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1.
J Clin Transl Sci ; 3(4): 140-146, 2019 Aug.
Article in English | MEDLINE | ID: mdl-31660238

ABSTRACT

Project management expertise is employed across many professional sectors, including clinical research organizations, to ensure that efforts undertaken by the organization are completed on time and according to specifications and are capable of achieving the needed impact. Increasingly, project leaders (PLs) who possess this expertise are being employed in academic settings to support clinical and preclinical translational research team science. Duke University's clinical and translational science enterprise has been an early adopter of project management to support clinical and preclinical programs. We review the history and evolution of project management and the PL role at Duke, examine case studies that illustrate their growing value to our academic research environment, and address challenges and solutions to employing project management in academia. Furthermore, we describe the critical role project leadership plays in accelerating and increasing the success of translational team science and team approaches frequently required for systems biology and "big data" scientific studies. Finally, we discuss perspectives from Duke project leadership professionals regarding the training needs and requirements for PLs working in academic clinical and translational science research settings.

2.
Appl Clin Inform ; 7(4): 912-929, 2016 10 05.
Article in English | MEDLINE | ID: mdl-27704138

ABSTRACT

OBJECTIVES: Electronic health information overload makes it difficult for providers to quickly find and interpret information to support care decisions. The purpose of this study was to better understand how clinicians use information in critical care to support the design of improved presentation of electronic health information. METHODS: We conducted a contextual analysis and visioning project. We used an eye-tracker to record 20 clinicians' information use activities in critical care settings. We played video recordings back to clinicians in retrospective cued interviews and queried: 1) context and goals of information use, 2) impacts of current display design on use, and 3) processes related to information use. We analyzed interview transcripts using grounded theory-based content analysis techniques and identified emerging themes. From these, we conducted a visioning activity with a team of subject matter experts and identified key areas for focus of design and research for future display designs. RESULTS: Analyses revealed four unique critical care information use activities including new patient assessment, known patient status review, specific directed information seeking, and review and prioritization of multiple patients. Emerging themes were primarily related to a need for better representation of dynamic data such as vital signs and laboratory results, usability issues associated with reducing cognitive load and supporting efficient interaction, and processes for managing information. Visions for the future included designs that: 1) provide rapid access to new information, 2) organize by systems or problems as well as by current versus historical patient data, and 3) apply intelligence toward detecting and representing change and urgency. CONCLUSIONS: The results from this study can be used to guide the design of future acute care electronic health information display. Additional research and collaboration is needed to refine and implement intelligent graphical user interfaces to improve clinical information organization and prioritization to support care decisions.


Subject(s)
Critical Care , Data Display , Electronic Health Records , Decision Making , Humans , User-Computer Interface
4.
Ther Innov Regul Sci ; 47(2): 152-160, 2013 Mar.
Article in English | MEDLINE | ID: mdl-30227522

ABSTRACT

Conducting randomized controlled trials entails a prolonged, costly study start-up (SSU) process that may create significant delays. Optimizing the operational aspects of multisite trials requires identifying benchmarks in the SSU process and the potential delays associated with them. We engaged in a collaborative effort to identify and describe key SSU intervals that correspond with necessary procedures and processes for activating multisite clinical trials in the US. After developing definitions for SSU benchmarks and obtaining data from research coordinating entities, we identified factors that were significantly associated with reduced cycle times, including the use of central institutional review boards for study approval and status as a private practice or independent research site. However, small sample sizes and large proportions of missing data hamper the interpretability of our results. Future development of standard measures of SSU efficiency will be critical to analyzing and improving study initiation processes at US research sites.

5.
J Med Chem ; 51(14): 4085-92, 2008 Jul 24.
Article in English | MEDLINE | ID: mdl-18578477

ABSTRACT

In the mammalian central nervous system (CNS), the action of sodium dependent excitatory amino acid transporters (EAATs) is responsible for termination of glutamatergic neurotransmission by reuptake of ( S) -glutamate (Glu) from the synaptic cleft. Five EAAT subtypes have been identified, of which EAAT1-4 are present in the CNS, while EAAT5 is localized exclusively in the retina. In this study, we have used an enantioselective chemo-enzymatic strategy to synthesize 10 new Glu analogues 2a- k ( 2d is exempt) with different functionalities in the 4 R-position and characterized their pharmacological properties at the human EAAT1-3. In particular, one compound, 2k, displayed a significant preference as inhibitor of the EAAT2 subtype over EAAT1,3. The compound also displayed very low affinities toward ionotropic and metabotropic Glu receptors, making it the most selective EAAT2 inhibitor described so far.


