Discovery of VNRX-7145 (VNRX-5236 Etzadroxil): An Orally Bioavailable ß-Lactamase Inhibitor for Enterobacterales Expressing Ambler Class A, C, and D Enzymes.

A major antimicrobial resistance mechanism in Gram-negative bacteria is the production of ß-lactamase enzymes. The increasing emergence of ß-lactamase-producing multi-drug-resistant "superbugs" has resulted in increases in costly hospital Emergency Department (ED) visits and hospitalizations due to the requirement for parenteral antibiotic therapy for infections caused by these difficult-to-treat bacteria. To address the lack of outpatient treatment, we initiated an iterative program combining medicinal chemistry, biochemical testing, microbiological profiling, and evaluation of oral pharmacokinetics. Lead optimization focusing on multiple smaller, more lipophilic active compounds, followed by an exploration of oral bioavailability of a variety of their respective prodrugs, provided 36 (VNRX-7145/VNRX-5236 etzadroxil), the prodrug of the boronic acid-containing ß-lactamase inhibitor 5 (VNRX-5236). In vitro and in vivo studies demonstrated that 5 restored the activity of the oral cephalosporin antibiotic ceftibuten against Enterobacterales expressing Ambler class A extended-spectrum ß-lactamases, class A carbapenemases, class C cephalosporinases, and class D oxacillinases.

Dance exposure, wellbeing and injury in collegiate Irish and contemporary dancers: A prospective study.

OBJECTIVES: Dance exposure and determinants of wellness in Irish dance (ID) and contemporary dance (CD) are under-investigated in pre-professional, collegiate cohorts. This study prospectively investigated these variables in ID and CD participants for one year. DESIGN: Prospective study. SETTING: University-level institutes of dance, United Kingdom (UK) and Ireland. PARTICIPANTS: Fifty (ID = 21, CD = 29) full time students of dance at Trinity Laban Conservatoire of Music and Dance, (UK) and the University of Limerick, Ireland. MAIN OUTCOME MEASURES: Weekly hours of dance, general health, sleep quality, injury defined as "any pain or injury that impacted upon their ability to dance". RESULTS: Dance exposure varied considerably for both genres across the year. CD participants danced for more hours weekly (p < 0.001). Overall injury incidence (time-loss and non-time-loss) was 10.6 and 8.4 injuries per 1000 h dancing for ID and CD groups respectively. 70.4% of injuries were non-time-loss. Better sleep (p = 0.007) and general health (p < 0.001) scores were negatively correlated with days lost/impacted by injury. CD participants reported a significantly higher dance exposure in the week prior to a time-loss injury than during the previous four weeks (p = 0.044). CONCLUSIONS: Dance exposure is erratic in these cohorts with dancers frequently performing when injured. Poor sleep, general health, and increased dance exposure may be associated with injury.

Red blood cell transfusion: a clinical practice guideline from the AABB*.

DESCRIPTION: Although approximately 85 million units of red blood cells (RBCs) are transfused annually worldwide, transfusion practices vary widely. The AABB (formerly, the American Association of Blood Banks) developed this guideline to provide clinical recommendations about hemoglobin concentration thresholds and other clinical variables that trigger RBC transfusions in hemodynamically stable adults and children. METHODS: These guidelines are based on a systematic review of randomized clinical trials evaluating transfusion thresholds. We performed a literature search from 1950 to February 2011 with no language restrictions. We examined the proportion of patients who received any RBC transfusion and the number of RBC units transfused to describe the effect of restrictive transfusion strategies on RBC use. To determine the clinical consequences of restrictive transfusion strategies, we examined overall mortality, nonfatal myocardial infarction, cardiac events, pulmonary edema, stroke, thromboembolism, renal failure, infection, hemorrhage, mental confusion, functional recovery, and length of hospital stay. RECOMMENDATION 1: The AABB recommends adhering to a restrictive transfusion strategy (7 to 8 g/dL) in hospitalized, stable patients (Grade: strong recommendation; high-quality evidence). RECOMMENDATION 2: The AABB suggests adhering to a restrictive strategy in hospitalized patients with preexisting cardiovascular disease and considering transfusion for patients with symptoms or a hemoglobin level of 8 g/dL or less (Grade: weak recommendation; moderate-quality evidence). RECOMMENDATION 3: The AABB cannot recommend for or against a liberal or restrictive transfusion threshold for hospitalized, hemodynamically stable patients with the acute coronary syndrome (Grade: uncertain recommendation; very low-quality evidence). RECOMMENDATION 4: The AABB suggests that transfusion decisions be influenced by symptoms as well as hemoglobin concentration (Grade: weak recommendation; low-quality evidence).

