Towards new business models for R&D for novel antibiotics.

In the face of a growing global burden of resistance to existing antibiotics, a combination of scientific and economic challenges has posed significant barriers to the development of novel antibacterials over the past few decades. Yet the bottlenecks at each stage of the pharmaceutical value chain-from discovery to post-marketing-present opportunities to reengineer an innovation pipeline that has fallen short. The upstream hurdles to lead identification and optimization may be eased with greater multi-sectoral collaboration, a growing array of alternatives to high-throughput screening, and the application of open source approaches. Product development partnerships and South-South innovation platforms have shown promise in bolstering the R&D efforts to tackle neglected diseases. Strategies that delink product sales from the firms' return on investment can help ensure that the twin goals of innovation and access are met. To effect these changes, both public and private sector stakeholders must show greater commitment to an R&D agenda that will address this problem, not only for industrialized countries but also globally.

Safety and efficacy of erythropoietin in traumatic brain injury patients: a pilot randomized trial.

Background. Erythropoietin (EPO) is a neuroprotective agent utilized in stroke patients. This pilot study represents the first randomized trial of EPO in traumatic brain injury (TBI) patients. Methods. Adult, blunt trauma patients with evidence of TBI were randomized to EPO or placebo within 6 hours of injury. Baseline and daily serum S-100B and Neuron Specific Enolase (NSE) levels were measured. Results. TBI was worse in the EPO (n = 11) group compared to placebo patients (n = 5). The use of EPO did not impact NSE (P = .89) or S100 B (P = .53) levels compared to placebo. Conclusions. At the dose used, EPO did not reduce neuronal cell death compared to placebo; however, TBI severity was worse in the EPO group while levels of NSE and S100-B were similar to the less injured placebo group making it difficult to rule out a treatment effect. A larger, balanced study is necessary to confirm a potential treatment effect.

Skin and soft tissue infections in hospitalised patients with diabetes: culture isolates and risk factors associated with mortality, length of stay and cost.

AIMS/HYPOTHESIS: Skin and soft tissue infections (SSTIs) cause substantial morbidity in persons with diabetes. There are few data on pathogens or risk factors associated with important outcomes in diabetic patients hospitalised with SSTIs. METHODS: Using a clinical research database from CareFusion, we identified 3,030 hospitalised diabetic patients with positive culture isolates and a diagnosis of SSTI in 97 US hospitals between 2003 and 2007. We classified the culture isolates and analysed their association with the anatomic location of infection, mortality, length of stay and hospital costs. RESULTS: The only culture isolate with a significantly increased prevalence was methicillin-resistant Staphylococcus aureus (MRSA); prevalence for infection of the foot was increased from 11.6 to 21.9% (p < 0.0001) and for non-foot locations from 14.0% to 24.6% (p = 0.006). Patients with non-foot (vs foot) infections were more severely ill at presentation and had higher mortality rates (2.2% vs 1.0%, p < 0.05). Significant independent risk factors associated with higher mortality rates included having a polymicrobial culture with Pseudomonas aeruginosa (OR 3.1), a monomicrobial culture with other gram-negatives (OR 8.9), greater illness severity (OR 1.9) and being transferred from another hospital (OR 5.1). These factors and need for major surgery were also independently associated with longer length of stay and higher costs. CONCLUSIONS/INTERPRETATION: Among diabetic patients hospitalised with SSTI from 2003 to 2007, only MRSA increased in prevalence. Patients with non-foot (vs foot) infections were more severely ill. Independent risk factors for increased mortality rates, length of stay and costs included more severe illness, transfer from another hospital and wound cultures with Pseudomonas or other gram-negatives.

Periodontal status and preterm low birth weight: a case control study.

BACKGROUND: Previous studies have suggested that periodontal disease may be an important risk factor for preterm low birth weight. However, the link between periodontal health status of pregnant women and preterm low birth weight is contentious, as recent studies found no association between periodontitis and pregnancy outcome. OBJECTIVE: The aim of this study was to investigate this potential link in a German Caucasian population. METHODS: Fifty-nine pregnant women with a high risk for a preterm low birth weight infant (suffering from preterm contractions, cases, group 1) as well as 42 control women with no preterm contractions during pregnancy and having an infant appropriate for date and weight (>or= 37 weeks gestation, >or= 2500 g, group 2) were examined. Clinical periodontal status was recorded on a full mouth basis. Subgingival plaque samples were taken and periodontal pathogens were identified by polymerase chain reaction. Additionally, interleukin-1 beta level in gingival crevicular fluid was analysed. RESULTS: The mean percentage of sites showing moderate to advanced attachment loss (>or=3 mm) was low in all study groups (group 1: 9.9 +/- 11.2%; group 2:10.6 +/- 14.1%, respectively). No significant differences between the groups in any aspects of the studied periodontitis parameters could be detected. Using a logistic regression model controlling for known preterm low birth weight risk factors, no periodontitis-associated factors increased risk for preterm contractions or preterm low birth weight. The odds ratio (OR) was 1.19 for preterm contractions, the 95% confidence interval (CI) 0.46; 3.11 and 0.73 for preterm low birth weight; 95% CI: 0.13; 4.19, respectively. CONCLUSION: In this population, periodontitis was not a detectable risk factor for preterm low birth weight in pregnant women.

