Let’s Be Reasonable: Why Neither Nollan/Dolan nor Penn Central Should Govern Generally-Applied Legislative Exactions After Koontz

This article explains why the Nollan/Dolan test should not apply to legislatively imposed exactions, provided that such exactions satisfy two key criteria: (1) the exaction is generally-applied; and (2) the exaction is applied based on a set legislative formula without any meaningful administrative discretion in that application. Legislative exactions that fail to meet those two criteria should be governed by the Nollan/Dolan standard of review in the same manner as the ad hoc adjudicative exaction in Koontz. Furthermore, legislative exactions that satisfy those two criteria also should not be governed by the factored analysis in Penn Central Transportation Co. v. New York City. Instead, a “reasonable relationship” test should be applied to legislative exactions that satisfy those two criteria. Part II of this Article discusses the constitutional rationales that guided the Court in reaching its decision in Koontz regarding adjudicative monetary exactions. Part III examines how those rationales, as well as the arguments raised by the Koontz dissent, demonstrate that Nollan/Dolan should not govern legislative exactions that are generally-applied and provide no meaningful discretion to administrators. Part IV explains why the Penn Central factored analysis also should not govern legislative exactions that meet those two criteria. Part V demonstrates why a reasonable relationship test that has been employed in various forms by state courts should govern legislative exactions that satisfy those two criteria. Applying that reasonable relationship test to qualifying legislative exactions lessens judicial interference with local land use decisions, reinforces the constitutional rationale in Koontz that development projects should pay for the external costs they create, and addresses the concern of property owners that some generally-applied legislative exactions may “go too far.

The mutant-prevention concentration (MPC) : ideas for restricting the development of fluoroquinolone resistance

The mutant-prevention concentration (MPC) is a novel susceptibility measurement defined by a concentration threshold that would require cells to contain two concurrent resistance mutations for growth. Pneuococcal pneumonia, infections caused by Pseudomonas aeruginosa, and urinary tract infections caused by Gram-negative bacilli represent three distinct clinical situations for which fluoroquinolone-resistance occurs. MPC results were defined and measured for fluoroquinolones against clinical isolates of Citrobacter freundii, Enterobacter cloacae, Escherichia. coli, Klebsiella pneumoniae, P. aeruginosa, and Streptococus pneumoniae. Against clinical isolates of S. pneumoniae, MPC results for six fluoroquinolones were measured. Based on their potential for restricting the selection of resistant mutants, the six fluoroquinolones, in descending order, were found to be gemifloxacin > moxifloxacin > trovafloxacin > gatifloxacin > grepafloxacin > levofloxacin. For several compounds, 90% of clinical isolates that lacked a known resistance mutation had a MPC value that was close to or below the serum levels that could be attained with a dosing regimen recommended by the manufacturers. These data identify gemifloxacin, moxifloxacin and gatifloxacin as good candidates for determining whether MPC can be used as a guide for choosing and eventually administering fluoroquinolones to significantly reduce the development of fluoroquinolone ¡Vresistant S. pneumoniae. MPC90 results for 155 clinical isolates of P. aeruginosa against ciprofloxacin and levofloxacin were 4 and 16 ƒÝg/ml, respectively. Serum drug concentrations reported previously for standard doses were above MPC90 for 5.5 hr for ciprofloxacin and 0 hr for levofloxacin. These data suggest that superior clinical performance of ciprofloxacin correlates with activity against resistant mutant subpopulations measured in vitro. MPC results were compared with minimum inhibitory concentrations (MIC) measurements preformed by agar dilution, and microbroth dilution and minimal inhibitory concentrations (MBC) for 100 clinical isolates of C. freundii (n=20), E. cloacae (n=20), E. coli (n=20), K. pneumoniae (n=20), and P. aeruginosa (n=20) for ciprofloxacin, levofloxacin and garenoxacin. MPC results were 2-to-8 fold higher than MIC or MBC results. Ciprofloxacin MPC results for E.coli, C. freundii, E. cloacae, K. pneumoniae, and P. aeruginosa were 0.5, 2, 1, 1, and 4 ƒÝg/ml, respectively. Levofloxacin, MPC results were were 1, 2, 4, 1, and 16 ƒÝg/ml, respectively. Garenoxacin, MPC were 1, 8, >8, 4, and >32 ƒÝg/ml, respectively. Garenoxacin had the highest MIC and MPC results and was the least active compound tested against isolates of C. freundii, E. cloacae, and P. aeruginosa. These data support the rational use of quinolones in the treatments of urinary tract infections and suppression of resistance. Incorporation of the MPC measurement into dosing strategies may preserve the longevity of antimicrobial compounds for future infectious diseases

