Effect of Algorithm-Based Therapy vs Usual Care on Clinical Success and Serious Adverse Events in Patients with Staphylococcal Bacteremia: A Randomized Clinical Trial

Importance: The appropriate duration of antibiotics for staphylococcal bacteremia is unknown. Objective: To test whether an algorithm that defines treatment duration for staphylococcal bacteremia vs standard of care provides noninferior efficacy without increasing severe adverse events. Design, Setting, and Participants: A randomized trial involving adults with staphylococcal bacteremia was conducted at 16 academic medical centers in the United States (n = 15) and Spain (n = 1) from April 2011 to March 2017. Patients were followed up for 42 days beyond end of therapy for those with Staphylococcus aureus and 28 days for those with coagulase-negative staphylococcal bacteremia. Eligible patients were 18 years or older and had 1 or more blood cultures positive for S aureus or coagulase-negative staphylococci. Patients were excluded if they had known or suspected complicated infection at the time of randomization. Interventions: Patients were randomized to algorithm-based therapy (n = 255) or usual practice (n = 254). Diagnostic evaluation, antibiotic selection, and duration of therapy were predefined for the algorithm group, whereas clinicians caring for patients in the usual practice group had unrestricted choice of antibiotics, duration, and other aspects of clinical care. Main Outcomes and Measures: Coprimary outcomes were (1) clinical success, as determined by a blinded adjudication committee and tested for noninferiority within a 15% margin; and (2) serious adverse event rates in the intention-to-treat population, tested for superiority. The prespecified secondary outcome measure, tested for superiority, was antibiotic days among per-protocol patients with simple or uncomplicated bacteremia. Results: Among the 509 patients randomized (mean age, 56.6 [SD, 16.8] years; 226 [44.4%] women), 480 (94.3%) completed the trial. Clinical success was documented in 209 of 255 patients assigned to algorithm-based therapy and 207 of 254 randomized to usual practice (82.0% vs 81.5%; difference, 0.5% [1-sided 97.5% CI, -6.2% to ∞]). Serious adverse events were reported in 32.5% of algorithm-based therapy patients and 28.3% of usual practice patients (difference, 4.2% [95% CI, -3.8% to 12.2%]). Among per-protocol patients with simple or uncomplicated bacteremia, mean duration of therapy was 4.4 days for algorithm-based therapy vs 6.2 days for usual practice (difference, -1.8 days [95% CI, -3.1 to -0.6]). Conclusions and Relevance: Among patients with staphylococcal bacteremia, the use of an algorithm to guide testing and treatment compared with usual care resulted in a noninferior rate of clinical success. Rates of serious adverse events were not significantly different, but interpretation is limited by wide confidence intervals. Further research is needed to assess the utility of the algorithm. Trial Registration: ClinicalTrials.gov Identifier: NCT01191840

Impact of associated injuries in the Floating knee: A retrospective study

<p>Abstract</p> <p>Background</p> <p>Floating knee injuries are usually associated with other significant injuries. Do these injuries have implications on the management of the floating knee and the final outcome of patients? Our study aims to assess the implications of associated injuries in the management and final outcome of floating knee.</p> <p>Methods</p> <p>29 patients with floating knees were assessed in our institution. A retrospective analysis of medical records and radiographs were done and all associated injuries were identified. The impact of associated injuries on delay in initial surgical management, delay in rehabilitation & final outcome of the floating knee were assessed.</p> <p>Results</p> <p>38 associated injuries were noted. 7 were associated with ipsilateral knee injuries. Lower limb injuries were most commonly associated with the floating knee. Patients with some associated injuries had a delay in surgical management and others a delay in post-operative rehabilitation. Knee ligament and vascular injuries were associated with poor outcome.</p> <p>Conclusion</p> <p>The associated injuries were quite frequent with the floating knee. Some of the associated injuries caused a delay in surgical management and post-operative rehabilitation. In assessment of the final outcome, patients with associated knee and vascular injuries had a poor prognosis. Majority of the patients with associated injuries had a good or excellent outcome.</p

