Structural basis for translation inhibition by the glycosylated drosocin peptide.

The proline-rich antimicrobial peptide (PrAMP) drosocin is produced by Drosophila species to combat bacterial infection. Unlike many PrAMPs, drosocin is O-glycosylated at threonine 11, a post-translation modification that enhances its antimicrobial activity. Here we demonstrate that the O-glycosylation not only influences cellular uptake of the peptide but also interacts with its intracellular target, the ribosome. Cryogenic electron microscopy structures of glycosylated drosocin on the ribosome at 2.0-2.8-Å resolution reveal that the peptide interferes with translation termination by binding within the polypeptide exit tunnel and trapping RF1 on the ribosome, reminiscent of that reported for the PrAMP apidaecin. The glycosylation of drosocin enables multiple interactions with U2609 of the 23S rRNA, leading to conformational changes that break the canonical base pair with A752. Collectively, our study reveals novel molecular insights into the interaction of O-glycosylated drosocin with the ribosome, which provide a structural basis for future development of this class of antimicrobials.

"Not just a checkbox": A qualitative study of the resident scholarly experience.

Objectives: Scholarship is a requirement of residency training; however, the scholarly productivity of trainees is highly variable. The purpose of this study was to explore the perspectives of residents who have been highly productive in scholarship. Methods: We performed a qualitative study using a constructivist-interpretivist paradigm and conducted semistructured interviews at seven Accreditation Council for Graduate Medical Education-accredited emergency medicine residency programs in the United States. We included sites of diverse locations and training formats (PGY-1 to -4 vs. PGY-1 to -3). Program leadership identified residents with high levels of scholarly productivity at their institutions. We used purposive sampling to seek out residents with diversity in gender and PGY level. Two researchers independently performed a thematic analysis of interview transcripts. Discrepancies were resolved through in-depth discussion and negotiated consensus. Results: We invited 14 residents and all consented to be interviewed. Residents felt scholarship enhanced their knowledge and skills, grew collaborative networks, and provided personal fulfillment and external rewards. Scholarship positively impacted their careers by focusing their professional interests and informing career decisions. Participants identified individual and institutional facilitators of success including personal prior knowledge and skills, project management skills, mindset, protected time, mentorship, and leadership support. Challenges to conducting scholarship included lack of time, expertise, and resources. Participants acknowledged that participating in scholarly activities was hard work and recommended that residents seek out quality mentorship, work on projects that they are passionate, start early, and be persistent in their efforts. Participants' advice to faculty supporting resident scholarship included recommendations to allow resident autonomy of projects, provide scholarly opportunities, and be responsive to trainee needs. Conclusions: Participants in this study highlighted benefits of participating in scholarly activity as well as challenges and strategies for success. These results can inform residencies seeking to enhance the scholarly experience of trainees.

Simulation-Based Mastery Learning Course for Tube Thoracostomy.

Introduction: Tube thoracostomy is a relatively infrequent, high-risk procedure that is a required competency for emergency medicine residents. Simulation-based mastery learning is the gold standard for procedure training and has been used to successfully train residents in high-risk procedures. Methods: We developed a simulation-based mastery learning course for tube thoracostomy for PGY 2 emergency medicine residents. The course included (1) precourse work, (2) baseline assessment using a modified version of the TUBE-iCOMPT checklist, (3) anatomy/radiology review, (4) deliberate practice to master individual aspects of the procedure, and (5) final assessment. If a minimum passing score was not achieved, additional coaching and deliberate practice occurred until the learner was able to achieve a minimum passing score. Results: After piloting the course with a cohort of seven PGY 2 emergency medicine residents, we successfully trained 24 additional PGY 2 residents in the subsequent two classes. Combining all three cohorts (N = 31), there was a statistically significant increase in learners' modified TUBE-iCOMPT scores (pretest M = 61.2, SD = 10.0; posttest M = 75.5, SD = 2.9; p < .001). Learners' confidence in their ability to correctly place a chest tube increased, rated on a 10-point Likert scale (1 = not very confident, 10 = very confident; precourse M = 5.6, SD = 1.8; postcourse M = 8.3, SD = 1.1; p < .001). Discussion: This simulation-based course was well received by learners. Our assessment demonstrated that learners improved directly observed procedural skills in simulation and confidence in tube thoracostomy placement.

