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Kusuma S.K.,Grant Medical Center | Ward J.,Loyola University New Orleans | Jacofsky M.,CORE Institute | Sporer S.M.,Rush University Medical Center | Della Valle C.J.,Rush University Medical Center
Clinical Orthopaedics and Related Research | Year: 2011

Background: Two-stage exchange arthroplasty is the gold standard for treatment of infected TKA. The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and synovial fluid white blood cell (WBC) count with differential are often used to determine treatment response; however, it is unclear whether these tests can answer the critical question of whether joint sepsis has been controlled between stages and if reimplantation is indicated. Questions/purposes: We therefore asked if (1) these serologies respond between stage one explantation and stage two reimplantation during two-stage knee reconstruction for infection; and (2) changes in the values of these serologies are predictive of resolution of joint infection. Methods: We retrospectively reviewed the serologies of 76 infected patients treated with a two-stage exchange protocol. The ESR, CRP, and aspiration were repeated a minimum of 2 weeks following antibiotic cessation and prior to second stage reoperation. Comparisons were made to identify trends in these serologies between the first and second stage procedures. Results: Eight knees (12%) were persistently infected at the time of second stage reoperation. The ESR remained persistently elevated in 37 knees (54%), and the CRP remained elevated in 14 knees (21%) where infection had been controlled. We were unable to identify an optimum cutoff value for the ESR, CRP, or the two combined. The best test for confirmation of infection control was the synovial fluid WBC count. Conclusions: Although the ESR, CRP, and synovial fluid WBC counts decreased in cases of infection control, these values frequently remained elevated. We were unable to identify any patterns in these tests indicative of persistent infection. Level of Evidence: Level II, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence. © The Association of Bone and Joint Surgeons® 2010.


News Article | February 23, 2017
Site: www.medicalnewstoday.com

Scientists from the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, have identified novel mutations in bacteria that promote the evolution of high-level antibiotic resistance. The findings, published in eLife, add to our understanding of how antibiotic resistance develops, which the team says is crucial for maintaining the effectiveness of both existing and future drugs. The rise of antibiotic-resistant bacteria is challenging clinicians, with some infections already resistant to nearly all available drugs. A 2013 report from the Centers for Disease Control and Prevention estimates that such infections kill at least 23,000 people each year in the United States alone*. Deborah Hung, senior author of the current study and Core Institute Member and Co-Director of the Infectious Disease and Microbiome Program at the Broad Institute, says: "Some species of bacteria, including mycobacteria, develop drug resistance as a result of mutations in their genes. We wanted to gain new insight into the molecular processes that promote resistance in these species by looking at the relationships between the concentration of antibiotics, their killing effects on bacteria, and the emergence of drug-resistant mutants." To do this, Hung and her team grew hundreds of cultures of the species Mycobacterium smegmatis (M. smegmatis), a cousin of the bacterium that causes tuberculosis. They exposed the bacteria to low antibiotic concentrations, where the drugs' microbe-killing effects were relatively slow. This allowed the team to monitor the killing of sensitive bacteria while isolating individual wells where mutants developed. "We detected the outgrowth of drug-resistant mutants in a fraction of our cultures," says first author James Gomez. "Each individual carried single mutations in different components of the ribosome, the complex molecular machine responsible for building proteins within cells." The team found that these novel ribosomal mutations granted the bacteria resistance to several different classes of antibiotics that do not even target the ribosome, and to which the mutants had never been exposed. They also enhanced resistance to two non-antibiotic stresses: heat shock and membrane stress. Gomez explains: "We did see a fitness cost to the bacteria in that the mutations reduced their growth rate. However, the reprogramming that occurred within the cells in response to the mutations made the bacteria much less sensitive to both antibiotic and non-antibiotic stresses. This suggests that, in species such as M. smegmatis, these types of mutations can enhance fitness in multidrug environments and serve as stepping stones toward the development of high-level drug resistance, despite the cost that the mutations have on growth." The team now wants to explore this phenomenon across diverse bacterial species, including Mycobacterium tuberculosis, by coupling experimental biological approaches with a thorough exploration of genome sequence information. A more complete understanding of how multidrug resistance emerges could help in the development or optimisation of new drugs for treating bacterial infections. Article: Ribosomal mutations promote the evolution of antibiotic resistance in a multidrug environment, James E Gomez, Benjamin B Kaufmann-Malaga, Carl N Wivagg, Peter B Kim, Melanie R Silvis, Nikolai Renedo, Thomas R Ioerger, Rushdy Ahmad, Jonathan Livny, Skye Fishbein, James C Sacchettini, Steven A Carr, Deborah T Hung, eLife, doi: 10.7554/eLife.20420, published 21 February 2017.