Close-to-threshold Meson Production in Hadronic Interactions

Studies of meson production at threshold in the hadron--hadron interaction began in the fifties when sufficient energies of accelerated protons were available. A strong interdependence between developments in accelerator physics, detector performance and theoretical understanding led to a unique vivid field of physics. Early experiments performed with bubble chambers revealed already typical ingredients of threshold studies, which were superseded by more complete meson production investigations at the nucleon beam facilities TRIUMF, LAMPF, PSI, LEAR and SATURNE. Currently, with the advent of the new cooler rings as IUCF, CELSIUS and COSY the field is entering a new domain of precision and the next step of further progress. The analysis of this new data in the short range limit permits a more fundamental consideration and a quantitative comparison of the production processes for different mesons in the few--body final states. The interpretation of the data take advantage of the fact that production reactions close-to-threshold are characterized by only a few degrees of freedom between a well defined combination of initial and exit channels. Deviations from predictions of phase-space controlled one-meson-exchange models are indications of new and exciting physics. Precision data on differential cross sections, isospin and spin observables -- partly but by no means adequately available -- are presently turning up on the horizon. There is work for the next years and excitement of the physics expected. Here we try to give a brief and at the same time comprehensive overview of this field of hadronic threshold production studies.Comment: 100 pages, Review article to be published in Prog. Part. Nucl. Phys. Vol. 49, issue 1 (2002

Resistant mutants of Mycobacterium tuberculosis selected in vitro do not reflect the in vivo mechanism of isoniazid resistance

The high prevalence of isoniazid-resistant Mycobacterium tuberculosis is often explained by a high mutation rate for this trait, although detailed information to support this theory is absent. We studied the development of isoniazid resistance in vitro, making use of a laboratory strain of M. tuberculosis. Spontaneous isoniazid-resistant mutants were characterized by molecular methods allowing identification of the most commonly encountered resistance-conferring mutations. Additionally, we determined the in vitro mutation rates for isoniazid and rifampicin resistance, and characterized the genome of a triple-resistant strain. Results confirm that the in vitro mutation rate for isoniazid resistance (3.2 x 10(-7) mutations/cell division) is much higher than the rate for rifampicin resistance (9.8 x 10(-9) mutations/cell division). However, in the majority of the in vitro mutants katG was partially or completely deleted and neither of the two most common in vivo mutations, katG-S315T or inhA-C(-)15T, were found in 120 isogenic mutants. This implies that clinically prevalent resistance mutations were present in <0.8% of isoniazid-resistant strains selected in vitro (95% CI 0%-2.5%). The triple-resistant strain had acquired isoniazid resistance via a 49 kbp deletion, which included katG. Apart from previously identified resistance-conferring mutations, three additional point mutations were acquired during sequential selection steps. These outcomes demonstrate that the in vivo mechanism of isoniazid resistance is not reflected by in vitro experiments. We therefore conclude that the high in vitro mutation rate for isoniazid resistance is not a satisfactory explanation for the fact that isoniazid monoresistance is significantly more widespread than monoresistance to rifampici

Technical Design Report for the PANDA Solenoid and Dipole Spectrometer Magnets

This document is the Technical Design Report covering the two large spectrometer magnets of the PANDA detector set-up. It shows the conceptual design of the magnets and their anticipated performance. It precedes the tender and procurement of the magnets and, hence, is subject to possible modifications arising during this process.Comment: 10 pages, 14MB, accepted by FAIR STI in May 2009, editors: Inti Lehmann (chair), Andrea Bersani, Yuri Lobanov, Jost Luehning, Jerzy Smyrski, Technical Coordiantor: Lars Schmitt, Bernd Lewandowski (deputy), Spokespersons: Ulrich Wiedner, Paola Gianotti (deputy