In vitro evaluation of the antibacterial activity of three different central venous catheters against gram-positive bacteria.

The aim of this study was to evaluate the activity of three different catheters against Staphylococcus aureus ATCC 29213 and the slime-producing Staphylococcus epidermidis ATCC 35984 (RP62A). Three central venous catheters were evaluated: one impregnated with silver sulfadiazine-chlorhexidine, one to which minocycline/rifampin is bonded and a novel one into which silver, platinum and carbon are incorporated. A nonantiseptic catheter was used as the control catheter. One-centimeter trisected pieces of catheter were immersed in phosphate-buffered saline (0.01 mol/l) with 0.25% dextrose and incubated. On days 1, 3, 7, 14 and 21, a 1 ml standardized inoculum was added for 30 min and then replaced with phosphate-buffered saline with 0.25% dextrose. One-third of the samples were immediately sonicated and plated to determine bacterial adherence. The remaining segments were incubated for 4 and 24 h to determine the persistence of bacterial adherence. Bacterial adherence to the catheters impregnated with silver sulfadiazine-chlorhexidine was reduced 91-98% for the first 7 days. Adherence of Staphylococcus aureus to catheters into which silver, platinum and carbon are incorporated was reduced 70% on day 1 and 35% on day 3. Adherence to minocycline/rifampin-bonded catheters was quite variable. There was an 85.6-99.8% reduction in the persistence of bacterial adherence to the three catheters compared to controls. Bacteriostatic and bactericidal studies indicated that the effluents from the catheters impregnated with silver sulfadiazine-chlorhexidine were bactericidal, while effluents from the minocycline/rifampin-bonded catheters were bacteriostatic. The antibacterial activity of the effluents from catheters impregnated with silver sulfadiazine-chlorhexidine dissipated by day 7, while the activity of effluents from the minocycline/rifampin-bonded catheters continued to show activity at day 21. No measurable antibacterial activity was detected in the effluents of the catheters into which silver, platinum and carbon are incorporated. These data suggest that catheters coated with antibiotic/antibacterial agents and the novel catheters that incorporate antiseptic agents have different activities against initial bacterial adherence. All of them, however, effectively prevent bacterial colonization by gram-positive bacteria.

NMR structure of the LCCL domain and implications for DFNA9 deafness disorder.

The LCCL domain is a recently discovered, conserved protein module named after its presence in Limulus factor C, cochlear protein Coch-5b2 and late gestation lung protein Lgl1. The LCCL domain plays a key role in the autosomal dominant human deafness disorder DFNA9. Here we report the nuclear magnetic resonance (NMR) structure of the LCCL domain from human Coch-5b2, where dominant mutations leading to DFNA9 deafness disorder have been identified. The fold is novel. Four of the five known DFNA9 mutations are shown to involve at least partially solvent-exposed residues. Except for the Trp91Arg mutant, expression of these four LCCL mutants resulted in misfolded proteins. These results suggest that Trp91 participates in the interaction with a binding partner. The unexpected sensitivity of the fold with respect to mutations of solvent-accessible residues might be attributed to interference with the folding pathway of this disulfide-containing domain.

Solution structure of the DNA binding domain of the human forkhead transcription factor AFX (FOXO4).

AFX is a human forkhead transcription factor. Based on results from studies of the orthologous transcription factor DAF-16 in Caenorhabditis elegans, it was suggested that some of the metabolic defects in both type I and type II diabetes may be due to unregulated activity of AFX. In the present study, we report the high-resolution NMR solution structure of the DNA binding domain of AFX. It is the first structure of the DNA binding domain from a small subfamily of forkhead transcription factors (i.e., AFX, FKHR, FKHRL1, FKHRL1P1, and FKHRP1). Despite rather low sequence identity for a protein within the forkhead family, the structure is remarkably similar to those of the DNA binding domains of HNF3-gamma and FREAC-11, and to a lesser extent the DNA binding domain of Genesis which displays a slightly altered orientation of the DNA recognition helix. The high degree of structural similarity between the DNA binding domains of different forkhead transcription factors implies that the repositioning of helix 3, observed for Genesis, cannot be a general feature for modulation of the DNA binding specificity. Other mechanisms that could influence the DNA binding specificity are discussed.