Scalability of preconditioners as a strategy for parallel computation of compressible fluid flow

Parallel implementations of a Newton-Krylov-Schwarz algorithm are used to solve a model problem representing low Mach number compressible fluid flow over a backward-facing step. The Mach number is specifically selected to result in a numerically {open_quote}stiff{close_quotes} matrix problem, based on an implicit finite volume discretization of the compressible 2D Navier-Stokes/energy equations using primitive variables. Newton`s method is used to linearize the discrete system, and a preconditioned Krylov projection technique is used to solve the resulting linear system. Domain decomposition enables the development of a global preconditioner via the parallel construction of contributions derived from subdomains. Formation of the global preconditioner is based upon additive and multiplicative Schwarz algorithms, with and without subdomain overlap. The degree of parallelism of this technique is further enhanced with the use of a matrix-free approximation for the Jacobian used in the Krylov technique (in this case, GMRES(k)). Of paramount interest to this study is the implementation and optimization of these techniques on parallel shared-memory hardware, namely the Cray C90 and SGI Challenge architectures. These architectures were chosen as representative and commonly available to researchers interested in the solution of problems of this type. The Newton-Krylov-Schwarz solution technique is increasingly being investigated for computational fluid dynamics (CFD) applications due to the advantages of full coupling of all variables and equations, rapid non-linear convergence, and moderate memory requirements. A parallel version of this method that scales effectively on the above architectures would be extremely attractive to practitioners, resulting in efficient, cost-effective, parallel solutions exhibiting the benefits of the solution technique

Multicenter Evaluation of the QIAstat-Dx Respiratory Panel for the Detection of Viruses and Bacteria in Nasopharyngeal Swab Specimens

The QIAstat-Dx Respiratory Panel (QIAstat-Dx RP) is a multiplex in vitro diagnostic test for the qualitative detection of 20 pathogens directly from nasopharyngeal swab (NPS) specimens. The assay is performed using a simple sample-to-answer platform with results available in approximately 69 min. The pathogens identified are adenovirus, coronavirus 229E, coronavirus HKU1, coronavirus NL63, coronavirus OC43, human metapneumovirus A and B, influenza A, influenza A H1, influenza A H3, influenza A H1N1/2009, influenza B, parainfluenza virus 1, parainfluenza virus 2, parainfluenza virus 3, parainfluenza virus 4, rhinovirus/enterovirus, respiratory syncytial virus A and B, Bordetella pertussis, Chlamydophila pneumoniae, and Mycoplasma pneumoniae. This multicenter evaluation provides data obtained from 1,994 prospectively collected and 310 retrospectively collected (archived) NPS specimens with performance compared to that of the BioFire FilmArray Respiratory Panel, version 1.7. The overall percent agreement between QIAstat-Dx RP and the comparator testing was 99.5%. In the prospective cohort, the QIAstat-Dx RP demonstrated a positive percent agreement of 94.0% or greater for the detection of all but four analytes: coronaviruses 229E, NL63, and OC43 and rhinovirus/enterovirus. The test also demonstrated a negative percent agreement of ≥97.9% for all analytes. The QIAstat-Dx RP is a robust and accurate assay for rapid, comprehensive testing for respiratory pathogens

The Need for Dedicated Microbiology Leadership in the Clinical Microbiology Laboratory

Clinical microbiology laboratories play a crucial role in patient care using traditional and innovative diagnostics. Challenges faced by laboratories include emerging pathogens, rapidly evolving technologies, healthcare-acquired infections, antibiotic-resistant organisms and diverse patient populations. Despite these challenges, many clinical microbiology laboratories in the United States are not directed by doctoral level microbiology-trained individuals with sufficient time dedicated to laboratory leadership. This manuscript highlights the need for medical microbiology laboratory directors with appropriate training and qualifications

Rigel: An interactive structured grid generation system

An interactive structured grid generation application that facilitates the construction of complex, discretized, simulation models directly from the original CAD geometry specifications is presented. The application, named Rigel, reads physical model descriptions generated by modern CAD packages. Rigel includes a suite of interactive geometry editing functions to assist the user in the construction of a topologically correct geometry from the original CAD specification. Once a topologically correct geometry is created, an interactively steered grid generation capability is provided to facilitate the construction of an appropriate discretization for the simulation. Grid quality enhancement is supported with the application of user-directed elliptic smoothing, refinement, and coarsening operators. After a grid is completed, various output filters are supplied to write an input file for the target simulation code. This paper is intended to provide an overview of the mechanics of this process and to highlight some of the novel algorithms and techniques employed

