Depolymerizing self-immolative polymeric lanthanide chelates for vascular imaging.

Medical imaging is widely used clinically and in research to understand disease progression and monitor responses to therapies. Vascular imaging enables the study of vascular disease and therapy, but exogenous contrast agents are generally needed to distinguish the vasculature from surrounding soft tissues. Lanthanide-based agents are commonly employed in MRI, but are also of growing interest for micro-CT, as the position of their k-edges allows them to provide enhanced contrast and also to be employed in dual-energy micro-CT, a technique that can distinguish contrast-enhanced blood vessels from tissues such as bone. Small molecule Gd3+ chelates are available, but are excreted too rapidly. At the same time, a lack of rapid clearance from the body for long-circulating agents presents toxicity concerns. To address these challenges, we describe here the use of self-immolative polymers for the development of new degradable chelates that depolymerize completely from end-to-end following the cleavage of a single end-cap from the polymer terminus. We demonstrate that tuning the end-cap allows the rate of depolymerization to be controlled, while tuning the polymer length enables the polymer to exhibit long circulation times in the blood of mice. After successfully providing one hour of blood contrast, depolymerization led to excretion of the resulting small molecule chelates into the bladder. Despite the high doses required for micro-CT, the agents were well tolerated in mice. Thus, these self-immolative polymeric chelates provide a new platform for the development of medical imaging contrast agents

Guideline: Appropriate use of tigecycline

INTRODUCTION: Tigecycline, the first of a new class of antibiotics, the glycylcyclines, was licensed in South Africa for the parenteral treatment of adult patients with complicated intraabdominal infections (cIAIs) and complicated skin and softtissue infections (cSSTIs). METHODS: A multidisciplinary meeting representative of the Association of Surgeons of South Africa, the Critical Care Society of Southern Africa, the Federation of Infectious Diseases Societies of Southern Africa, the South African Thoracic Society and the Trauma Society of South Africa was held to draw up a national guideline for the appropriate use of tigecycline. Background information reviewed included randomised controlled trials, other relevant publications and local antibiotic susceptibility patterns. The initial document was drafted at the meeting. Subsequent drafts were circulated to members of the working group for modification. OUTPUT: The guideline addresses several important aspects of the new agent, summarising key clinical data and highlighting important considerations with the use of the drug. The recommendations in this guideline are based on currently available scientific evidence together with the consensus opinion of the authors. CONCLUSION: This statement was written out of concern regarding the widespread misuse of antibiotics. Its primary intention is to facilitate heterogeneous use of antibiotics as a component of antibiotic stewardship and to highlight the appropriate use of tigecycline in particular.Sponsored through an unrestricted educational grant from Wyeth

Guideline summary : appropriate use of tigecycline

Tigecycline, the first of a new class of broad-spectrum antibiotics (the glycylcyclines), has been licensed in South Africa for the parenteral treatment of adult patients with complicated intra-abdominal infections (cIAIs) and complicated skin and soft-tissue infections (cSSTIs).http://www.hmpg.co.za/journaldetail.php?journalno=