An objective analysis of process errors in trauma resuscitations.

OBJECTIVE: A computer-based system to apply trauma resuscitation protocols to patients with penetrating thoracoabdominal trauma was previously validated for 97 consecutive patients at a Level 1 trauma center by a panel of the trauma attendings and further refined by a panel of national trauma experts. The purpose of this article is to describe how this system is now used to objectively critique the actual care given to those patients for process errors in reasoning, independent of outcome. METHODS: A chronological narrative of the care of each patient was presented to the computer program. The actual care was compared with the validated computer protocols at each decision point and differences were classified by a predetermined scoring system from 0 to 100, based on the potential impact on outcome, as critical/noncritical/no errors of commission, omission, or procedure selection. RESULTS: Errors in reasoning occurred in 100% of the 97 cases studied, averaging 11.9/case. Errors of omission were more prevalent than errors of commission (2. 4 errors/case vs 1.2) and were of greater severity (19.4/error vs 5. 1). The largest number of errors involved the failure to record, and perhaps observe, beside information relevant to the reasoning process, an average of 7.4 missing items/patient. Only 2 of the 10 adverse outcomes were judged to be potentially related to errors of reasoning. CONCLUSIONS: Process errors in reasoning were ubiquitous, occurring in every case, although they were infrequently judged to be potentially related to an adverse outcome. Errors of omission were assessed to be more severe. The most common error was failure to consider, or document, available relevant information in the selection of appropriate care.

Prediction of outcome in intensive care unit trauma patients: a multicenter study of Acute Physiology and Chronic Health Evaluation (APACHE), Trauma and Injury Severity Score (TRISS), and a 24-hour intensive care unit (ICU) point system.

OBJECTIVE: To conduct a multicenter study to validate the accuracy of the Acute Physiology and Chronic Health Evaluation (APACHE) II system, APACHE III system, Trauma and Injury Severity Score (TRISS) methodology, and a 24-hour intensive care unit (ICU) point system for prediction of mortality in ICU trauma patient admissions. METHODS: The study population consisted of retrospectively identified, consecutive ICU trauma admissions (n = 2,414) from six Level I trauma centers. Probabilities of death were calculated by using logistic regression analysis. The predictive power of each system was evaluated by using decision matrix analysis to compare observed and predicted outcomes with a decision criterion of 0.50 for risk of hospital death. The Youden Index (YI) was used to compare the proportion of patients correctly classified by each system. Measures of model calibration were based on goodness-of-fit testing (Hosmer-Lemeshow statistic less than 15.5) and model discrimination were based on the area under the receiver operating characteristic curve (AUC). RESULTS: Overall, APACHE II (sensitivity, 38%; specificity, 99%; YI, 37%; H-L statistic, 92.6; AUC, 0.87) and TRISS (sensitivity, 52%; specificity, 94%; YI, 46%; H-L statistic, 228.1; AUC, 0.82) were poor predictors of aggregate mortality, because they did not meet the acceptable thresholds for both model calibration and discrimination. APACHE III (sensitivity, 60%; specificity, 98%; YI, 58%; H-L statistic, 7.0; AUC, 0.89) was comparable to the 24-hour ICU point system (sensitivity, 51%; specificity, 98%; YI, 50%; H-L statistic, 14.7; AUC, 0.89) with both systems showing strong agreement between the observed and predicted outcomes based on acceptable thresholds for both model calibration and discrimination. The APACHE III system significantly improved upon APACHE II for estimating risk of death in ICU trauma patients (p < 0.001). Compared with the overall performance, for the subset of patients with nonoperative head trauma, the percentage correctly classified was decreased to 46% for APACHE II; increased to 71% for APACHE III (p < 0.001 vs. APACHE II); increased to 59% for TRISS; and increased to 62% for 24-hour ICU points. For operative head trauma, the percentage correctly classified was increased to 60% for APACHE II; increased to 61% for APACHE III; decreased to 43% for TRISS (p < 0.004 vs. APACHE III); and increased to 54% for 24-hour ICU points. For patients without head injuries, all of the systems were unreliable and considerably underestimated the risk of death. The percentage of nonoperative and operative patients without head trauma who were correctly classified was decreased, respectively, to 26% and 30% for APACHE II; 33% and 29% for APACHE III; 33% and 19% for TRISS; 20% and 23% for 24-hour ICU points. CONCLUSION: For the overall estimation of aggregate ICU mortality, the APACHE III system was the most reliable; however, performance was most accurate for subsets of patients with head trauma. The 24-hour ICU point system also demonstrated acceptable overall performance with improved performance for patients with head trauma. Overall, APACHE II and TRISS did not meet acceptable thresholds of performance. When estimating ICU mortality for subsets of patients without head trauma, none of these systems had an acceptable level of performance. Further multicenter studies aimed at developing better outcome prediction models for patients without head injuries are warranted, which would allow trauma care providers to set uniform standards for judging institutional performance.