Plasma components: properties, differences, and uses.

General use of plasma components includes replacement for multiple coagulation factor deficiencies, for treatment of single coagulation factor deficiencies for which a concentrate is unavailable, and as a replacement fluid used in therapeutic plasma exchange for thrombotic thrombocytopenic purpura. Four major products currently transfused are fresh-frozen plasma (FFP), plasma frozen within 24 hours of phlebotomy (FP24), cryoprecipitate-poor plasma (CPP), and thawed plasma. FP24, CPP, and thawed plasma contain decreased amounts of labile coagulation factors. Pathogen reduction technology has included solvent/detergent, methylene blue, and ultraviolet light irradiation with psoralen or riboflavin treatment and is available in Europe but not in the United States. Pathogen-reduced plasma may contain reduced levels of certain coagulant and/or anticoagulant factors compared to FFP. Clinical findings with pathogen-reduced plasma have provided an impetus to the US Food and Drug Administration to promulgate specific requirements for approval of novel plasma products, some of which may be too burdensome for the industry to readily overcome.

Performance evaluation of the Bio-Rad Laboratories GS HIV Combo Ag/Ab EIA, a 4th generation HIV assay for the simultaneous detection of HIV p24 antigen and antibodies to HIV-1 (groups M and O) and HIV-2 in human serum or plasma.

BACKGROUND: A multi-center study was conducted to evaluate the Bio-Rad GS HIV Combo Ag/Ab EIA, a 4th generation HIV-1/HIV-2 assay for the simultaneous detection of HIV p24 antigen and antibodies to HIV-1 (groups M and O) and HIV-2 in human serum or plasma in adult and pediatric populations. OBJECTIVES: The objectives of the study were to assess assay performance for the detection of acute HIV infections; sensitivity in known HIV positive samples; percent agreement with HIV status; specificity in low and high risk individuals of unknown HIV status; and to compare assay performance to a 3rd generation HIV assay. STUDY DESIGN: The evaluation included testing 9150 samples at four U.S. clinical trial sites, using three kit lots. Unlinked samples were from routine testing, repositories or purchased from vendors. RESULTS: GS HIV Combo Ag/Ab EIA detection in samples from individuals in two separate populations with acute HIV infection was 95.2% (20/21) and 86.4% (38/44). Sensitivity was 100% (1603/1603) in known antibody positive [HIV-1 Groups M and O, and HIV-2] samples. HIV p24 antigen detection was 100% (53/53) in HIV-1 culture supernatants. HIV-1 seroconversion panel detection improved by a range of 0-20 days compared to a 3rd generation HIV test. Specificity was 99.9% (5989/5996) in low risk, 99.9% (959/960) in high risk and 100% (100/100) in pediatric populations. CONCLUSION: The GS HIV Combo Ag/Ab EIA significantly reduced the diagnostic window when compared to the 3rd generation screening assay, enabling earlier diagnosis of HIV infection. The performance parameters of the Bio-Rad GS HIV Combo Ag/Ab EIA are well suited for use in HIV diagnostic settings.

Prospective Aspergillus galactomannan antigen testing in pediatric hematopoietic stem cell transplant recipients.

