Chanmin Kim, Michael J. Daniels, Joseph W. Hogan, Christine Choirat, Corwin M. Zigler.

Source: The Annals of Applied Statistics, Volume 13, Number 3, 1927--1956.

Abstract:
Emission control technologies installed on power plants are a key feature of many air pollution regulations in the US. While such regulations are predicated on the presumed relationships between emissions, ambient air pollution and human health, many of these relationships have never been empirically verified. The goal of this paper is to develop new statistical methods to quantify these relationships. We frame this problem as one of mediation analysis to evaluate the extent to which the effect of a particular control technology on ambient pollution is mediated through causal effects on power plant emissions. Since power plants emit various compounds that contribute to ambient pollution, we develop new methods for multiple intermediate variables that are measured contemporaneously, may interact with one another, and may exhibit joint mediating effects. Specifically, we propose new methods leveraging two related frameworks for causal inference in the presence of mediating variables: principal stratification and causal mediation analysis. We define principal effects based on multiple mediators, and also introduce a new decomposition of the total effect of an intervention on ambient pollution into the natural direct effect and natural indirect effects for all combinations of mediators. Both approaches are anchored to the same observed-data models, which we specify with Bayesian nonparametric techniques. We provide assumptions for estimating principal causal effects, then augment these with an additional assumption required for causal mediation analysis. The two analyses, interpreted in tandem, provide the first empirical investigation of the presumed causal pathways that motivate important air quality regulatory policies.

Ahmed Aziz Ezzat, Mikyoung Jun, Yu Ding.

Source: The Annals of Applied Statistics, Volume 13, Number 3, 1484--1510.

Abstract:
Accurate short-term forecasts are indispensable for the integration of wind energy in power grids. On a wind farm, local wind conditions exhibit sizeable variations at a fine temporal resolution. Existing statistical models may capture the in-sample variations in wind behavior, but are often shortsighted to those occurring in the near future, that is, in the forecast horizon. The calibrated regime-switching method proposed in this paper introduces an action of regime dependent calibration on the predictand (here the wind speed variable), which helps correct the bias resulting from out-of-sample variations in wind behavior. This is achieved by modeling the calibration as a function of two elements: the wind regime at the time of the forecast (and the calibration is therefore regime dependent), and the runlength, which is the time elapsed since the last observed regime change. In addition to regime-switching dynamics, the proposed model also accounts for other features of wind fields: spatio-temporal dependencies, transport effect of wind and nonstationarity. Using one year of turbine-specific wind data, we show that the calibrated regime-switching method can offer a wide margin of improvement over existing forecasting methods in terms of both wind speed and power.

Marie Ernst, Gesine Reinert, Yvik Swan.

Source: Bernoulli, Volume 26, Number 3, 2051--2081.

Abstract:
We propose probabilistic representations for inverse Stein operators (i.e., solutions to Stein equations) under general conditions; in particular, we deduce new simple expressions for the Stein kernel. These representations allow to deduce uniform and nonuniform Stein factors (i.e., bounds on solutions to Stein equations) and lead to new covariance identities expressing the covariance between arbitrary functionals of an arbitrary univariate target in terms of a weighted covariance of the derivatives of the functionals. Our weights are explicit, easily computable in most cases and expressed in terms of objects familiar within the context of Stein’s method. Applications of the Cauchy–Schwarz inequality to these weighted covariance identities lead to sharp upper and lower covariance bounds and, in particular, weighted Poincaré inequalities. Many examples are given and, in particular, classical variance bounds due to Klaassen, Brascamp and Lieb or Otto and Menz are corollaries. Connections with more recent literature are also detailed.

Michael V. Boutsikas, Eutichia Vaggelatou

Source: Bernoulli, Volume 16, Number 2, 301--330.

