A Randomized Exchange Algorithm for Computing Optimal Approximate Designs of Experiments

We propose a class of subspace ascent methods for computing optimal approximate designs that covers both existing as well as new and more efficient algorithms. Within this class of methods, we construct a simple, randomized exchange algorithm (REX). Numerical comparisons suggest that the performance of REX is comparable or superior to the performance of state-of-the-art methods across a broad range of problem structures and sizes. We focus on the most commonly used criterion of D-optimality that also has applications beyond experimental design, such as the construction of the minimum volume ellipsoid containing a given set of data-points. For D-optimality, we prove that the proposed algorithm converges to the optimum. We also provide formulas for the optimal exchange of weights in the case of the criterion of A-optimality. These formulas enable one to use REX for computing A-optimal and I-optimal designs.Comment: 23 pages, 2 figure

Pneumocystis Pneumonia: Immunity, Vaccines, and Treatments

For individuals who are immunocompromised, the opportunistic fungal pathogen Pneumocystis jirovecii is capable of causing life-threatening pneumonia as the causative agent of Pneumocystis pneumonia (PCP). PCP remains an acquired immunodeficiency disease (AIDS)-defining illness in the era of antiretroviral therapy. In addition, a rise in non-human immunodeficiency virus (HIV)-associated PCP has been observed due to increased usage of immunosuppressive and immunomodulating therapies. With the persistence of HIV-related PCP cases and associated morbidity and mortality, as well as difficult to diagnose non-HIV-related PCP cases, an improvement over current treatment and prevention standards is warranted. Current therapeutic strategies have primarily focused on the administration of trimethoprim-sulfamethoxazole, which is effective at disease prevention. However, current treatments are inadequate for treatment of PCP and prevention of PCP-related death, as evidenced by consistently high mortality rates for those hospitalized with PCP. There are no vaccines in clinical trials for the prevention of PCP, and significant obstacles exist that have slowed development, including host range specificity, and the inability to culture Pneumocystis spp. in vitro. In this review, we overview the immune response to Pneumocystis spp., and discuss current progress on novel vaccines and therapies currently in the preclinical and clinical pipeline

Oxidative killing of encapsulated and nonencapsulated Streptococcus pneumoniae by lactoperoxidase-generated hypothiocyanite.

Streptococcus pneumoniae (Pneumococcus) infections affect millions of people worldwide, cause serious mortality and represent a major economic burden. Despite recent successes due to pneumococcal vaccination and antibiotic use, Pneumococcus remains a significant medical problem. Airway epithelial cells, the primary responders to pneumococcal infection, orchestrate an extracellular antimicrobial system consisting of lactoperoxidase (LPO), thiocyanate anion and hydrogen peroxide (H2O2). LPO oxidizes thiocyanate using H2O2 into the final product hypothiocyanite that has antimicrobial effects against a wide range of microorganisms. However, hypothiocyanite's effect on Pneumococcus has never been studied. Our aim was to determine whether hypothiocyanite can kill S. pneumoniae. Bactericidal activity was measured in a cell-free in vitro system by determining the number of surviving pneumococci via colony forming units on agar plates, while bacteriostatic activity was assessed by measuring optical density of bacteria in liquid cultures. Our results indicate that hypothiocyanite generated by LPO exerted robust killing of both encapsulated and nonencapsulated pneumococcal strains. Killing of S. pneumoniae by a commercially available hypothiocyanite-generating product was even more pronounced than that achieved with laboratory reagents. Catalase, an H2O2 scavenger, inhibited killing of pneumococcal by hypothiocyanite under all circumstances. Furthermore, the presence of the bacterial capsule or lytA-dependent autolysis had no effect on hypothiocyanite-mediated killing of pneumococci. On the contrary, a pneumococcal mutant deficient in pyruvate oxidase (main bacterial H2O2 source) had enhanced susceptibility to hypothiocyanite compared to its wild-type strain. Overall, results shown here indicate that numerous pneumococcal strains are susceptible to LPO-generated hypothiocyanite

Does the MCAT predict medical school and PGY-1 performance?

© Association of Military Surgeons of the U.S. All rights reserved. Background: The Medical College Admissions Test (MCAT) is a high-stakes test required for entry to most U. S. medical schools; admissions committees use this test to predict future accomplishment. Although there is evidence that the MCAT predicts success on multiple choice–based assessments, there is little information on whether the MCAT predicts clinical-based assessments of undergraduate and graduate medical education performance. This study looked at associations between the MCAT and medical school grade point average (GPA), Medical Licensing Examination (USMLE) scores, observed patient care encounters, and residency performance assessments. Methods: This study used data collected as part of the Long-Term Career Outcome Study to determine associations between MCAT scores, USMLE Step 1, Step 2 clinical knowledge and clinical skill, and Step 3 scores, Objective Structured Clinical Examination performance, medical school GPA, and PGY-1 program director (PD) assessment of physician performance for students graduating 2010 and 2011. Results: MCAT data were available for all students, and the PGY PD evaluation response rate was 86.2% (N = 340). All permutations of MCAT scores (first, last, highest, average) were weakly associated with GPA, Step 2 clinical knowledge scores, and Step 3 scores. MCAT scores were weakly to moderately associated with Step 1 scores. MCAT scores were not significantly associated with Step 2 clinical skills Integrated Clinical Encounter and Communication and Interpersonal Skills subscores, Objective Structured Clinical Examination performance or PGY-1 PD evaluations. Discussion: MCAT scores were weakly to moderately associated with assessments that rely on multiple choice testing. The association is somewhat stronger for assessments occurring earlier in medical school, such as USMLE Step 1. The MCAT was not able to predict assessments relying on direct clinical observation, nor was it able to predict PD assessment of PGY-1 performance

Influenza virus strains used in this work.