ATLS: a foundation for trauma training.

The Advanced Trauma Life Support (ATLS) course is sponsored by the American College of Surgeons Committee on Trauma. This course was developed to provide a consistent method of care for the resuscitation and evaluation of the injured patient. The ATLS course provides an easily remembered method for evaluating and treating the victim of a traumatic event. It also provides a scaffold for evaluation, treatment, education, and quality improvement of our ability to provide quality medical care to our patients. This article chronicles the past, present, and future of ATLS. The process of revising the ATLS course is reviewed. The changes recently introduced in the sixth edition of the ATLS course are highlighted. The worldwide growth of ATLS is acknowledged. The strength of this educational course remains the commitment to our primary goal of optimal care for the injured patient.

NMR structure of the N-terminal domain of E. coli DnaB helicase: implications for structure rearrangements in the helicase hexamer.

BACKGROUND: DnaB is the primary replicative helicase in Escherichia coli. Native DnaB is a hexamer of identical subunits, each consisting of a larger C-terminal domain and a smaller N-terminal domain. Electron-microscopy data show hexamers with C6 or C3 symmetry, indicating large domain movements and reversible pairwise association. RESULTS: The three-dimensional structure of the N-terminal domain of E. coli DnaB was determined by nuclear magnetic resonance (NMR) spectroscopy. Structural similarity was found with the primary dimerisation domain of a topoisomerase, the gyrase A subunit from E. coli. A monomer-dimer equilibrium was observed for the isolated N-terminal domain of DnaB. A dimer model with C2 symmetry was derived from intermolecular nuclear Overhauser effects, which is consistent with all available NMR data. CONCLUSIONS: The monomer-dimer equilibrium observed for the N-terminal domain of DnaB is likely to be of functional significance for helicase activity, by participating in the switch between C6 and C3 symmetry of the helicase hexamer.

Oral contrast solution and computed tomography for blunt abdominal trauma: a randomized study.

HYPOTHESIS: Oral contrast solution (OC) is unnecessary in the acute computed tomographic (CT) evaluation of the patient with blunt abdominal trauma. DESIGN: Randomized controlled clinical trial. SETTING: Level I trauma center at a university-affiliated teaching hospital. PATIENTS: Five hundred adult patients sustaining blunt abdominal trauma and requiring urgent resuscitation and CT evaluation of the abdomen were eligible for the study. Those patients who were younger than 18 years, pregnant, or in police custody were excluded. One hundred six patients were excluded from the analysis (15 for inappropriate enrollment, 9 because a CT scan had not been performed, 1 owing to inability to accept a nasogastric tube, and 81 owing to missing or incomplete records). Three hundred ninety-four patients with an average age of 36 years, an average Revised Trauma Score of 10, and an average Glasgow Coma Scale score of 12 are included in the analysis. INTERVENTIONS: Patients were randomized via computer-generated assignment to 1 of 2 groups either receiving OC or not receiving OC (no OC) after placement of a nasogastric tube. All patients received intravenous contrast solution and then underwent helical CT scan of the abdomen and pelvis using the GE HiSpeed Advantage CT scanner (GE Medical Systems, Milwaukee, Wis). MAIN OUTCOME MEASURES: Abnormal CT results, need for laparotomy, missed gastrointestinal tract and solid organ injuries, nausea, and vomiting. RESULTS: There were 199 patients in the OC group and 195 patients in the no OC group. Vomiting occurred in 12.9% of patients and the incidence was not different between groups. One hundred five abnormal scans (50 OC and 55 no OC) were obtained and 33 patients with abnormal scans (19 OC and 14 no OC) underwent laparotomy. There was 1 nontherapeutic laparotomy in each group. There was 1 missed small-bowel injury in the OC group (sensitivity, 86%) and no missed small-bowel injuries in the no OC group (sensitivity, 100%). Six bowel injuries were identified at laparotomy in the OC group. Two of the injuries were perforations without contrast extravasation but with pneumoperitoneum in 1. Three bowel injuries were identified in the no OC group, none of which were perforations. Seven of the 9 patients with bowel injury at laparotomy had associated intra-abdominal injury. Specificity for solid organ injury was 94% in the OC group and 57.1% in the no OC group. Sensitivity for solid organ injury was 84.2% in the OC group and 88.9% in the no OC group. The average time to abdominal CT scanning after placement of a nasogastric tube was 39.02+/-18.73 minutes in the no OC group and 45.92+/-24.17 minutes in the OC group (P= .008). CONCLUSION: The addition of OC to the acute CT protocol for the evaluation of the patient with blunt abdominal trauma is unnecessary and delays time to CT scanning.