Abstract:
Let X 1 , X 2 , …, X n be a sequence of independent or locally dependent random variables taking values in ℤ + . In this paper, we derive sharp bounds, via a new probabilistic method, for the total variation distance between the distribution of the sum ∑ i =1 n X i and an appropriate Poisson or compound Poisson distribution. These bounds include a factor which depends on the smoothness of the approximating Poisson or compound Poisson distribution. This “smoothness factor” is of order O( σ −2 ), according to a heuristic argument, where σ 2 denotes the variance of the approximating distribution. In this way, we offer sharp error estimates for a large range of values of the parameters. Finally, specific examples concerning appearances of rare runs in sequences of Bernoulli trials are presented by way of illustration.

Cristiano Villa, Jeong Eun Lee.

Source: Bayesian Analysis, Volume 15, Number 2, 533--558.

Abstract:
In this work we propose a novel model prior for variable selection in linear regression. The idea is to determine the prior mass by considering the worth of each of the regression models, given the number of possible covariates under consideration. The worth of a model consists of the information loss and the loss due to model complexity. While the information loss is determined objectively, the loss expression due to model complexity is flexible and, the penalty on model size can be even customized to include some prior knowledge. Some versions of the loss-based prior are proposed and compared empirically. Through simulation studies and real data analyses, we compare the proposed prior to the Scott and Berger prior, for noninformative scenarios, and with the Beta-Binomial prior, for informative scenarios.

Jon Cockayne, Chris J. Oates, Ilse C.F. Ipsen, Mark Girolami.

Source: Bayesian Analysis, Volume 14, Number 3, 937--1012.

Abstract:
A fundamental task in numerical computation is the solution of large linear systems. The conjugate gradient method is an iterative method which offers rapid convergence to the solution, particularly when an effective preconditioner is employed. However, for more challenging systems a substantial error can be present even after many iterations have been performed. The estimates obtained in this case are of little value unless further information can be provided about, for example, the magnitude of the error. In this paper we propose a novel statistical model for this error, set in a Bayesian framework. Our approach is a strict generalisation of the conjugate gradient method, which is recovered as the posterior mean for a particular choice of prior. The estimates obtained are analysed with Krylov subspace methods and a contraction result for the posterior is presented. The method is then analysed in a simulation study as well as being applied to a challenging problem in medical imaging.

Chao Du, S. C. Kou.

Source: Statistical Science, Volume 35, Number 1, 75--91.

Abstract:
Toward the last quarter of the 20th century, the emergence of single-molecule experiments enabled scientists to track and study individual molecules’ dynamic properties in real time. Unlike macroscopic systems’ dynamics, those of single molecules can only be properly described by stochastic models even in the absence of external noise. Consequently, statistical methods have played a key role in extracting hidden information about molecular dynamics from data obtained through single-molecule experiments. In this article, we survey the major statistical methodologies used to analyze single-molecule experimental data. Our discussion is organized according to the types of stochastic models used to describe single-molecule systems as well as major experimental data collection techniques. We also highlight challenges and future directions in the application of statistical methodologies to single-molecule experiments.

Susan Gruber, Mark J. van der Laan.

Source: Statistical Science, Volume 34, Number 1, 82--85.

Abstract:
Dorie and co-authors (DHSSC) are to be congratulated for initiating the ACIC Data Challenge. Their project engaged the community and accelerated research by providing a level playing field for comparing the performance of a priori specified algorithms. DHSSC identified themes concerning characteristics of the DGP, properties of the estimators, and inference. We discuss these themes in the context of targeted learning.

Elizabeth A. Stuart

Source: Statist. Sci., Volume 25, Number 1, 1--21.

Abstract:
When estimating causal effects using observational data, it is desirable to replicate a randomized experiment as closely as possible by obtaining treated and control groups with similar covariate distributions. This goal can often be achieved by choosing well-matched samples of the original treated and control groups, thereby reducing bias due to the covariates. Since the 1970s, work on matching methods has examined how to best choose treated and control subjects for comparison. Matching methods are gaining popularity in fields such as economics, epidemiology, medicine and political science. However, until now the literature and related advice has been scattered across disciplines. Researchers who are interested in using matching methods—or developing methods related to matching—do not have a single place to turn to learn about past and current research. This paper provides a structure for thinking about matching methods and guidance on their use, coalescing the existing research (both old and new) and providing a summary of where the literature on matching methods is now and where it should be headed.