Calculated decisions: Injury severity score.

A review of the uses and evidence for the Injury Severity Score, which standardizes the severity of traumatic injury based on the 3 worst injuries from 6 body systems.

Calculated decisions: Jones criteria for acute rheumatic fever diagnosis

The Jones criteria are use to diagnose acute rheumatic fever based on major and minor criteria.

Calculated Decisions: Injury Severity Score (ISS)

The Injury Severity Score (ISS) standardizes the severity of traumatic injury based on the 3 worst injuries from 6 body systems.

Perioperative Testosterone Supplementation Increases Lean Mass in Healthy Men Undergoing Anterior Cruciate Ligament Reconstruction: A Randomized Controlled Trial.

BACKGROUND: Rehabilitation after repair of the anterior cruciate ligament (ACL) is complicated by the loss of leg muscle mass and strength. Prior studies have shown that preoperative rehabilitation may improve muscle strength and postoperative outcomes. Testosterone supplementation may likewise counteract this muscle loss and potentially improve clinical outcomes. PURPOSE: The purpose was to investigate the effect of perioperative testosterone administration on lean mass after ACL reconstruction in men and to examine the effects of testosterone on leg strength and clinical outcome scores. It was hypothesized that testosterone would increase lean mass and leg strength and improve clinical outcome scores relative to placebo. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Male patients (N = 13) scheduled for ACL reconstruction were randomized into 2 groups: testosterone and placebo. Participants in the testosterone group received 200 mg of intramuscular testosterone weekly for 8 weeks beginning 2 weeks before surgery. Participants in the placebo group received saline following the same schedule. Both groups participated in a standard rehabilitation protocol. The primary outcome was the change in total lean body mass at 6 and 12 weeks. Secondary outcomes were extensor muscle strength, Tegner activity score, and Knee injury and Osteoarthritis Outcome Score. RESULTS: There was an increase in lean mass of a mean 2.7 ± 1.7 kg at 6 weeks postoperatively in the testosterone group compared with a decrease of a mean 0.1 ± 1.5 kg in the placebo group (P = .01). Extensor muscle strength of the uninjured leg also increased more from baseline in the testosterone group (+20.8 ± 25.6 Nm) compared with the placebo group (-21.4 ± 36.7 Nm) at 12 weeks (P = .04). There were no significant between-group differences in injured leg strength or clinical outcome scores. There were no negative side effects of testosterone noted. CONCLUSION: Perioperative testosterone supplementation increased lean mass 6 weeks after ACL reconstruction, suggesting that this treatment may help minimize the effects of muscle atrophy associated with ACL injuries and repair. This study was not powered to detect differences in strength or clinical outcome scores to assess the incidence of testosterone-related adverse events. CLINICAL RELEVANCE: Supraphysiological testosterone supplementation may be a useful adjunct therapy for counteracting muscle atrophy after ACL reconstruction. Further investigation is necessary to determine the safety profile and effects of perioperative testosterone administration on leg strength and clinical outcomes after surgery. REGISTRATION: NCT01595581 (ClinicalTrials.gov).

The Prediction of Speech Recognition in Noise With a Semi-Implantable Bone Conduction Hearing System by External Bone Conduction Stimulation With Headband: A Prospective Study.

Semi-implantable transcutaneous bone conduction devices are treatment options for conductive and mixed hearing loss (CHL/MHL). For counseling of patients, realistic simulation of the functional result is desirable. This study compared speech recognition in noise with a semi-implantable transcutaneous bone conduction device to external stimulation with a bone conduction device fixed by a headband. Eight German-language adult patients were enrolled after a semi-implantable transcutaneous bone conduction device (Bonebridge, Med-El) was implanted and fitted. Patients received a bone conduction device for external stimulation (Baha BP110, Cochlear) fixed by a headband for comparison. The main outcome measure was speech recognition in noise (Oldenburg Sentence Test). Pure-tone audiometry was performed and subjective benefit was assessed using the Glasgow Benefit Inventory and Abbreviated Profile of Hearing Aid Benefit questionnaires. Unaided, patients showed a mean signal-to-noise ratio threshold of 4.6 ± 4.2 dB S/N for speech recognition. The aided results were -3.3 ± 7.2 dB S/N by external bone conduction stimulation and -1.2 ± 4.0 dB S/N by the semi-implantable bone conduction device. The difference between the two devices was not statistically significant, while the difference was significant between unaided and aided situation for both devices. Both questionnaires for subjective benefit favored the semi-implantable device over external stimulation. We conclude that it is possible to simulate the result of speech recognition in noise with a semi-implantable transcutaneous bone conduction device by external stimulation. This should be part of preoperative counseling of patients with CHL/MHL before implantation of a bone conduction device.

