The risk assessment of relapse among newly enrolled participants in methadone maintenance treatment: A group-LASSO based Bayesian network study

BackgroundRelapse is a great barrier to improving the effectiveness of methadone maintenance treatment (MMT). Participants with different treatment durations could vary in their compliance with MMT, which may lead to different levels of relapse risk. This study aims to identify the risk factors for relapse and assess the relapse risk of MMT participants of different treatment durations.MethodThis retrospective study used data collected from seven MMT clinics in Guangdong Province, China, from January 2010 to April 2017. Newly enrolled participants who received 6 (n = 903) and 12 (n = 710) months of consecutive treatment with complete data were included. We selected significant risk factors for relapse through the group lasso regression and then incorporated them into Bayesian networks to reveal relationships between factors and predict the relapse risk.ResultsThe results showed that participants who received 6-month treatment had a lower relapse rate (32.0%) than those of 12-month treatment (39.0%, P < 0.05). Factors including personal living status and daily methadone dose were only influential to those who received the 6-month treatment. However, age, age at the initial drug use, HIV infection status, sexual behaviors, and continuous treatment days were common factors of both durations. The highest relapse risk for those after the 6-month treatment was inferred as 66.7% while that of the 12-month treatment was 83.3%. Farmers and those who have high accessibility to MMT services may require additional attention.ConclusionIt is necessary to implement targeted interventions and education based on the treatment durations of participants to decrease the relapse rate. Meanwhile, those about HIV/sexually transmitted infection prevention and anti-narcotics should be held in the whole process

Metalloproteinase/Presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling

Bidirectional signaling triggered by interacting ephrinB receptors (EphB) and ephrinB ligands is crucial for development and function of the vascular and nervous systems. A signaling cascade triggered by this interaction involves activation of Src kinase and phosphorylation of ephrinB. The mechanism, however, by which EphB activates Src in the ephrinB-expressing cells is unknown. Here we show that EphB stimulates a metalloproteinase cleavage of ephrinB2, producing a carboxy-terminal fragment that is further processed by PS1/γ-secretase to produce intracellular peptide ephrinB2/CTF2. This peptide binds Src and inhibits its association with inhibitory kinase Csk, allowing autophosphorylation of Src at residue tyr418. EphrinB2/CTF2-activated Src phosphorylates ephrinB2 and inhibits its processing by γ-secretase. These data show that the PS1/γ-secretase system controls Src activation and ephrinB phosphorylation by regulating production of Src activator ephrinB2/CTF2. Accordingly, γ-secretase inhibitors prevented the EphB-induced sprouting of endothelial cells and the recruitment of Grb4 to ephrinB. PS1 FAD and γ-secretase dominant-negative mutants inhibited the EphB-induced cleavage of ephrinB2 and Src autophosphorylation, raising the possibility that FAD mutants interfere with the functions of Src and ephrinB2 in the CNS