A unified way of analyzing some greedy algorithms

A unified way of analyzing different greedy-type algorithms in Banach spaces is presented. We define a class of Weak Biorthogonal Greedy Algorithms and prove convergence and rate of convergence results for algorithms from this class. In particular, the following well known algorithms --- Weak Chebyshev Greedy Algorithm and Weak Greedy Algorithm with Free Relaxation --- belong to this class. We consider here one more algorithm --- Rescaled Weak Relaxed Greedy Algorithm --- from the above class. We also discuss modifications of these algorithms, which are motivated by applications. We analyze convergence and rate of convergence of the algorithms under assumption that we may perform steps of these algorithms with some errors. We call such algorithms approximate greedy algorithms. We prove convergence and rate of convergence results for the Approximate Weak Biorthogonal Greedy Algorithms. These results guarantee stability of Weak Biorthogonal Greedy Algorithms

TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection.

HIV infection induces phenotypic and functional changes to CD8+ T cells defined by the coordinated upregulation of a series of negative checkpoint receptors that eventually result in T cell exhaustion and failure to control viral replication. We report that effector CD8+ T cells during HIV infection in blood and SIV infection in lymphoid tissue exhibit higher levels of the negative checkpoint receptor TIGIT. Increased frequencies of TIGIT+ and TIGIT+ PD-1+ CD8+ T cells correlated with parameters of HIV and SIV disease progression. TIGIT remained elevated despite viral suppression in those with either pharmacological antiretroviral control or immunologically in elite controllers. HIV and SIV-specific CD8+ T cells were dysfunctional and expressed high levels of TIGIT and PD-1. Ex-vivo single or combinational antibody blockade of TIGIT and/or PD-L1 restored viral-specific CD8+ T cell effector responses. The frequency of TIGIT+ CD4+ T cells correlated with the CD4+ T cell total HIV DNA. These findings identify TIGIT as a novel marker of dysfunctional HIV-specific T cells and suggest TIGIT along with other checkpoint receptors may be novel curative HIV targets to reverse T cell exhaustion

Ocean acidification with (de)eutrophication will alter future phytoplankton growth and succession

Human activity causes ocean acidification (OA) though the dissolution of anthropogenically generated CO2 into seawater, and eutrophication through the addition of inorganic nutrients. Eutrophication increases the phytoplankton biomass that can be supported during a bloom, and the resultant uptake of dissolved inorganic carbon during photosynthesis increases water-column pH (bloom-induced basification). This increased pH can adversely affect plankton growth. With OA, basification commences at a lower pH. Using experimental analyses of the growth of three contrasting phytoplankton under different pH scenarios, coupled with mathematical models describing growth and death as functions of pH and nutrient status, we show how different conditions of pH modify the scope for competitive interactions between phytoplankton species. We then use the models previously configured against experimental data to explore how the commencement of bloom-induced basification at lower pH with OA, and operating against a background of changing patterns in nutrient loads, may modify phytoplankton growth and competition. We conclude that OA and changed nutrient supply into shelf seas with eutrophication or de-eutrophication (the latter owing to pollution control) has clear scope to alter phytoplankton succession, thus affecting future trophic dynamics and impacting both biogeochemical cycling and fisheries

Contamination Control of the SABER Cryogenic Infrared Telescope

The SABER instrument (Sounding of the Atmosphere using Broadband Emission Spectroscopy) is a cryogenic infrared sensor on the TIMED spacecraft with stringent molecular and particulate contamination control requirements. The sensor measures infrared emissions from atmospheric constituents in the earth limb at altitudes ranging from 60 to 180 km using radiatively-cooled 240 K optics and a mechanicallyrefrigerated 75 K detector. The stray light performance requirements necessitate nearly pristine foreoptics. The cold detector in a warm sensor presents challenges in controlling the cryodeposition of water and other condensable vapors. Accordingly, SABER incorporates several unique design features and test strategies to control and measure the particulate and molecular contamination environment. These include internal witness mirrors, dedicated purge/depressurization manifolds, labyrinths, cold stops, and validated procedures for bakeout, cooldown, and warmup. The pre-launch and on-orbit contamination control performance for the SABER telescope will be reviewed