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“Identifying genetic factors responsible for serious adverse drug reaction (SADR) is of critical importance to personalized medicine. However, genome-wide I-BET151 association studies are hampered due to the lack of case-control samples,
and the selection of candidate genes is limited by the lack of understanding of the underlying mechanisms of SADRs. We hypothesize that drugs causing the same type of SADR might share a common mechanism by targeting unexpectedly the same SADR-mediating protein. Hence we propose an approach of identifying the common SADR-targets through constructing and mining an in silico chemical-protein interactome (CPI), a matrix of binding strengths among 162 drug molecules known to cause at least one type of SADR and 845 proteins. Drugs sharing the same SADR outcome were also found to possess similarities in their CPI profiles towards this 845 protein set. This methodology identified the candidate gene of sulfonamide-induced toxic epidermal necrolysis (TEN): selleck chemical all nine sulfonamides that cause TEN were found to bind strongly to MHC I (Cw*4), whereas none of the 17 control drugs that do not cause TEN were found to bind to it. Through an insight into the CPI, we found the Y116S substitution of MHC I (B*5703) enhances the unexpected binding of abacavir
to its antigen presentation groove, which explains why B*5701, not B*5703, is the risk allele of abacavir-induced hypersensitivity. In conclusion, SADR targets and the patient-specific off-targets could be identified through a systematic investigation of the CPI, generating important hypotheses for prospective experimental validation of the candidate genes.”
“The objective of this paper is to compare retropubic (RP) and transobturator (TO) midurethral slings using decision analysis techniques.
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decision analysis was constructed including efficacy and complication data. Probability of complication-free surgery and overall utility were analyzed using two models: ALL (all 42 trials) and RCT (seven randomized controlled trials with higher quality data, but missing data BMS202 on some complications).
Surgery was complication-free more frequently with TO approach with 83.7% vs. 55.7% (ALL) and 70.9% vs. 62.8% (RCT). One-year overall utility favored TO in the ALL model (0.943 vs. 0.895). Conversely, the RCT model favored RP (0.936 vs. 0.910). These differences were both less than published minimally important differences (MID) for utilities. Multiple one-way sensitivity analyses confirmed robustness of results.
The difference between the two surgeries in both utility-based models was less than the MID. Therefore, the separate approaches are highly comparable with similar overall utility. Complications are more frequent with the retropubic approach.”
“A critical step on the way to understanding a sensory system is the analysis of the input it receives.