<p>Influenza virus strains used in this work.</p

Hemagglutinin subtypes are associated with LPO substrate preference supporting IAV inactivation.

<p>Susceptibilities of tested IAV strains to OSCN^- and OI^- in the cell-free system were compared according to their types of (A) hemagglutinin (H1, H3) and (B) neuraminidase (N1, N2). “SCN^-/I^- substrate preference ratios” were also calculated as described in the text for all nine IAV strains and compared among HA and NA types (upper and lower right panels). Ns, non-significant, *, p<0.05. SCN^-, thiocyanate; OSCN^-, hypothiocyanite; I^-, iodide; OI^-, hypoiodite; LPO, lactoperoxidase; GO, glucose oxidase; HA, hemagglutinin; NA, neuraminidase. The gray area highlights the only significant difference in the figure.</p

The cell-free H₂O₂/LPO/(SCN^-/I^-) system inactivates A/Swine/Illinois/02860/2009 H1N2 influenza A virus.

<p>The antiviral action of the cell-free H₂O₂/LPO/(SCN^-/I^-) system was tested against the A/Swine/Illinois/02860/2009 (H1N2) influenza A virus. Viruses were incubated in the presence or absence of the components of the cell-free system as indicated for 1 hour when (A) SCN^- or (B) I^- was used as LPO substrate. Viral inactivation was assessed by plate-forming unit assay using MDCK cells. Mean+/-S.E.M., n = 4–5. (C) SCN^- and I^- dose-dependence of A/Swine/Illinois/02860/2009 inactivation. Mean+/-S.E.M., n = 3. One-way ANOVA, Tukey’ multiple comparison test. Ns, non-significant, **, p<0.01; ***, p<0.001. SCN^-, thiocyanate; OSCN^-, hypothiocyanite; I^-, iodide; OI^-, hypoiodite; LPO, lactoperoxidase; GO, glucose oxidase; MDCK, Madin-Darby canine kidney cells; PFU, plaque-forming unit.</p

LPO substrate preference of Influenza B virus inactivation is strain-dependent.

<p>(A) The antiviral action of the cell-free H₂O₂/LPO/(SCN^-/I^-) system was tested against influenza B strains: B/Yamagata/16/1988, B/Great Lakes/1739/1954 and B/New York/1056/2003. Viruses were incubated in the presence or absence of the components of the cell-free system as indicated for 1 hour and viral inactivation was assessed by plate-forming unit assay using MDCK cells. Mean+/-S.E.M., n = 5. One-way ANOVA, Dunn’s multiple comparison test. (B) B/Yamagata/16/1988 Virus inactivation was measured at increasing I^- concentrations (0.4–40 mM) in the cell-free system by the PFU assay. Mean+/-S.E.M., n = 5. One-way ANOVA, Dunn’s multiple comparison test. (C) The extents of IBV inactivation by OSCN^- and OI^- of the three strains tested were compared. Mean+/-S.E.M., Mann-Whitney test. Ns, not significant; *, p<0.05; **, p<0.01; ***, p<0.001. SCN^-, thiocyanate; OSCN^-, hypothiocyanite; I^-, iodide; OI^-, hypoiodite; LPO, lactoperoxidase; GO, glucose oxidase; MDCK, Madin-Darby canine kidney cells; PFU, plaque-forming unit; IBV, Influenza B virus.</p

Hypoiodite and hypothiocyanite are equally efficient in inactivating H1N1 influenza A viruses in the cell-free system.

<p>(A) The antiviral action of the cell-free H₂O₂/LPO/(SCN^-/I^-) system was tested against H1N1 influenza A strains, A/Brisbane/59/2007 (n = 3), A/California/04/2009 (n = 5), A/Mississippi/3/2001 (n = 4) and A/Turkey/Kansas/4880/1980 (n = 2). Viruses were incubated in the presence or absence of the components of the cell-free system as indicated for 1 hour and viral inactivation was assessed by plate-forming unit assay using MDCK cells. Mean+/-S.E.M. One-way ANOVA, Dunn’s multiple comparison test. (B) No significant difference can be observed in virus inactivation of the four H1N1 strains tested. Virus inactivation is calculated as the difference in viable viral titers between the sample containing the cell-free system and the sample containing the full, cell-free system plus catalase. Mean+/-S.E.M., n = 2–5. Mann-Whitney test. Ns, non-significant, *, p<0.05; **, p<0.01; ***, p<0.001. SCN^-, thiocyanate; OSCN^-, hypothiocyanite; I^-, iodide; OI^-, hypoiodite; LPO, lactoperoxidase; GO, glucose oxidase; MDCK, Madin-Darby canine kidney cells; PFU, plaque-forming unit; IAV, Influenza A virus.</p

Susceptibility of influenza viruses to hypothiocyanite and hypoiodite produced by lactoperoxidase in a cell-free system - Fig 7

<p><b>Comparison of influenza A and B strains for their susceptibilities to the virucidal effects of LPO.</b> The nine IAV and three IBV influenza strains tested were compared regarding their susceptibilities to OSCN^- (left panel), to OI^- (middle panel) or their LPO substrate preference ratios (right panel) in the cell-free system. This figure does not show new experimental data but presents new analysis of experimental results obtained in Figs <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0199167#pone.0199167.g002" target="_blank">2</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0199167#pone.0199167.g006" target="_blank">6</a>. The gray area highlights the only significant difference in the figure. Mean+/-S.E.M., Mann-Whitney test. Ns, not significant; *, p<0.05. OSCN^-, hypothiocyanite; OI^-, hypoiodite; IAV, influenza A virus; IBV, influenza B virus.</p