Treatment of occult pneumothoraces from blunt trauma.

BACKGROUND: Occult pneumothoraces (OPTXs) are seen on abdominal computed tomographic (CT) scans but not on routine chest x-ray films. Optimal treatment for blunt trauma OPTXs has not been defined. We hypothesized that OPTXs could be safely observed without need for a chest tube (CT). METHODS: A prospective trial randomized blunt trauma patients with OPTXs to CT scan or observation. Patients were not excluded for positive pressure ventilation. Primary outcome measures were respiratory distress and pneumothoraces progression. RESULTS: Thirty-nine patients with 44 pneumothoraces were enrolled. Eighteen patients received a CT scan, and 21 patients were observed. Nine patients in each group received positive pressure ventilation. There was no difference in overall complication rate. No patient had respiratory distress related to the OPTX or required emergent CT scan. CONCLUSIONS: Observation of OPTX is not associated with an increased incidence of pneumothorax progression or respiratory distress. These pneumothoraces can be safely observed in patients with blunt trauma injury regardless of the need for positive pressure ventilation.

Management of penetrating colon trauma: a cost-utility analysis.

BACKGROUND: Management of penetrating colon injuries in the presence of multiple associated risk factors is controversial. Issues not considered in previous management strategies are patient perception of quality of life with a colostomy and the true cost of each therapeutic option, which includes colostomy supplies and costs of colostomy takedown. To evaluate these issues, we performed a cost-utility analysis. METHODS: We constructed a decision tree with 3 options: primary repair, resection and anastomosis, and colostomy. Chance and decision nodes on each decision branch represent injury severity, complications, colostomy takedown, and death. Chance node frequencies and utility assignments were taken from published data. We obtained actual costs for all components of perioperative care. The outcomes reported are cost and quality of life. RESULTS: Colostomy has the least quality of life and the greatest cost. Primary repair and resection each dominate colostomy in the baseline analysis. No variable significantly altered these conclusions in sensitivity analyses. CONCLUSIONS: Simple suture or resection and anastomosis at the time of initial exploration is the dominant management method for penetrating colon trauma. It also demonstrates the trade-off between cost and life expectancy of the 3 management options.

Spin-state selection filters for the measurement of heteronuclear one-bond coupling constants.

Novel alpha/beta-half-filter elements are proposed for the separation of the high-field and low-field component of 1JHC and 1JHN splittings into different subspectra. The alpha/beta-half-filter elements are of the same duration as the S3CT pulse sequence element and, like this, are less sensitive to cross talk between different subspectra than the original shorter alpha/beta-half-filters. The filter elements are demonstrated with the measurement of 1JHC coupling constants of C alpha H groups in 2D and 3D experiments and the subspectral editing of the four different multiplet components observed in two-dimensional alpha/beta-HSQC-alpha/beta spectra recorded without heteronuclear decoupling in either dimension.

Dedicated operating room for trauma: a costly recommendation.

BACKGROUND: A dedicated operating room (OR) for urgent trauma cases is suggested by the American College of Surgeons Committee on Trauma as a necessary component of a Level I or II trauma center. We describe a cost analysis of this recommendation. METHODS: Two models for staffing urgent trauma cases were constructed. Urgent trauma cases were defined as those taken to the OR within 30 minutes of arrival. In one model the OR was available 24 hours a day with in-hospital personnel. The second model used an out-of-hospital call schedule, assuming a patient-ready OR in 30 minutes. Costs and revenue per urgent case were calculated. A break-even analysis shows the number of cases required for costs to equal revenue. RESULTS: In the 24-hour model, the cost/urgent case is $14,288; in the call-schedule model $3,243. The number of cases to break even in the 24-hour model is 1210; in the call-schedule model 375. CONCLUSIONS: A call-schedule model is the least costly way to staff an OR for urgent trauma cases.