Characterization of a FourU RNA Thermometer in the 5' Untranslated Region of Autolysin Gene blyA in the Bacillus subtilis 168 Prophage SPß.

RNA thermometers are noncoding RNA structures located in the 5' untranslated regions (UTRs) of genes that regulate gene expression through temperature-dependent conformational changes. The fourU class of RNA thermometers contains a specific motif in which four consecutive uracil nucleotides are predicted to base pair with the Shine-Dalgarno (SD) sequence in a stem. We employed a bioinformatic search to discover a fourU RNA thermometer in the 5'-UTR of the blyA gene of the Bacillus subtilis phage SPßc2, a bacteriophage that infects B. subtilis 168. blyA encodes an autolysin enzyme, N-acetylmuramoyl-l-alanine amidase, which is involved in the lytic life cycle of the SPß prophage. We have biochemically validated the predicted RNA thermometer in the 5'-UTR of the blyA gene. Our study suggests that RNA thermometers may play an underappreciated yet critical role in the lytic life cycle of bacteriophages.

A comparison of response in the presence or absence of a delay in induction therapy with bortezomib, lenalidomide, and dexamethasone.

PURPOSE: Lenalidomide, bortezomib, and dexamethasone (RVd) has emerged as a preferred induction therapy in multiple myeloma (MM) in the United States. Due to lenalidomide's teratogenic risk, patients and prescribers must comply with a risk evaluation and mitigation strategy (REMS) program. The REMS program limits dispensing to certain third-party specialty pharmacies, whose average prescription fill times are longer than in-house specialty pharmacies. In practice, a delay in procurement of lenalidomide may mean that patients start therapy with only bortezomib and dexamethasone, delaying the start of more effective triplet therapy. The primary objective of this study is to determine if a delay from start of bortezomib and dexamethasone to start of triplet therapy with lenalidomide impacts rate of achievement of very good partial response (VGPR) after four cycles of RVd. METHODS: This was a single-center retrospective review of adults with newly diagnosed MM who received RVd induction therapy at University of North Carolina Medical Center between April 2014 and June 2017. Patients who started lenalidomide ≥10 days after bortezomib comprised the "Delay" group, while those who started lenalidomide concurrently with bortezomib or within 1-9 days after bortezomib comprised the "No Delay" group. The primary outcome was VGPR or better response rate after four cycles of RVd. RESULTS: Thirty-eight patients met inclusion criteria. Nine patients (23.7%) experienced any delay in initiation of lenalidomide, with a mean delay of 7.8 days (range 1-18). Four patients (10.5%) experienced a delay ≥10 days. No patients in the Delay group were of reproductive potential, compared to 8.8% in the No Delay group (p = 0.54). VGPR or better response rate did not differ between the Delay and No Delay groups (66.7% vs. 58.8%, p = 0.79). The mean number of lenalidomide prescriptions generated per RVd cycle was 1.35 (range 1-5, SD 0.74). CONCLUSIONS: This study did not demonstrate an effect on clinical response after delays ≥10 days between bortezomib and lenalidomide initiation. No patients in the delay group were females of reproductive potential, which is the primary target for increased safety behind the REMS program.

Comparison of Weight-Based Dosing Strategies for Intravenous Immunoglobulin in Patients with Hematologic Malignancies.

STUDY OBJECTIVE: Intravenous immunoglobulin (IVIG) is a weight-based therapy used to treat and prevent infections in patients with hematologic malignancies. IVIG doses were calculated traditionally using actual body weight (ABW). However, limited pharmacokinetic data suggest dosing strategies using ideal body weight (IBW) or adjusted body weight (adjBW) may be appropriate given the small volume of distribution of IVIG. Our objective was to compare the effectiveness of using a precision-dosing strategy (IBW or adjBW) with a traditional-dosing strategy (ABW) for IVIG in patients with hematologic malignancies or those undergoing hematopoietic stem cell transplant, as well as to perform an IVIG drug use analysis. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PATIENTS: Between April 2014 and September 2016, 209 IVIG encounters met inclusion criteria for the primary outcome. Of those encounters, 125 were dosed using the traditional-dosing strategy, and 84 used the precision-dosing strategy. MEASUREMENTS AND MAIN RESULTS: The primary outcome was infection rate within 30 days of IVIG administration. Secondary outcomes included 60-day infection rate, immunoglobulin G (IgG)-level response (IgG higher than 400 mg/dl), and realized and potential IVIG savings. No difference in 30-day infection rate between precision- and traditional-dosing strategies was identified (15.5% vs 16%, respectively, p=0.823). Similarly, no difference was identified in the 60-day infection rate between groups (23.2% vs 19.8%, respectively, p=0.568). Levels of IgG obtained after IVIG repletion showed a treatment response rate of 86% in both groups. Use of a precision-dosing strategy achieved $2600/month in institutional savings with the opportunity for an additional $4600/month in savings with complete adherence to this dosing strategy. CONCLUSION: No differences in infection rate and IgG-level response were identified when a precision-dosing strategy was used. Implementation of an IVIG precision-dosing strategy provided institutional cost savings.