Randomized control trial to evaluate the effects of acute testosterone administration in men on muscle mass, strength, and physical function following ACL reconstructive surgery: rationale, design, methods.

BACKGROUND: The anterior cruciate ligament (ACL) is one of four major ligaments in the knee that provide stability during physical activity. A tear in the ACL is characterized by joint instability that leads to decreased activity, knee dysfunction, reduced quality of life and a loss of muscle mass and strength. While rehabilitation is the standard-of-care for return to daily function, additional surgical reconstruction can provide individuals with an opportunity to return to sports and strenuous physical activity. Over 200,000 ACL reconstructions are performed in the United States each year, and rehabilitation following surgery is slow and expensive. One possible method to improve the recovery process is the use of intramuscular testosterone, which has been shown to increase muscle mass and strength independent of exercise. With short-term use of supraphysiologic doses of testosterone, we hope to reduce loss of muscle mass and strength and minimize loss of physical function following ACL reconstruction compared to standard-of-care alone. METHODS/DESIGN: This study is a double-blinded randomized control trial. Men 18-50 years of age, scheduled for ACL reconstruction are randomized into two groups. Participants randomized to the testosterone group receive intramuscular testosterone administration once per week for 8 weeks starting 2 weeks prior to surgery. Participants randomized to the control group receive a saline placebo intramuscularly instead of testosterone. Lean mass, muscle strength and physical function are measured at 5 time points: 2 weeks pre-surgery, 1 day pre-surgery, and 6, 12, 24 weeks post-surgery. Both groups follow standard-of-care rehabilitation protocol. DISCUSSION: We believe that testosterone therapy will help reduce the loss of muscle mass and strength experienced after ACL injury and reconstruction. Hopefully this will provide a way to shorten the rehabilitation necessary following ACL reconstruction. If successful, testosterone therapy may also be used for other injuries involving trauma and muscle atrophy. TRIAL REGISTRATION: NCT01595581, REGISTRATION: May 8, 2012.

Modulation of the arcuate nucleus-medial preoptic nucleus lordosis regulating circuit: a role for GABAB receptors.

Estradiol rapidly activates a microcircuit in the arcuate nucleus of the hypothalamus (ARH) that is needed for maximal female sexual receptivity. Membrane estrogen receptor-α complexes with and signals through the metabotropic glutamate receptor-1a stimulating NPY release within the ARH activating proopiomelanocortin (POMC) neurons. These POMC neurons project to the medial preoptic nucleus (MPN) and release ß-endorphin. Estradiol treatment induces activation/internalization of MPN µ-opioid receptors (MOR) to inhibit lordosis. Estradiol membrane action modulates ARH gamma-aminobutyric acid receptor-B (GABAB) activity. We tested the hypothesis that ARH GABAB receptors mediate estradiol-induced MOR activation and facilitation of sexual receptivity. Double-label immunohistochemistry revealed expression of GABAB receptors in NPY, ERα and POMC expressing ARH neurons. Approximately 70% of POMC neurons expressed GABAB receptors. Because estradiol initially activates an inhibitory circuit and maintains activation of this circuit, the effects of blocking GABAB receptors were evaluated before estradiol benzoate (EB) treatment and after at the time of lordosis testing. Bilateral infusions of the GABAB receptor antagonist, CGP52432, into the ARH prior to EB treatment of ovariectomized rats prevented estradiol-induced activation/internalization of MPN MOR, and the rats remained unreceptive. However, in EB-treated rats, bilateral CGP52432 infusions 30 min before behavior testing attenuated MOR internalization and facilitated lordosis. These results indicated that GABAB receptors were located within the lordosis-regulating ARH microcircuit and are necessary for activation and maintenance of the estradiol inhibition of lordosis behavior. Although GABAB receptors positively influence estradiol signaling, they negatively regulate lordosis behavior since GABAB activity maintains the estradiol-induced inhibition.