Boosting treatment stabilization in patients of amphetamine-type stimulant use disorder.

BACKGROUND: To investigate boosting effects on treatment stabilization in the mandatory treatment modality for patients of amphetamine-type stimulant use disorder. METHODS: This is a retrospective follow-up study over a period from January 2013 to December 2018. We analyzed 425 patients of amphetamine-type stimulant use disorder under mandating treatments. Treatment stabilization for a given patient was defined once 4 negative urinalysis had been observed. We developed a dynamic monitoring model of boosting effects informed by the available data, specifically the number of negative urine samples required to reach stabilization, the sum of urinalyses done at the time when the given number of negative urine samples had been observed and who the patient was. To represent the simulated population, a Monte Carlo method was used to generate p-values from 1000 experiments conducted on a computer. RESULTS: In the observed samples, the probability of 4 negative results in urinalysis from 4 outpatient visits was 75.5%. In comparison, the probability for achieving 4th negative results in urinalysis over 4 visits from negative binominal distribution was 57.3%, and from the computer simulation, 49.8%. The observed samples had significantly higher probability of achieving 4 negative results in urinalysis over 4 outpatient visits (p < 0.001). CONCLUSIONS: The mandatory treatment modality boosted treatment stabilization for patients of amphetamine-type stimulant use disorder. The major benefit of using the monitoring model is the ability to monitor boosting effects of stabilization. Results supported the effectiveness of this mandatory treatment modality and can be implemented in deferred-prosecution based treatment modality.

The N253F mutant structure of trehalose synthase from Deinococcus radiodurans reveals an open active-site topology.

Trehalose synthase (TS) catalyzes the reversible conversion of maltose to trehalose and belongs to glycoside hydrolase family 13 (GH13). Previous mechanistic analysis suggested a rate-limiting protein conformational change, which is probably the opening and closing of the active site. Consistently, crystal structures of Deinococcus radiodurans TS (DrTS) in complex with the inhibitor Tris displayed an enclosed active site for catalysis of the intramoleular isomerization. In this study, the apo structure of the DrTS N253F mutant displays a new open conformation with an empty active site. Analysis of these structures suggests that substrate binding induces a domain rotation to close the active site. Such a substrate-induced domain rotation has also been observed in some other GH13 enzymes.

Structures of trehalose synthase from Deinococcus radiodurans reveal that a closed conformation is involved in catalysis of the intramolecular isomerization.

Trehalose synthase catalyzes the simple conversion of the inexpensive maltose into trehalose with a side reaction of hydrolysis. Here, the crystal structures of the wild type and the N253A mutant of Deinococcus radiodurans trehalose synthase (DrTS) in complex with the inhibitor Tris are reported. DrTS consists of a catalytic (ß/α)8 barrel, subdomain B, a C-terminal ß domain and two TS-unique subdomains (S7 and S8). The C-terminal domain and S8 contribute the majority of the dimeric interface. DrTS shares high structural homology with sucrose hydrolase, amylosucrase and sucrose isomerase in complex with sucrose, in particular a virtually identical active-site architecture and a similar substrate-induced rotation of subdomain B. The inhibitor Tris was bound and mimics a sugar at the -1 subsite. A maltose was modelled into the active site, and subsequent mutational analysis suggested that Tyr213, Glu320 and Glu324 are essential within the +1 subsite for the TS activity. In addition, the interaction networks between subdomains B and S7 seal the active-site entrance. Disruption of such networks through the replacement of Arg148 and Asn253 with alanine resulted in a decrease in isomerase activity by 8-9-fold and an increased hydrolase activity by 1.5-1.8-fold. The N253A structure showed a small pore created for water entry. Therefore, our DrTS-Tris may represent a substrate-induced closed conformation that will facilitate intramolecular isomerization and minimize disaccharide hydrolysis.