Thymidylyltransferases (thymidine diphospho pyrophosphorylases) are nucleotidylyltransferases that play key roles in the biosynthesis of carbohydrate components within bacterial cell walls and in the biosynthesis of glycosylated natural products. They catalyze the formation of sugar nucleotides concomitant with the release of pyrophosphate. Protein engineering of thymidylyltransferases has been an approach for the production of a variety of non-physiological sugar nucleotides. In this work, we have explored chemical approaches towards modifying the activity of the thymidylyltransferase (Cps2L) cloned from S. pneumoniae, through the use of chemically synthesized 'activated' nucleoside triphosphates with enhanced leaving groups, or by switching the metal ion co-factor specificity. Within a series of phosphonate-containing nucleoside triphosphate analogues, thymidylyltransferase activity is enhanced based on the acidity of the leaving group and a Brønsted-type analysis indicated that leaving group departure is rate limiting. We have also determined IC50 values for a series of bisphosphonates as inhibitors of thymidylyltransferases. No correlation between the acidity of the inhibitors (pKa) and the magnitude of enzyme inhibition was found.

Application of N,O carboxymethyl chitosan products significantly reduces severity of postsurgical adhesion formation after cardiac surgery in the rabbit and pig models. N,O carboxymethyl chitosan products may act as a biophysical barrier.

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BACKGROUND The Canadian Paediatric Society (CPS) recommends that every Canadian physician caring for young children provide an enhanced 18-month well-baby visit including the use of a developmental screening tool, such as the Nipissing District Developmental Screen (NDDS). The Province of Ontario implemented an enhanced 18-month well-baby visit specifically emphasizing the NDDS, which is now widely used in Ontario primary care. However, the diagnostic accuracy of the NDDS in identifying early developmental delays in real-world clinical settings is unknown. OBJECTIVES To assess the predictive validity of the NDDS in primary care for identifying developmental delay and prompting a specialist referral at the 18-month health supervision visit. DESIGN/METHODS This was a prospective longitudinal cohort study enrolling healthy children from primary care practices. Parents completed the 18-month NDDS during their child’s scheduled health supervision visit between January 2012 and February 2015. Using a standardized data collection form, research personnel abstracted data from the child’s health records regarding the child’s developmental outcomes following the 18-month assessment. Data collected included confirmed diagnoses of a development delay, specialist referrals, family history, and interventions. Research personnel were blind to the results of the NDDS. We assessed the diagnostic test properties of the NDDS with a confirmed diagnosis of developmental delay as the criterion measure. The specificity, sensitivity, positive predictive value, and negative predictive value were calculated, with 95% confidence intervals. RESULTS We included 255 children with a mean age of 18.5 months (range, 17.5–20.6) and 139 (55%) were male. 102 (40%) screened positive (1+ flag result on their NDDS). A total of 48 (19%) children were referred, and 23 (9%) had a confirmed diagnosis of a developmental delay (speech and language: 14; gross motor: 4; autism spectrum disorder: 3; global developmental delay: 1; developmental delay: 1). The sensitivity was 74% (95% CI: 52–90%), specificity was 63% (95% CI: 57–70%), positive predictive value was 17% (95% CI:10–25%), and the negative predictive value was 96% (95% CI: 92–99%). CONCLUSION For developmental screening tools, sensitivity between 70%-80% and specificity of 80% have been suggested. The NDDS has moderate sensitivity and specificity in identifying developmental delay at the 18-month health supervision visit. The 1+NDDS flag cut-point may lead to overdiagnosis with more children with typical development being referred, leading to longer wait times for specialist referrals among children in need. Future work includes investigating the diagnostic accuracy of combining the NDDS with other screening tools.