Subject(s)
Excitatory Amino Acid Antagonists/chemical synthesis , Excitatory Amino Acid Antagonists/pharmacology , Glutamate Plasma Membrane Transport Proteins/antagonists & inhibitors , Glutarates/chemical synthesis , Glutarates/pharmacology , Cell Line , Excitatory Amino Acid Transporter 2 , Humans , Magnetic Resonance Spectroscopy , Membrane Potentials/drug effects , Spectrometry, Mass, Electrospray Ionization , Stereoisomerism
6.
J Med Chem ; 51(14): 4093-103, 2008 Jul 24.
Article in English | MEDLINE | ID: mdl-18578478

ABSTRACT

( S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the central nervous system (CNS) activating the plethora of ionotropic Glu receptors (iGluRs) and metabotropic Glu receptors (mGluRs). In this paper, we present a chemo-enzymatic strategy for the enantioselective synthesis of five new Glu analogues 2a- f ( 2d is exempt) holding a functionalized substituent in the 4-position. Nine Glu analogues 2a- j are characterized pharmacologically at native 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), kainic acid (KA), and N-methyl- d-aspartic acid (NMDA) receptors in rat synaptosomes as well as in binding assays at cloned rat iGluR5-7 subtypes. A detailed in silico study address as to why 2h is a high-affinity ligand at iGluR5-7 ( K i = 3.81, 123, 57.3 nM, respectively), while 2e is only a high affinity ligand at iGluR5 ( K i = 42.8 nM). Furthermore, a small series of commercially available iGluR ligands are characterized in iGluR5-7 binding.


Subject(s)
Glutamic Acid/analogs & derivatives , Receptors, Glutamate/drug effects , Amination , Animals , Glutamic Acid/biosynthesis , Glutamic Acid/chemical synthesis , Glutamic Acid/pharmacology , Magnetic Resonance Spectroscopy , Mass Spectrometry , Rats , Spectrophotometry, Infrared , Structure-Activity Relationship , Synaptosomes/drug effects
7.
J Med Chem ; 49(22): 6532-8, 2006 Nov 02.
Article in English | MEDLINE | ID: mdl-17064071

ABSTRACT

The four stereoisomers of l-2-(2-carboxycyclobutyl)glycine, l-CBG-I, l-CBG-II, l-CBG-III, and l-CBG-IV, were synthesized in good yield and high enantiomeric excess, from the corresponding cis and trans-2-oxalylcyclobutanecarboxylic acids 5 and 6 using the enzymes aspartate aminotransferase (AAT) and branched chain aminotransferase (BCAT) from Escherichia coli. The four stereoisomeric compounds were evaluated as potential ligands for the human excitatory amino acid transporters, subtypes 1, 2, and 3 (EAAT1, EAAT2, and EAAT3) in the FLIPR membrane potential assay. While the one trans-stereoisomer, l-CBG-I, displayed weak substrate activity at all three transporters, EAAT1-3, we found a particular pharmacological profile for the other trans-stereoisomer, l-CBG-II, which displayed EAAT1 substrate activity and inhibitory activity at EAAT2 and EAAT3. Whereas l-CBG-III was found to be a weak inhibitor at all three EAAT subtypes, the other cis-stereoisomer l-CBG-IV was a moderately potent inhibitor with 20-30-fold preference for EAAT2/3 over EAAT1.


