Implementation of a Clinical Decision Support (CDS) Tool for the Management of Functional Constipation in Pediatric Primary Care.

Constipation is common in general pediatrics and often results in potentially unnecessary referrals to pediatric gastroenterology. We hypothesized that a clinical decision-making tool would support primary care providers to manage pediatric constipation, improve workflow, and prevent unnecessary subspecialty care. In this pilot quality improvement initiative, a multidisciplinary team completed a root cause analysis related to challenges with the care of pediatric constipation. The results informed the development of interventions including a Clinical Decision Support tool and patient educational materials embedded within an existing order-set in the electronic health record, which we implemented in our primary care network. The use of the updated order-set continues to increase monthly, and there is reported improved workflow and increased confidence by providers. These interventions demonstrated that it is feasible to implement tools to support primary care clinicians in their management of pediatric patients with constipation.

Engineered antibody-drug conjugates with defined sites and stoichiometries of drug attachment.

The chimeric anti-CD30 IgG1, cAC10, conjugated to eight equivalents of monomethyl auristatin E (MMAE) was previously shown to have potent antitumor activity against CD30-expressing tumors xenografts in mice. Moreover, the therapeutic index was increased by lowering the stoichiometry from 8 drugs/antibody down to 2 or 4. Limitations of such 'partially-loaded' conjugates are low yield (10-30%) as they are purified from mixtures with variable stoichiometry (0-8 drugs/antibody), and heterogeneity as the 2 or 4 drugs are distributed over eight possible cysteine conjugation sites. Here, the solvent-accessible cysteines that form the interchain disulfide bonds in cAC10 were replaced with serine, to reduce the eight potential conjugation sites down to 4 or 2. These Cys-->Ser antibody variants were conjugated to MMAE in near quantitative yield (89-96%) with defined stoichiometries (2 or 4 drugs/antibody) and sites of drug attachment. The engineered antibody-drug conjugates have comparable antigen-binding affinities and in vitro cytotoxic activities with corresponding purified parental antibody-drug conjugates. Additionally, the engineered and parental antibody-drug conjugates have similar in vivo properties including antitumor activity, pharmacokinetics and maximum tolerated dose. Our strategy for generating antibody-drug conjugates with defined sites and stoichiometries of drug loading is potentially broadly applicable to other antibodies as it involves engineering of constant domains.