News Article | February 21, 2017
Site: www.eurekalert.org

Scientists from the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, have identified novel mutations in bacteria that promote the evolution of high-level antibiotic resistance. The findings, published in eLife, add to our understanding of how antibiotic resistance develops, which the team says is crucial for maintaining the effectiveness of both existing and future drugs. The rise of antibiotic-resistant bacteria is challenging clinicians, with some infections already resistant to nearly all available drugs. A 2013 report from the Centers for Disease Control and Prevention estimates that such infections kill at least 23,000 people each year in the United States alone*. Deborah Hung, senior author of the current study and Core Institute Member and Co-Director of the Infectious Disease and Microbiome Program at the Broad Institute, says: "Some species of bacteria, including mycobacteria, develop drug resistance as a result of mutations in their genes. We wanted to gain new insight into the molecular processes that promote resistance in these species by looking at the relationships between the concentration of antibiotics, their killing effects on bacteria, and the emergence of drug-resistant mutants." To do this, Hung and her team grew hundreds of cultures of the species Mycobacterium smegmatis (M. smegmatis), a cousin of the bacterium that causes tuberculosis. They exposed the bacteria to low antibiotic concentrations, where the drugs' microbe-killing effects were relatively slow. This allowed the team to monitor the killing of sensitive bacteria while isolating individual wells where mutants developed. "We detected the outgrowth of drug-resistant mutants in a fraction of our cultures," says first author James Gomez. "Each individual carried single mutations in different components of the ribosome, the complex molecular machine responsible for building proteins within cells." The team found that these novel ribosomal mutations granted the bacteria resistance to several different classes of antibiotics that do not even target the ribosome, and to which the mutants had never been exposed. They also enhanced resistance to two non-antibiotic stresses: heat shock and membrane stress. Gomez explains: "We did see a fitness cost to the bacteria in that the mutations reduced their growth rate. However, the reprogramming that occurred within the cells in response to the mutations made the bacteria much less sensitive to both antibiotic and non-antibiotic stresses. This suggests that, in species such as M. smegmatis, these types of mutations can enhance fitness in multidrug environments and serve as stepping stones toward the development of high-level drug resistance, despite the cost that the mutations have on growth." The team now wants to explore this phenomenon across diverse bacterial species, including Mycobacterium tuberculosis, by coupling experimental biological approaches with a thorough exploration of genome sequence information. A more complete understanding of how multidrug resistance emerges could help in the development or optimisation of new drugs for treating bacterial infections. The paper 'Ribosomal mutations promote the evolution of antibiotic resistance in a multidrug environment' can be freely accessed online at http://dx. . Contents, including text, figures, and data, are free to reuse under a CC BY 4.0 license. *CDC. Antibiotic Resistance Threats in the United States, 2013. Centers for Disease Control and Prevention, 2013: https:/ eLife is a unique collaboration between the funders and practitioners of research to improve the way important research is selected, presented, and shared. eLife publishes outstanding works across the life sciences and biomedicine -- from basic biological research to applied, translational, and clinical studies. All papers are selected by active scientists in the research community. Decisions and responses are agreed by the reviewers and consolidated by the Reviewing Editor into a single, clear set of instructions for authors, removing the need for laborious cycles of revision and allowing authors to publish their findings quickly. eLife is supported by the Howard Hughes Medical Institute, the Max Planck Society, and the Wellcome Trust. Learn more at elifesciences.org.