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IMPORTANCE The cost of bilateral cochlear implantation (BCI) is usually not reimbursed by insurance companies because of a lack of well-designed studies reporting the benefits of a second cochlear implant. OBJECTIVE To determine the benefits of simultaneous BCI compared with unilateral cochlear implantation (UCI) in adults with postlingual deafness. DESIGN, SETTING, AND PARTICIPANTS A multicenter randomized clinical trial was performed. The study took place in 5 Dutch tertiary referral centers: the University Medical Centers of Utrecht, Maastricht, Groningen, Leiden, and Nijmegen. Forty patients eligible for cochlear implantation met the study criteria and were included from January 12, 2010, through November 2, 2012. The main inclusion criteria were postlingual onset of hearing loss, age of 18 to 70 years, duration of hearing loss of less than 20 years, and a marginal hearing aid benefit. Two participants withdrew from the study before implantation. Nineteen participants were randomized to undergo UCI and 19 to undergo BCI. INTERVENTIONS The BCI group received 2 cochlear implants during 1 surgery. The UCI group received 1 cochlear implant. MAIN OUTCOMES AND MEASURES The primary outcome was the Utrecht Sentence Test with Adaptive Randomized Roving levels (speech in noise, both presented from straight ahead). Secondary outcomes were consonant-vowel-consonant words in silence, speech-intelligibility test with spatially separated sources (speech in noise from different directions), sound localization, and quality of hearing questionnaires. Before any data were collected, the hypothesis was that the BCI group would perform better on the objective and subjective tests that concerned speech intelligibility in noise and spatial hearing. RESULTS Thirty-eight patients were included in the study. Fifteen patients in the BCI group used hearing aids before implantation compared with 19 in the UCI group. Otherwise, there were no significant differences between the groups' baseline characteristics. At 1-year follow-up, there were no significant differences between groups on the Utrecht Sentence Test with Adaptive Randomized Roving levels (9.1 dB, UCI group; 8.2 dB, BCI group; P = .39) or the consonant-vowel-consonant test (median percentage correct score 85.0% in the UCI group and 86.8% in the BCI group; P = .21). The BCI group performed significantly better than the UCI group when noise came from different directions (median speech reception threshold in noise, 14.4 dB, BCI group; 5.6 dB, BCI group; P <.001). The BCI group was better able to localize sounds (median correct score of 50.0% at 60 degrees, UCI group; 96.7%, BCI group; P CONCLUSIONS AND RELEVANCE This randomized clinical trial demonstrates a significant benefit of simultaneous BCI above UCI in daily listening situations for adults with postlingual deafness

Guideline: Appropriate use of tigecycline

Introduction. Tigecycline, the first of a new class of antibiotics, the glycylcyclines, was licensed in South Africa for the parenteral treatment of adult patients with complicated intra-abdominal infections (cIAIs) and complicated skin and soft-tissue infections (cSSTIs). Methods. A multidisciplinary meeting representative of the Association of Surgeons of South Africa, the Critical Care Society of Southern Africa, the Federation of Infectious Diseases Societies of Southern Africa, the South African Thoracic Society and the Trauma Society of South Africa was held to draw up a national guideline for the appropriate use of tigecycline. Background information reviewed included randomised controlled trials, other relevant publications and local antibiotic susceptibility patterns. The initial document was drafted at the meeting. Subsequent drafts were circulated to members of the working group for modification. Output. The guideline addresses several important aspects of the new agent, summarising key clinical data and highlighting important considerations with the use of the drug. The recommendations in this guideline are based on currently available scientific evidence together with the consensus opinion of the authors. Conclusion. This statement was written out of concern regarding the widespread misuse of antibiotics. Its primary intention is to facilitate heterogeneous use of antibiotics as a component of antibiotic stewardship and to highlight the appropriate use of tigecycline in particular

No Difference in Behavioral and Self-Reported Outcomes for Simultaneous and Sequential Bilateral Cochlear Implantation:Evidence From a Multicenter Randomized Controlled Trial

