Transient vs Permanent Congenital Hypothyroidism in Ontario, Canada: Predictive Factors and Scoring System.

CONTEXT: The apparent increased incidence of congenital hypothyroidism (CH) is partly due to increased detection of transient disease. OBJECTIVE: This work aims to identify predictors of transient CH (T-CH) and establish a predictive tool for its earlier differentiation from permanent CH (P-CH). METHODS: A retrospective cohort study was conducted of patients diagnosed with CH from 2006 to 2015 through Newborn Screening Ontario (NSO). RESULTS: Of 469 cases, 360 (76.8%) were diagnosed with P-CH vs 109 (23.2%) with T-CH. Doses of levothyroxine predicting T-CH were less than 3.9 µg/kg at age 6 months, less than 3.0 µg/kg at ages 1 and 2 years, and less than 2.5 µg/kg at age 3 years. Descriptive statistics and multivariable logistic modeling demonstrated several diverging key measures between patients with T-CH vs P-CH, with optimal stratification at age 1 year. Thyroid imaging was the strongest predictor (P < .001). Excluding imaging, significant predictors in the first year of life included thyroxine dose/kg (P < .001-.002), increase in thyrotropin (TSH) above the reference interval during treatment (P = .002), screening TSH (P = .03), and a history of maternal thyroid disease (P = .02). Based on the 1-year model without imaging, a risk score was developed to identify children with T-CH who may benefit from an earlier trial off therapy, to reduce excess medicalization and health care costs. CONCLUSION: A levothyroxine dose of less than 3 µg/kg at ages 1 and 2 years and less than 2.5 µg/kg at age 3 years can be predictive of T-CH. A novel risk score was developed that can be clinically applied to predict the likelihood of a successful trial off therapy for a given patient at age 1 year.

Exploiting the Sensitivity of Nutrient Transporter Deletion Strains in Discovery of Natural Product Antimetabolites.

Actinomycete secondary metabolites are a renowned source of antibacterial chemical scaffolds. Herein, we present a target-specific approach that increases the detection of antimetabolites from natural sources by screening actinomycete-derived extracts against nutrient transporter deletion strains. On the basis of the growth rescue patterns of a collection of 22 Escherichia coli (E. coli) auxotrophic deletion strains representative of the major nutrient biosynthetic pathways, we demonstrate that antimetabolite detection from actinomycete-derived extracts prepared using traditional extraction platforms is masked by nutrient supplementation. In particular, we find poor sensitivity for the detection of antimetabolites targeting vitamin biosynthesis. To circumvent this and as a proof of principle, we exploit the differential activity of actinomycete extracts against E. coli ΔyigM, a biotin transporter deletion strain versus wildtype E. coli. We achieve more than a 100-fold increase in antimetabolite sensitivity using this method and demonstrate a successful bioassay-guided purification of the known biotin antimetabolite, amiclenomycin. Our findings provide a unique solution to uncover the full potential of naturally derived antibiotics.