Jun 6.

VA Medical Center, White River Junction, Vermont, and Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.

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http://dx.doi.org/10.1016/j.gie.2017.04.003DOI Listing
July 2017

Exploring the Relationships Between USMLE Performance and Disciplinary Action in Practice: A Validity Study of Score Inferences From a Licensure Examination.

Acad Med 2017 12;92(12):1780-1785

M.M. Cuddy is measurement scientist, Center for Advanced Assessment, National Board of Medical Examiners, Philadelphia, Pennsylvania. A. Young is assistant vice president, Research and Data Integration, Federation of State Medical Boards, Euless, Texas. A. Gelman is professor, Departments of Statistics and Political Science, Columbia University, New York, New York. D.B. Swanson is vice president, Academic Programs and Services, American Board of Medical Specialties, Chicago, Illinois, and professor (honorary appointment), Department of Medical Education, University of Melbourne Medical School, Melbourne, Australia. D.A. Johnson is senior vice president, Assessment Services, Federation of State Medical Boards, Euless, Texas. G.F. Dillon is vice president, Licensure, National Board of Medical Examiners, Philadelphia, Pennsylvania. B.E. Clauser is vice president, Center for Advanced Assessment, National Board of Medical Examiners, Philadelphia, Pennsylvania.

Purpose: Physicians must pass the United States Medical Licensing Examination (USMLE) to obtain an unrestricted license to practice allopathic medicine in the United States. Little is known, however, about how well USMLE performance relates to physician behavior in practice, particularly conduct inconsistent with safe, effective patient care. The authors examined the extent to which USMLE scores relate to the odds of receiving a disciplinary action from a U.S. state medical board.

Method: Controlling for multiple factors, the authors used non-nested multilevel logistic regression analyses to estimate the relationships between scores and receiving an action. The sample included 164,725 physicians who graduated from U.S. MD-granting medical schools between 1994 and 2006.

Results: Physicians had a mean Step 1 score of 214 (standard deviation [SD] = 21) and a mean Step 2 Clinical Knowledge (CK) score of 213 (SD = 23). Of the physicians, 2,205 (1.3%) received at least one action. Physicians with higher Step 2 CK scores had lower odds of receiving an action. A 1-SD increase in Step 2 CK scores corresponded to a decrease in the chance of disciplinary action by roughly 25% (odds ratio = 0.75; 95% CI = 0.70-0.80). After accounting for Step 2 CK scores, Step 1 scores were unrelated to the odds of receiving an action.

Conclusions: USMLE Step 2 CK scores provide useful information about the odds a physician will receive an official sanction for problematic practice behavior. These results provide validity evidence supporting current interpretation and use of Step 2 CK scores.
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http://dx.doi.org/10.1097/ACM.0000000000001747DOI Listing
December 2017

Colorectal Cancer Screening: Recommendations for Physicians and Patients from the U.S. Multi-Society Task Force on Colorectal Cancer.

Am J Gastroenterol 2017 Jul 6;112(7):1016-1030. Epub 2017 Jun 6.

VA Medical Center, White River Junction, Vermont, and Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.

This document updates the colorectal cancer (CRC) screening recommendations of the U.S. Multi-Society Task Force of Colorectal Cancer (MSTF), which represents the American College of Gastroenterology, the American Gastroenterological Association, and The American Society for Gastrointestinal Endoscopy. CRC screening tests are ranked in 3 tiers based on performance features, costs, and practical considerations. The first-tier tests are colonoscopy every 10 years and annual fecal immunochemical test (FIT). Colonoscopy and FIT are recommended as the cornerstones of screening regardless of how screening is offered. Thus, in a sequential approach based on colonoscopy offered first, FIT should be offered to patients who decline colonoscopy. Colonoscopy and FIT are recommended as tests of choice when multiple options are presented as alternatives. A risk-stratified approach is also appropriate, with FIT screening in populations with an estimated low prevalence of advanced neoplasia and colonoscopy screening in high prevalence populations. The second-tier tests include CT colonography every 5 years, the FIT-fecal DNA test every 3 years, and flexible sigmoidoscopy every 5 to 10 years. These tests are appropriate screening tests, but each has disadvantages relative to the tier 1 tests. Because of limited evidence and current obstacles to use, capsule colonoscopy every 5 years is a third-tier test. We suggest that the Septin9 serum assay (Epigenomics, Seattle, Wash) not be used for screening. Screening should begin at age 50 years in average-risk persons, except in African Americans in whom limited evidence supports screening at 45 years. CRC incidence is rising in persons under age 50, and thorough diagnostic evaluation of young persons with suspected colorectal bleeding is recommended. Discontinuation of screening should be considered when persons up to date with screening, who have prior negative screening (particularly colonoscopy), reach age 75 or have <10 years of life expectancy. Persons without prior screening should be considered for screening up to age 85, depending on age and comorbidities. Persons with a family history of CRC or a documented advanced adenoma in a first-degree relative age <60 years or 2 first-degree relatives with these findings at any age are recommended to undergo screening by colonoscopy every 5 years, beginning 10 years before the age at diagnosis of the youngest affected relative or age 40, whichever is earlier. Persons with a single first-degree relative diagnosed at ≥60 years with CRC or an advanced adenoma can be offered average-risk screening options beginning at age 40 years.
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http://dx.doi.org/10.1038/ajg.2017.174DOI Listing
July 2017

Recommendations on Surveillance and Management of Biallelic Mismatch Repair Deficiency (BMMRD) Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer.

Gastroenterology 2017 05 28;152(6):1605-1614. Epub 2017 Mar 28.

Indiana University School of Medicine, Indianapolis, Indiana.

The US Multi-Society Task Force on Colorectal Cancer, with invited experts, developed a consensus statement and recommendations to assist health care providers with appropriate management of patients with biallelic mismatch repair deficiency (BMMRD) syndrome, also called constitutional mismatch repair deficiency syndrome. This position paper outlines what is known about BMMRD, the unique genetic and clinical aspects of the disease, and reviews the current management approaches to this disorder. This article represents a starting point from which diagnostic and management decisions can undergo rigorous testing for efficacy. There is a lack of strong evidence and a requirement for further research. Nevertheless, providers need direction on how to recognize and care for BMMRD patients today. In addition to identifying areas of research, this article provides guidance for surveillance and management. The major challenge is that BMMRD is rare, limiting the ability to accumulate unbiased data and develop controlled prospective trials. The formation of effective international consortia that collaborate and share data is proposed to accelerate our understanding of this disease.
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http://dx.doi.org/10.1053/j.gastro.2017.02.011DOI Listing
May 2017