Objective: The primary aim of this study was to longitudinally compare the behavioral and self-reported outcomes of simultaneous bilateral cochlear implantation (simBiCI) and sequential BiCI (seqBiCI) in adults with severe-to-profound postlingual sensorineural hearing loss. Design: This study is a multicenter randomized controlled trial with a 4-year followup period after the first moment of implantation. Participants were allocated by randomization to receive bilateral cochlear implants (Cis) either, simultaneously (simBiCKI group) or sequentially with an inter-implant interval of 2 years (UCI/seqBiCI group). All sequential patients where encouraged to use their hearing aid on the non-implanted ear over of the first 2 years. Patients were followed-up on an annual basis. The primary outcome was speech perception in noise coming from a source directly in front of the patient. Other behavioral outcome measures were speech intelligibility-innoise from spatially separated sources, localization and speech perception in quiet. Self-reported outcome measures encompassed questionnaires on quality of life, quality of hearing and tinnitus. All outcome measures were analyzed longitudinally using a linear or logistic regression analysis with an autoregressive residual covariance matrix (generalized estimating equations type). Results: Nineteen participants were randomly allocated to the simBiCl group and 19 participants to the UCI/seqBiCI group. Three participants in the UCI/seqBiCI group did not proceed with their second implantation and were therefore unavailable for followup. Both study groups performed equally well on speech perception in noise from a source directly in front of the patient longitudinally. During all 4 years of follow-up the UCI/seqBiCI group performed significantly worse compared to the simBiCl group on spatial speech perception in noise in the best performance situation (8.70 dB [3.96 13.44], p <0.001) and localization abilities (largest difference 60 degrees configuration: -44.45% [-52.15 - -36.74], p <0.0001). Furthermore, during all years of follow-up, the UCI/seqBiCI group performed significantly worse on quality of hearing and quality of life questionnaires. The years of unilateral CI use were the reason for the inferior results in the UCI/SeqBiCI group. One year after receiving CI2, the UCI/seqBiCI group performance did not statistically differ from the performance of the simBiCl group on all these outcomes. Furthermore, no longitudinal differences were seen in tinnitus burden prevalence between groups. Finally, the complications that occurred during this trial were infection, dysfunction of CI, facial nerve palsy, tinnitus and vertigo. Conclusion: This randomized controlled trial on bilaterally severely hearing impaired participants found a significantly worse longitudinal performance of UCI/seqBiCI compared to simBiCI on multiple behavioral and self-reported outcomes regarding speech perception in noise and localization abilities. This difference is associated with the inferior performance of the UCI/seqBiCI participants during the years of unilateral CI use. After receiving the second CI however, the performance of the UCI/seqBiCI group did not significantly differ from the simBiCI group

Antimicrobial susceptibility of gram-negative pathogens isolated from patients with complicated intra-abdominal infections in South African hospitals (SMART Study 2004-2009) : impact of the new carbapenem breakpoints

BACKGROUND: The Study for Monitoring Antimicrobial Resistance Trends (SMART) follows trends in resistance among aerobic and facultative anaerobic gram-negative bacilli (GNB) isolated from complicated intra-abdominal infections (cIAIs) in patients around the world. METHODS: During 2004–2009, three centralized clinical microbiology laboratories serving 59 private hospitals in three large South African cities collected 1,218 GNB from complicated intra-abdominal infections (cIAIs) and tested them for susceptibility to 12 antibiotics according to the 2011 Clinical Laboratory Standards Institute (CLSI) guidelines. RESULTS: Enterobacteriaceae comprised 83.7% of the isolates. Escherichia coli was the species isolated most commonly (46.4%), and 7.6% of these were extended-spectrum b-lactamase (ESBL)-positive. The highest ESBL rate was documented for Klebsiella pneumoniae (41.2%). Overall, ertapenem was the antibiotic most active against susceptible species for which it has breakpoints (94.6%) followed by amikacin (91.9%), piperacillin-tazobactam (89.3%), and imipenem-cilastatin (87.1%), whereas rates of resistance to ceftriaxone, cefotaxime, ciprofloxacin, and levofloxacin were documented to be 29.7%, 28.7%, 22.5%, and 21.1%, respectively. Multi-drug resistance (MDR), defined as resistance to three or more antibiotic classes, was significantly more common in K. pneumoniae (27.9%) than in E. coli (4.9%; p < 0.0001) or Proteus mirabilis (4.1%; p < 0.05). Applying the new CLSI breakpoints for carbapenems, susceptibility to ertapenem was reduced significantly in ESBL-positive E. coli compared with ESBL-negative isolates (91% vs. 98%; p < 0.05), but this did not apply to imipenem-cilastatin (95% vs. 99%; p = 0.0928). A large disparity between imipenem-cilastatin and ertapenem susceptibility in P. mirabilis and Morganella morganii was documented (24% vs. 96% and 15% vs. 92%, respectively), as most isolates of these two species had imipenem-cilastatin minimum inhibitory concentrations in the 2–4 mcg/mL range, which is no longer regarded as susceptible. CONCLUSIONS: This study documented substantial resistance to standard antimicrobial therapy among GNB commonly isolated from cIAIs in South Africa. With the application of the new CLSI carbapenem breakpoints, discrepancies were noted between ertapenem and imipenem-cilastatin with regard to the changes in their individual susceptibilities. Longitudinal surveillance of susceptibility patterns is useful to guide recommendations for empiric antibiotic use in cIAIs.Merck & Co., Inc.http://www.liebertpub.com/overview/surgical-infections/53/am2013ay201