An Open-Label, Pragmatic, Randomized Controlled Clinical Trial to Evaluate the Comparative Effectiveness of Daptomycin Versus Vancomycin for the Treatment of Complicated Skin and Skin Structure Infection

Treatment of complicated skin and skin structure infection (cSSSI) places a tremendous burden on the health care system. Understanding relative resource utilization associated with different antimicrobials is important for decision making by patients, health care providers, and payers. Methods: The authors conducted an open-label, pragmatic, randomized (1:1) clinical study (N = 250) to compare the effectiveness of daptomycin with that of vancomycin for treatment of patients hospitalized with cSSSI caused by suspected or documented methicillin-resistant Staphylococcus aureus infection. The primary study end point was infection-related length of stay (IRLOS). Secondary end points included health care resource utilization, cost, clinical response, and patient-reported outcomes. Patient assessments were performed daily until the end of antibiotic therapy or until hospital discharge, and at 14 days and 30 days after discharge. Results: No difference was found for IRLOS, total LOS, and total inpatient cost between cohorts. Hospital LOS contributed 85.9 % to the total hospitalization cost, compared with 6.4 % for drug costs. Daptomycin showed a nonsignificant trend toward a higher clinical success rate, compared with vancomycin, at treatment days 2 and 3. In the multivariate analyses, vancomycin was associated with a lower likelihood of day 2 clinical success (odds ratio [OR] = 0.498, 95 % confidence interval [CI], 0.249-0.997; P < 0.05). Conclusion: This study did not provide conclusive evidence of the superiority of one treatment over the other in terms of clinical, economic, or patient outcomes. The data suggest that physician and patient preference, rather than drug acquisition cost, should be the primary driver of initial antibiotic selection for hospitalized patients with cSSSI.Merck & Co., Inc., Kenilworth, NJ USAKinesiology and Health Educatio

Pre-Existing Isoniazid Resistance, but Not the Genotype of Mycobacterium Tuberculosis Drives Rifampicin Resistance Codon Preference in Vitro

Both the probability of a mutation occurring and the ability of the mutant to persist will influence the distribution of mutants that arise in a population. We studied the interaction of these factors for the in vitro selection of rifampicin (RIF)-resistant mutants of Mycobacterium tuberculosis. We characterised two series of spontaneous RIF-resistant in vitro mutants from isoniazid (INH)-sensitive and -resistant laboratory strains and clinical isolates, representing various M. tuberculosis genotypes. The first series were selected from multiple parallel 1 ml cultures and the second from single 10 ml cultures. RIF-resistant mutants were screened by Multiplex Ligation-dependent Probe Amplification (MLPA) or by sequencing the rpoB gene. For all strains the mutation rate for RIF resistance was determined with a fluctuation assay. The most striking observation was a shift towards rpoB-S531L (TCG→TTG) mutations in a panel of laboratory-generated INH-resistant mutants selected from the 10-ml cultures (p<0.001). All tested strains showed similar mutation rates (1.33×10−8 to 2.49×10−7) except one of the laboratory-generated INH mutants with a mutation rate measured at 5.71×10−7, more than 10 times higher than that of the INH susceptible parental strain (5.46–7.44×10−8). No significant, systematic difference in the spectrum of rpoB-mutations between strains of different genotypes was observed. The dramatic shift towards rpoB-S531L in our INH-resistant laboratory mutants suggests that the relative fitness of resistant mutants can dramatically impact the distribution of (subsequent) mutations that accumulate in a M. tuberculosis population, at least in vitro. We conclude that, against specific genetic backgrounds, certain resistance mutations are particularly likely to spread. Molecular screening for these (combinations of) mutations in clinical isolates could rapidly identify these particular pathogenic strains. We therefore recommend that isolates are screened for the distribution of resistance mutations, especially in regions that are highly endemic for (multi)drug resistant tuberculosis

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe

Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification