eSIMPLER: A Dynamic, Electronic Health Record-Integrated Checklist for Clinical Decision Support During PICU Daily Rounds.

OBJECTIVES: Design, implement, and evaluate a rounding checklist with deeply embedded, dynamic electronic health record integration. DESIGN: Before-after quality-improvement study. SETTING: Quaternary PICU in an academic, free-standing children's hospital. PATIENTS: All patients in the PICU during daily morning rounds. INTERVENTIONS: Implementation of an updated dynamic checklist (eSIMPLER) providing clinical decision support prompts with display of relevant data automatically pulled from the electronic health record. MEASUREMENTS AND MAIN RESULTS: The prior daily rounding checklist, eSIMPLE, was implemented for 49,709 patient-days (7,779 patients) between October 30, 2011, and October 7, 2018. eSIMPLER was implemented for 5,306 patient-days (971 patients) over 6 months. Checklist completion rates were similar (eSIMPLE: 95% [95% CI, 88-98%] vs eSIMPLER: 98% [95% CI, 92-100%] of patient-days; p = 0.40). eSIMPLER required less time per patient (28 ± 1 vs 47 ± 24 s; p < 0.001). Users reported improved satisfaction with eSIMPLER (p = 0.009). Several checklist-driven process measures-discordance between electronic health record orders for stress ulcer prophylaxis and user-recorded indication for stress ulcer prophylaxis, rate of venous thromboembolism prophylaxis prescribing, and recognition of reduced renal function-improved during the eSIMPLER phase. CONCLUSIONS: eSIMPLER, a dynamic, electronic health record-informed checklist, required less time to complete and improved certain care processes compared with a prior, static checklist with limited electronic health record data. By focusing on the "Five Rights" of clinical decision support, we created a well-accepted clinical decision support tool that was integrated efficiently into daily rounds. Generalizability of eSIMPLER's effectiveness and its impact on patient outcomes need to be examined.

Catalytic properties of the metal ion variants of mandelate racemase reveal alterations in the apparent electrophilicity of the metal cofactor.

Mandalate racemase (MR) from Pseudomonas putida requires a divalent metal cation, usually Mg2+, to catalyse the interconversion of the enantiomers of mandelate. Although the active site Mg2+ may be replaced by Mn2+, Co2+, or Ni2+, substitution by these metal ions does not markedly (<10-fold) alter the kinetic parameters Kappm, kappcat, and (kcat/Km)app for the substrates (R)- and (S)-mandelate, and the alternative substrate (S)-trifluorolactate. Viscosity variation experiments with Mn2+-MR showed that the metal ion plays a role in the uniform binding of the transition states for enzyme-substrate association, the chemical step, and enzyme-product dissociation. Surprisingly, the competitive inhibition constants (Ki) for inhibition of each metalloenzyme variant by benzohydroxamate did not vary significantly with the identity of the metal ion unlike the marked variation of the stability constants (K1) observed for M2+·BzH complex formation in solution. A similar trend was observed for the inhibition of the metalloenzyme variants by F-, except for Mg2+-MR, which bound F- tighter than would be predicted based on the stability constants for formation of M2+·F- complexes in solution. Thus, the enzyme modifies the enatic state of the bound metal ion cofactor so that the apparent electrophilicity of Mg2+ is enhanced, while that of Ni2+ is attenuated, resulting in a levelling effect relative to the trends observed for the free metals in solution.

Inhibition of serine and proline racemases by substrate-product analogues.

d-Amino acids can play important roles as specific biosynthetic building blocks required by organisms or act as regulatory molecules. Consequently, amino acid racemases that catalyze the formation of d-amino acids are potential therapeutic targets. Serine racemase catalyzes the reversible formation of d-serine (a modulator of neurotransmission) from l-serine, while proline racemase (an essential enzymatic and mitogenic protein in trypanosomes) catalyzes the reversible conversion of l-proline to d-proline. We show the substrate-product analogue α-(hydroxymethyl)serine is a modest, linear mixed-type inhibitor of serine racemase from Schizosaccharomyces pombe (Ki=167±21mM, Ki'=661±81mM, cf. Km=19±2mM). The bicyclic substrate-product analogue of proline, 7-azabicyclo[2.2.1]heptan-7-ium-1-carboxylate is a weak inhibitor of proline racemase from Clostridium sticklandii, giving only 29% inhibition at 142.5mM. However, the more flexible bicyclic substrate-product analogue tetrahydro-1H-pyrrolizine-7a(5H)-carboxylate is a noncompetitive inhibitor of proline racemase from C. sticklandii (Ki=111±15mM, cf. Km=5.7±0.5mM). These results suggest that substrate-product analogue inhibitors of racemases may only be effective when the active site is capacious and/or plastic, or when the inhibitor is sufficiently flexible.