Subject(s)
Cyclobutanes/chemical synthesis , Cyclobutanes/pharmacology , Excitatory Amino Acid Transporter 1/drug effects , Excitatory Amino Acid Transporter 3/drug effects , Glutamate Plasma Membrane Transport Proteins/drug effects , Glycine/analogs & derivatives , Catalysis , Chemical Phenomena , Chemistry, Physical , Excitatory Amino Acid Transporter 2 , Glutamates/chemical synthesis , Glycine/chemical synthesis , Glycine/pharmacology , Humans , Indicators and Reagents , Models, Molecular , Molecular Conformation , Stereoisomerism , Structure-Activity Relationship
8.
J Org Chem ; 71(3): 894-902, 2006 Feb 03.
Article in English | MEDLINE | ID: mdl-16438498

ABSTRACT

The synthesis of two enantiomerically pure iminosugars, analogues of 1-L-deoxynojirimycin (l-DNJ) and 1-D-deoxymannojirimycin (DMJ), was achieved using cyclic sulfate substituted isoxazoline derivatives. The piperidine ring was formed via the reduction of an isoxazoline into an amine which underwent a spontaneous intramolecular cyclization by reaction with the cyclic sulfate moiety. The nucleophilic attack of these two trisubstituted piperidines and morpholine on L- and D-erythritol-1,3-cyclic sulfates gave six new nitrogen analogues of salacinol. The inhibitory properties of the synthesized salacinol analogues were evaluated on several commercial glycosidases.


Subject(s)
1-Deoxynojirimycin/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Glycoside Hydrolases/antagonists & inhibitors , Nitrogen/chemistry , Sugar Alcohols/chemistry , Sulfates/chemistry , 1-Deoxynojirimycin/chemical synthesis , Alkylation , Enzyme Inhibitors/chemistry , Glycoside Hydrolases/metabolism , Hydroxylation , Molecular Structure , Morpholines/chemistry , Sugar Alcohols/chemical synthesis , Sulfates/chemical synthesis
9.
J Med Chem ; 48(25): 7980-92, 2005 Dec 15.
Article in English | MEDLINE | ID: mdl-16335922

ABSTRACT

A series of nine L-2,4-syn-4-alkylglutamic acid analogues (1a-i) were synthesized in high yield and high enantiomeric excess (>99% ee) from their corresponding 4-substituted ketoglutaric acids (2a-i), using the enzyme aspartate aminotransferase (AAT) from pig heart or E. coli. The synthesized compounds were evaluated as potential ligands for the glutamate transporters EAAT1, EAAT2, and EAAT3 (excitatory amino acid transporter, subtypes 1-3) in the FLIPR membrane potential (FMP) assay. We found a distinct change in the pharmacological profile when the 4-methyl group (compound 1a, an EAAT1 substrate and EAAT2,3 inhibitor) was extended to a 4-ethyl group, compound 1b, as this analogue is an inhibitor at all three subtypes, EAAT1-3. Furthermore, we conclude that both large and bulky hydrophobic substituents in the 4-position of L-2,4-syn Glu are allowed by all three glutamate transporter subtypes EAAT1-3 while maintaining inhibitory activity.


Subject(s)
Aspartate Aminotransferases/chemical synthesis , Excitatory Amino Acid Transporter 2/metabolism , Excitatory Amino Acid Transporter 3/metabolism , Glutamates/chemical synthesis , Animals , Cell Line , Glutamates/chemistry , Glutamates/metabolism , Humans , Ketoglutaric Acids/chemistry , Membrane Potentials/drug effects , Models, Molecular , Myocardium/enzymology , Stereoisomerism , Structure-Activity Relationship , Swine
10.
J Org Chem ; 69(26): 9310-2, 2004 Dec 24.
Article in English | MEDLINE | ID: mdl-15609974

ABSTRACT

Dihydroxyacetone phosphate (DHAP) was synthesized in high purity and yield in four steps starting from dihydroxyacetone dimer (DHA) (47% overall yield). DHA was converted into 2,2-dimethoxypropane-1,3-diol, which was desymmetrized by acetylation with lipase AK. The alcohol function was phosphorylated to give dibenzyl phosphate ester 4. From 4, two routes were investigated for large-scale synthesis of DHAP. First, acetate hydrolysis was performed prior to hydrogenolysis of the phosphate protective groups. The acetal hydrolysis was finally catalyzed by the phosphate group itself. Second, acetate and acetal hydrolysis were performed in one single step after hydrogenolysis.

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