BACKGROUND: The galactomannan (GM) assay is an approved noninvasive test for detection of invasive aspergillosis (IA) that has been validated in adult patients with hematologic malignancies who are undergoing bone marrow transplantation. There have been few studies with this assay in pediatric patients, but early reports suggest that there may be differences in the performance such that false-positive GM tests in pediatric patients are more common than in adult patients. METHODS: We performed a prospective study in pediatric hematopoietic stem cell transplant recipients with twice-weekly sampling for GM detection during the highest risk periods of neutropenia and graft-versus-host disease. We analyzed 826 serum samples from 64 patients, including 15 serum samples from one patient diagnosed with probable IA according to defined criteria. RESULTS: Twenty of 811 samples tested positive on repeat testing (specificity, 97.5%; 95% CI: 96.2-98.4%) including samples from 8 of 63 patients without clinical evidence of IA according to study criteria (specificity, 87.3%; 95% CI: 76.9-93.4%). Eleven patients received piperacillin/tazobactam therapy, and 4 of the 11 patients had a positive assay result coinciding with the dates of piperacillin/tazobactam administration. When samples from these patients were excluded, specificity increased to 98.4% (95% CI: 97.2-99.1%) by sample and to 91.5% (95% CI: 81.6-96.3%) by patient. CONCLUSIONS: The GM assay holds promise for early, noninvasive diagnosis of IA in high-risk children and false-positive results were not common or unexplainable. This study supports further validation of this assay in a large-scale, pediatric-dedicated format.

Aspergillus galactomannan antigen in the bronchoalveolar lavage fluid for the diagnosis of invasive aspergillosis in lung transplant recipients.

BACKGROUND: The clinical utility of Platelia Aspergillus enzyme immunoassay (EIA) for galactomannan (GM) antigen detection in bronchoalveolar lavage (BAL) for the diagnosis of invasive aspergillosis (IA) in lung transplant recipients is not known. METHODS: BAL fluid samples from consecutive lung transplant recipients who underwent bronchoscopy were prospectively analyzed for GM. RESULTS: A total of 333 BAL samples from 116 patients were tested. Invasive aspergillosis was documented in 5.2% (6/116) of the patients. Samples analyzed included 9 BALs from two patients with proven IA, 19 BALs from four patients with probable IA, and 305 BALs from 110 patients without IA. At the index cutoff value of > or =0.5, the sensitivity was 60%; specificity was 95%, with positive and negative likelihood ratios of 14 and 0.41, respectively. Increasing the index cutoff value to > or =1.0 yielded a sensitivity of 60%, a specificity of 98%, and the positive and negative likelihood ratios of 28 and 0.40, respectively. Two of six patients with IA receiving antifungal prophylaxis had false-negative results. CONCLUSIONS: A Platelia EIA index cut-off > or =1.0 in the BAL fluid in a lung transplant recipient with a compatible clinical illness may be considered as suggestive of IA.

Detection of galactomannan antigenemia by enzyme immunoassay for the diagnosis of invasive aspergillosis: variables that affect performance.

Invasive aspergillosis (IA) is a frequent complication of blood or marrow transplantation. Previous studies have reported that the Aspergillus galactomannan enzyme immunoassay (GM EIA) may be a useful diagnostic tool for IA, but its sensitivity is variable. We examined the performance of the GM EIA in 986 serum samples from 67 patients. Results demonstrated that decreasing the index cutoff for positivity to 0.5 increased its sensitivity, with minimal loss of specificity. The low cutoff increased the duration of test positivity before diagnosis by clinical means. Sensitivity was highest in patients who did not receive preventative mold-active antifungals (87.5%). A rabbit model demonstrated that the level of circulating antigen correlated with the tissue fungus burden. A quantifiable response to antifungal therapy in clinical samples and the rabbit model supports the development of this assay for early diagnosis and therapeutic monitoring. The 0.5 cutoff may allow for better performance as an early diagnostic test.