News Article | February 21, 2017
Site: phys.org

The findings, published in eLife, add to our understanding of how antibiotic resistance develops, which the team says is crucial for maintaining the effectiveness of both existing and future drugs. The rise of antibiotic-resistant bacteria is challenging clinicians, with some infections already resistant to nearly all available drugs. A 2013 report from the Centers for Disease Control and Prevention estimates that such infections kill at least 23,000 people each year in the United States alone*. Deborah Hung, senior author of the current study and Core Institute Member and Co-Director of the Infectious Disease and Microbiome Program at the Broad Institute, says: "Some species of bacteria, including mycobacteria, develop drug resistance as a result of mutations in their genes. We wanted to gain new insight into the molecular processes that promote resistance in these species by looking at the relationships between the concentration of antibiotics, their killing effects on bacteria, and the emergence of drug-resistant mutants." To do this, Hung and her team grew hundreds of cultures of the species Mycobacterium smegmatis (M. smegmatis), a cousin of the bacterium that causes tuberculosis. They exposed the bacteria to low antibiotic concentrations, where the drugs' microbe-killing effects were relatively slow. This allowed the team to monitor the killing of sensitive bacteria while isolating individual wells where mutants developed. "We detected the outgrowth of drug-resistant mutants in a fraction of our cultures," says first author James Gomez. "Each individual carried single mutations in different components of the ribosome, the complex molecular machine responsible for building proteins within cells." The team found that these novel ribosomal mutations granted the bacteria resistance to several different classes of antibiotics that do not even target the ribosome, and to which the mutants had never been exposed. They also enhanced resistance to two non-antibiotic stresses: heat shock and membrane stress. Gomez explains: "We did see a fitness cost to the bacteria in that the mutations reduced their growth rate. However, the reprogramming that occurred within the cells in response to the mutations made the bacteria much less sensitive to both antibiotic and non-antibiotic stresses. This suggests that, in species such as M. smegmatis, these types of mutations can enhance fitness in multidrug environments and serve as stepping stones toward the development of high-level drug resistance, despite the cost that the mutations have on growth." The team now wants to explore this phenomenon across diverse bacterial species, including Mycobacterium tuberculosis, by coupling experimental biological approaches with a thorough exploration of genome sequence information. A more complete understanding of how multidrug resistance emerges could help in the development or optimisation of new drugs for treating bacterial infections. Explore further: Bacteria sleep, then rapidly evolve, to survive antibiotic treatments More information: James E Gomez et al, Ribosomal mutations promote the evolution of antibiotic resistance in a multidrug environment, eLife (2017). DOI: 10.7554/eLife.20420 *CDC. Antibiotic Resistance Threats in the United States, 2013. Centers for Disease Control and Prevention, 2013: www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf


News Article | September 30, 2016
Site: www.biosciencetechnology.com

We have a reasonable understanding of the rules behind the genome’s protein-coding components. We can look at a DNA sequence and point with confidence to where a gene’s coding region begins, where it ends, and pieces of its geography. For the remaining 98 percent of the genome — the part that dictates which genes a cell reads — it’s a different story. What knowledge we have of the rules governing this “dark matter” comes from from studying and manipulating individual bits of noncoding DNA one at a time. The rulebook that governs how the noncoding genome works, however, has remained out of reach. “Ninety percent of the genetic variations that affect human disease are in the noncoding regions,” said Broad founding director Eric Lander. “But we haven’t had any way to tell, in a systematic way, which regulators affect which genes.” In a pair of newly published Science papers, two research teams at the Broad show how methods leveraging CRISPR gene editing could help grasp those rules. Using two complementary approaches, the teams — one from the Lander lab, the other from that of Broad Core Institute Member and McGovern Institute for Brain Research investigator Feng Zhang— used CRISPR as a tool to systematically probe thousands of noncoding DNA sequences simultaneously (much as Zhang and others did previously with coding DNA). In the process, both identified several interesting genetic regulators, including ones millions of bases away from the genes they control. “We’d like to be able to catalog the noncoding elements that control every gene’s expression in every cell type,” said Jesse Engreitz, a postdoctoral fellow in the Lander lab and senior author on one of the papers. “This is a massive problem in biology, and it’s a rate-limiting step for connecting many genetic associations to their fundamental molecular mechanisms and to human disease.” Both teams used pooled CRISPR screens (which scan and edit large swaths of the genome simultaneously using a molecular scalpel called the Cas9 enzyme and thousands of guide RNAs, which target Cas9 to specific sequences) to perturb noncoding DNA. But they did so in different ways. Zhang, Neville Sanjana (a Zhang lab alum and now a core member of the New York Genome Center), and Jason Wright (another Zhang alum, now at Homology Medicines) used Cas9 to make precise edits to overlapping stretches of noncoding DNA — in their case, in regions surrounding three genes (NF1, NF2, and CUL3) whose functional loss has been linked to drug resistance in a form of melanoma. “This approach lets us induce a wide diversity of mutations,” Sanjana explained. “We don’t have to speculate how a given sequence might best be disrupted.” Engreitz, Lander, and graduate student Charles Fulco, on the other hand, employed a CRISPR interference system, using an inactive or “dead” form of Cas9 fused to a protein fragment called a KRAB domain to silence their target sequences (around MYC and GATA1, the genes for two important transcription factors). “This system provides a good quantitative estimate of a given noncoding region’s regulatory influence,” Engreitz said. “It both shows you where the dials are that control a given gene, and tells you how much each dial matters.” Each team then used a functional readout (increased drug resistance in melanoma cells for Sanjana, Wright, and Zhang; a drop in cell growth for Fulco, Lander, and Engreitz) and deep sequencing to see which of their guide RNAs impacted expression of their genes of interest and map the regulators those guide RNAs affected. The two teams’ findings, confirmed with an array of additional techniques (e.g., chromatin profiling, 3D conformational capture, transcription factor profiling), point to the potential for tracing the noncoding genome’s regulatory wiring leveraging CRISPR tools. Fulco, Lander, and Engreitz found and ranked the relative importance of seven MYC and three GATA1 enhancers (short pieces of noncoding DNA that boost a gene’s chances of being read). Sanjana, Wright, and Zhang’s screen pinpointed numerous enhancers and transcription factor binding sites just for CUL3 alone. While similar in principle to traditional reporter assays (where scientists couple interesting sequences to reporter genes in plasmids), these pooled CRISPR screens have a distinct difference: they probe the sequences directly, in their native habitat. “The screens interrogate the sequences in their endogenous context,” Sanjana emphasized. “Reporter assays can be very helpful, but they lack the 3D conformation or local chromatin environment of the native genomic context. Here, the regulatory sequences undergo all of their normal interactions.” “For example, we could see long-range loops between gene promoters and noncoding sites thousands of bases away,” he continued. “We would have missed these interesting 3D interactions entirely if we just looked at these regulatory elements in isolation.” One limitation, Engreitz noted, is that neither CRISPR approach, in its current form, addresses the genome’s inherent redundancy. “Maybe it's not enough to break one enhancer to really understand how a gene is controlled. Maybe you have to break more than one,” he said. “We can’t do that yet.” But Engreitz, Sanjana, and Lander are all optimistic about the potential for using CRISPR-based approaches to reveal the noncoding genome’s underlying order. “One interesting challenge with the noncoding genome is that while it is huge, the individual functional elements within it can be quite small,” Sanjana said. “In the future, it will be important to think about how we can develop new approaches that interrogate larger regions while maintaining high resolution.” Engreitz agreed, adding, “There's a potential that as we map more of these connections we're going to learn the rules that let us predict them for the rest of the noncoding genome.” “These approaches, using libraries of guide RNAs to bring CRISPR in to cut or bring in inhibitors, let you directly see the effects of large areas of noncoding DNA on different genes,” Lander said. “I think this is going to crack open systematic maps of gene regulation.”