No Difference in Behavioral and Self-Reported Outcomes for Simultaneous and Sequential Bilateral Cochlear Implantation: Evidence From a Multicenter Randomized Controlled Trial

Objective: The primary aim of this study was to longitudinally compare the behavioral and self-reported outcomes of simultaneous bilateral cochlear implantation (simBiCI) and sequential BiCI (seqBiCI) in adults with severe-to-profound postlingual sensorineural hearing loss.Design: This study is a multicenter randomized controlled trial with a 4-year follow-up period after the first moment of implantation. Participants were allocated by randomization to receive bilateral cochlear implants (CIs) either, simultaneously (simBiCI group) or sequentially with an inter-implant interval of 2 years (UCI/seqBiCI group). All sequential patients where encouraged to use their hearing aid on the non-implanted ear over of the first 2 years. Patients were followed-up on an annual basis. The primary outcome was speech perception in noise coming from a source directly in front of the patient. Other behavioral outcome measures were speech intelligibility-in-noise from spatially separated sources, localization and speech perception in quiet. Self-reported outcome measures encompassed questionnaires on quality of life, quality of hearing and tinnitus. All outcome measures were analyzed longitudinally using a linear or logistic regression analysis with an autoregressive residual covariance matrix (generalized estimating equations type).Results: Nineteen participants were randomly allocated to the simBiCI group and 19 participants to the UCI/seqBiCI group. Three participants in the UCI/seqBiCI group did not proceed with their second implantation and were therefore unavailable for follow-up. Both study groups performed equally well on speech perception in noise from a source directly in front of the patient longitudinally. During all 4 years of follow-up the UCI/seqBiCI group performed significantly worse compared to the simBiCI group on spatial speech perception in noise in the best performance situation (8.70 dB [3.96 – 13.44], p &lt; 0.001) and localization abilities (largest difference 60 degrees configuration: -44.45% [-52.15 – -36.74], p &lt; 0.0001). Furthermore, during all years of follow-up, the UCI/seqBiCI group performed significantly worse on quality of hearing and quality of life questionnaires. The years of unilateral CI use were the reason for the inferior results in the UCI/SeqBiCI group. One year after receiving CI2, the UCI/seqBiCI group performance did not statistically differ from the performance of the simBiCI group on all these outcomes. Furthermore, no longitudinal differences were seen in tinnitus burden prevalence between groups. Finally, the complications that occurred during this trial were infection, dysfunction of CI, facial nerve palsy, tinnitus and vertigo.Conclusion: This randomized controlled trial on bilaterally severely hearing impaired participants found a significantly worse longitudinal performance of UCI/seqBiCI compared to simBiCI on multiple behavioral and self-reported outcomes regarding speech perception in noise and localization abilities. This difference is associated with the inferior performance of the UCI/seqBiCI participants during the years of unilateral CI use. After receiving the second CI however, the performance of the UCI/seqBiCI group did not significantly differ from the simBiCI group.Trial Registration: Dutch Trial Register NTR1722