RESTORE-IMI 1: A Multicenter, Randomized, Doubleblind Trial Comparing Efficacy and Safety of Imipenem/Relebactam vs Colistin Plus Imipenem in Patients With Imipenem-nonsusceptible Bacterial Infections

Background. The β-lactamase inhibitor relebactam can restore imipenem activity against imipenem-nonsusceptible gram-negative pathogens. We evaluated imipenem/relebactam for treating imipenem-nonsusceptible infections. Methods. Randomized, controlled, double-blind, phase 3 trial. Hospitalized patients with hospital-acquired/ventilatorassociated pneumonia, complicated intraabdominal infection, or complicated urinary tract infection caused by imipenemnonsusceptible (but colistin- and imipenem/relebactam-susceptible) pathogens were randomized 2:1 to 5–21 days imipenem/ relebactam or colistin+imipenem. Primary endpoint: favorable overall response (defined by relevant endpoints for each infection type) in the modified microbiologic intent-to-treat (mMITT) population (qualifying baseline pathogen and ≥1 dose study treatment). Secondary endpoints: clinical response, all-cause mortality, and treatment-emergent nephrotoxicity. Safety analyses included patients with ≥1 dose study treatment. Results. Thirty-one patients received imipenem/relebactam and 16 colistin+imipenem. Among mITT patients (n = 21 imipenem/relebactam, n = 10 colistin+imipenem), 29% had Acute Physiology and Chronic Health Evaluation II scores >15, 23% had creatinine clearance <60 mL/min, and 35% were aged ≥65 years. Qualifying baseline pathogens: Pseudomonas aeruginosa (77%), Klebsiella spp. (16%), other Enterobacteriaceae (6%). Favorable overall response was observed in 71% imipenem/relebactam and 70% colistin+imipenem patients (90% confidence interval [CI] for difference, –27.5, 21.4), day 28 favorable clinical response in 71% and 40% (90% CI, 1.3, 51.5), and 28-day mortality in 10% and 30% (90% CI, –46.4, 6.7), respectively. Serious adverse events (AEs) occurred in 10% of imipenem/relebactam and 31% of colistin+imipenem patients, drug-related AEs in 16% and 31% (no drugrelated deaths), and treatment-emergent nephrotoxicity in 10% and 56% (P = .002), respectively. Conclusions. Imipenem/relebactam is an efficacious and well-tolerated treatment option for carbapenem-nonsusceptible infection

WNT7B promotes bone formation in part through mTORC1

WNT signaling has been implicated in both embryonic and postnatal bone formation. However, the pertinent WNT ligands and their downstream signaling mechanisms are not well understood. To investigate the osteogenic capacity of WNT7B and WNT5A, both normally expressed in the developing bone, we engineered mouse strains to express either protein in a Cre-dependent manner. Targeted induction of WNT7B, but not WNT5A, in the osteoblast lineage dramatically enhanced bone mass due to increased osteoblast number and activity; this phenotype began in the late-stage embryo and intensified postnatally. Similarly, postnatal induction of WNT7B in Runx2-lineage cells greatly stimulated bone formation. WNT7B activated mTORC1 through PI3K-AKT signaling. Genetic disruption of mTORC1 signaling by deleting Raptor in the osteoblast lineage alleviated the WNT7B-induced high-bone-mass phenotype. Thus, WNT7B promotes bone formation in part through mTORC1 activation

Effects of Role-Play for Problem-Solving Skills and Engagement in Online Forums

The body of research found that it is difficult to improve the quality of an online discussion experience because of the affordances and the limitations of asynchronous online communication technologies (An et al., Comput Educ 53: 749–760, 2009; Bachner, Cases on critical and qualitative perspectives in online higher education. Hershey, PA: IGI Global, 2014; Dennen and Wieland, Dis Educ 28(3): 281–297, 2007; Rourke and Kanuka, J Dis Educ 23(1): 19–48, 2009; Thomas, J Comput Assist Learn 18: 351–366, 2002). To address this issue, this study investigated an instructional strategy to increase engagement using a collaborative role-play online discussion where students assumed different roles. This study aimed to assess the quality of interaction by means of the Interaction Analysis Model (IAM) for examining social construction of knowledge and of learning experiences of teachers during computer conferencing designed to learn problem-solving skills. Two major models guided the study: Problem Solving Approach Model (Branford and Stein, The IDEAL problem solver: A guide for improving thinking, learning, and creativity. New York, NY: Freeman, 1993) and Interaction Analysis Model (IAM) for Computer-Mediated Communication rooted in social constructivist theory (Gunawardena et al., J Educ Comput Res 17(4): 397–431, 1997). After analyzing the progress of the discussion transcripts, this study found that the role-play discussion constructed better knowledge socially and improved higher mental operation. The threaded discussion postings from four structured online debates showed that the algorithmic format of problem-solving steps promoted and were closely interrelated to five phases of IAM. The study also found that this problem-solving exercise through computer-mediated communication helped teachers be equipped with a frame of reference to the problems, which resulted in helping teachers to establish boundaries, name problems, form opinions, and uncover solutions (Entman, J Commun 43(4): 51–58, 1993; Goffman, Frame analysis: An essay on the organization of experience. London: Harper and Row, 1974). This study will benefit online instructors as well as instructional designers who strive to find ways to make online discussion engaging