Bailey A.,Precision Spine and Orthopaedic Specialists | Araghi A.,CORE Institute | Blumenthal S.,The Texas Institute | Huffmon G.V.,Atlantic Neurosurgical and Spine Specialists
Spine | Year: 2013

Study Design. Prospective, multicenter, single-blind, randomized, controlled clinical study. Objective. To investigate outcomes associated with repairing the anulus fi brosus after lumbar discectomy for the surgical management of herniated nucleus pulposus. Summary of Background Data. In patients undergoing discectomy, the incidence of reherniation ranges from 10% to 15%. Repair of the anulus fi brosus defect after lumbar discectomy may decrease the incidence of recurrent herniation for these patients. Methods. A total of 750 patients were treated for herniated lumbar discs and randomly assigned in a 2:1 ratio to discectomy with the Xclose Tissue Repair System (Anulex Technologies, Minnetonka, MN) for anular repair (n = 500) or discectomy without anular repair (n = 250). Patient self-reported measures included visual analogue scales for leg and back pain, Oswestry Disability Index, and Short Form-12 Health Survey. Adverse events and subsequent reherniation surgical procedures were documented. Preoperative outcome measures were compared with follow-up visits at 2 weeks, 6 months, 1 year, and 2 years. Results. Patient symptoms were improved after surgery in an equivalent manner in both study groups. In the overall study analysis, the rate of reherniation surgery was lower for Xclose patients at all follow-up time points, but these differences were not statistically signifi cant. In patients with predominant leg pain, there was a signifi cant reduction in reherniation risk at 3 and 6 months postoperation for patients receiving Xclose. A positive reduction was maintained through 2 years, with a clinically relevant risk reduction of 45%, although not statistically signifi cant. Safety was demonstrated with similar improvements in patient outcomes and no difference in reported adverse events. Conclusion. Without a safe and effective method for closing the anulus fi brosus after discectomy, current practice has been to leave the anulus in a compromised state. This multicenter randomized study demonstrated that, while not statistically signifi cant, anular repair reduced the need for subsequent reherniation surgery while retaining the benefi ts of discectomy with no increased risk for patients. Copyright © 2013 Lippincott Williams & Wilkins.


Loftus T.,Banner Health | Dahl D.,Banner Health | Ohare B.,Banner Health | Power K.,Banner Health | And 4 more authors.
Journal of the American College of Surgeons | Year: 2015

Background Patient safety in the perioperative period is essential for delivery of quality patient care. Mainstream quality organizations have implemented safe surgery recommended practices for ensuring patient safety. Effectively implementing safe surgery practices should result in a reduction in serious reportable event (SRE) rates.Study Design This retrospective cohort study compared results before and after implementation of a standardized safe surgery program across a large health care system. Observational audits were performed to assure adoption of the new process. Serious reportable event rates (retained surgical item, wrong site, wrong patient, and wrong procedure) were tracked. Statistical analyses were performed on the SRE rate and days between SREs.Results A total of 683,193 cases in the operating room and labor and delivery were evaluated over a 4-year period. The SRE rate before implementation was 0.075/1,000 cases and after implementation was 0.037/1,000 cases. There was a 52% reduction in the SRE rate (p < 0.05). The mean time between SREs increased from 27.4 days to 60.6 days (p < 0.05). Robotic and nonrobotic cases were affected equally; however, a significant difference in SRE rate persisted between robotic and non-robotic cases (p < 0.05). Robotic cases are 7 times more likely to incur an SRE. Audits demonstrated that the compliance rates for the program improved to 96% after complete system implementation.Conclusions An effectively implemented standardized safe surgery program results in a significant reduction in SREs. Robotic cases are at high risk for an SRE.


Scalise J.J.,CORE Institute | Ciccone J.,Cleveland Clinic | Iannotti J.P.,Cleveland Clinic
Journal of Bone and Joint Surgery - Series A | Year: 2010

Background: Recently, a lesser tuberosity osteotomy has been promoted as an alternative to tenotomy for release of the subscapularis during shoulder arthroplasty. To our knowledge, no direct comparison of the clinical results of the two techniques has been presented. Methods: Thirty-five shoulders in thirty-four consecutive patients with osteoarthritis who had a primary total shoulder arthroplasty, performed with use of a standard subscapularis tenotomy (Group 1) or lesser tuberosity osteotomy (Group 2) to release the subscapularis, were evaluated retrospectively at an average of thirty-three months. Group 1 consisted of fifteen shoulders in fourteen patients (seven in males and eight in females, with an average age of sixty-seven years). Group 2 consisted of twenty shoulders in twenty patients (fourteen males and six females, with an average age of sixty-nine years). Assessment included a physical examination, clinical outcome questionnaires, conventional radiography, ultrasound examination of the subscapularis, and measurement of internal rotation strength. Results: The postoperative total Penn Shoulder Scores improved significantly from the preoperative levels in both groups (mean and standard deviation, 29 ± 15 points to 81 ± 20 points [p < 0.00001] in Group 1 and 29 ± 16 points to 92 ± 11 points [p < 0.00001] in Group 2). However, the postoperative mean total Penn Shoulder Score was higher in Group 2 (92 ± 11 points) than in Group 1 (81 ± 20 points) (p = 0.04). At one year, an abnormal subscapularis on ultrasound was associated with a lower mean Penn Shoulder Score in Group 1 (73 ± 19 points compared with 92 ± 3 points; p = 0.01). However, at a minimum two-year follow-up, this difference was not significant (mean, 74 ± 24 points and 86 ± 15 points, respectively; p = 0.25). There were more abnormal subscapularis tendons in Group 1 (six attenuated tendons and one full-thickness tear) than in Group 2 (two attenuated tendons). Internal rotation strength did not differ between the groups when controlled for sex (mean, 117 ± 8 N and 127 ± 21 N for males in Group 1 and Group 2, respectively [p = 0.22] and 77 ± 27 N and 101 ± 26 N, respectively, for females [p = 0.1]). Conclusions: Both techniques resulted in improved clinical outcome scores. The lesser tuberosity osteotomy resulted in higher clinical outcome scores, a lower rate of subscapularis tendon tears, and universal healing of the osteotomy. This technique offers a means by which the rate of postoperative subscapularis tears may be reduced in patients undergoing total shoulder arthroplasty. Level of Evidence: Therapeutic Level III. See Instructions to Authors for a complete description of levels of evidence. Copyright © 2010 by The Journal of Bone and Joint Surgery, Incorporated.


Tom J.A.,Hahnemann University | Tom J.A.,Brandywine Institute of Orthopedics | Tom J.A.,CORE Institute
Clinical Journal of Sport Medicine | Year: 2014

OBJECTIVE: To elucidate mechanism of injury, nonoperative protocols, surgical techniques, rehabilitation schedules, and return to sports guidelines for partial and complete triceps tendon injuries. DATA SOURCES: The PubMed and OVID databases were searched in 2010 and peer-reviewed English language articles in 2011. MAIN RESULTS: After a fall on an outstretched hand, direct trauma on the elbow, or lifting against resistance, patients often present with pain and weakness of extension. Examination may reveal a palpable tendon gap, and radiographs may reveal a Flake sign. Acute partial injuries have positive outcomes with immobilization in 30-degree flexion for 4 to 6 weeks. Primary repair for complete rupture can restore normal extensor function after 3 to 4 months. Reconstruction returns normal extensor function up to 4 years. Most authors support postoperative immobilization for 2 to 3 weeks at 30- to 40-degree flexion, flexion block bracing for an additional 3 weeks, and unrestricted activity at 6 months. Athletes may be able to return to sports after 4 to 5 weeks of recovery from a partial injury, but return may be delayed if operative tendon repair is performed. CONCLUSIONS: Acute partial triceps tendon injuries may be managed conservatively at first and should be repaired primarily if this fails or if presentation is delayed. Reconstruction should first use the anconeus rotation technique. If the anconeus is devitalized, the Achilles tendon may be the allograft of choice.


Each month, this column summarizes a Level I article and provides a thought-provoking review on how the treatment in the article has either stood the test of time or serves as an example of how conventional wisdom has changed.

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