Peter Klivenyi
Jan 1, 2000; 20:1-7
Cellular

New Something Awful smilies

The eerie inhumanity of Donald Trump.

The general field of quantitative biology has advanced significantly on the back of recent improvements in both sequencing technology and proteomics methods. The development of high-throughput, short-read sequencing has revolutionized RNA-based expression studies, while improvements in proteomics methods have enabled quantitative studies to attain better resolution. Here we introduce methods to undertake global analyses of gene expression through RNA and protein quantification in Xenopus embryos and tissues.

Determining the concentration of protein samples generally is accomplished either by measuring the UV absorbance at 280 nm or by reacting the protein quantitatively with dyes and/or metal ions (Bradford, Lowry, or BCA assays). For purified proteins, UV absorbance remains the most popular method because it is fast, convenient, and reproducible; it does not consume the protein; and it requires no additional reagents, standards, or incubations. No method of protein concentration determination is perfect because each is subject to a different set of constraints such as interference of buffer components and contaminating proteins in direct UV determination (A₂₈₀) or reactivity of individual proteins and buffer components with the detecting reagents in colorimetric assays. In cases in which protein concentration is critical (e.g., determination of catalytic rate constants for an enzyme), it may be advisable to compare the results of several assays.

One of the main mechanisms of azole resistance of Aspergillus fumigatus is thought to be a reduction in the drug’s affinity for the target molecule, Cyp51A, due to its amino acid mutation(s). It is known that the azole resistance pattern is closely related to the mutation site(s) of the molecule. In this study, we tried to develop a simple and rapid detection method for cyp51A mutations using the endonuclease Surveyor nuclease. The Surveyor nuclease assay was verified using several azole-resistant strains of A. fumigatus that possess point mutations in Cyp51A. For validation of the Surveyor nuclease assay, blind tests were conducted using 48 strains of A. fumigatus (17 azole-resistant and 31 azole-susceptible strains). The Surveyor nuclease assay could rapidly detect cyp51A mutations with one primer set. Also, all the tested strains harboring different cyp51A single point mutations could be clearly distinguished from the wild type. The Surveyor nuclease assay is a simple method that can detect cyp51A mutations rapidly.

New findings on a state initiative in Wisconsin suggest that to make the most out of smaller class sizes in the early grades, teachers should focus on basic skills when they have one-on-one contact with students, ask children to discuss and demonstrate what they know, and have a firm, but nurturing,

Few epidemiological studies, which included varied exposure assessment, have investigated the relation between drinking-water–disinfection byproducts such as trihalomethanes and hypospadias, and their results have been inconclusive.

Little evidence was found for an association between trihalomethanes and hypospadias, but a novel association between water consumption and hypospadias was found. Factors that influence maternal water consumption, or other contaminants in tap or bottled water, might explain this finding. (Read the full article)

Cardiovascular risk factors predict the development of premature atherosclerosis. As the number of risk factors increases, so does the extent of these lesions. Assessment of cardiovascular risk factors is an accepted practice in adults but is not used in pediatrics.

In this study, the authors discuss how the presence of ≥2 cardiovascular risk factors is associated with vascular changes in adolescents. The findings were compared with the Patholobiological Determinants of Atherosclerosis in Youth risk score to demonstrate that a simple method of clustering is a reliable tool to use in clinical practice. (Read the full article)

Recent studies have called into question the benefit of perioperative corticosteroids in children undergoing heart surgery, but have been limited by small sample size, the lack of placebo control, and the grouping of various steroid regimens together in analysis.

We evaluated outcomes across methylprednisolone regimens versus no steroids in a large cohort of neonates and found no mortality or length-of-stay benefit associated with any regimen, and a higher risk of infection in certain subgroups. (Read the full article)

There is a perception among clinicians that methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and/or meningitis result in a greater burden of disease than invasive infections attributed to methicillin-susceptible Staphylococcus aureus (MSSA) among very low birth weight (VLBW) infants.

VLBW infants with MRSA and MSSA bacteremia and/or meningitis have equivalent morbidity and mortality. These findings suggest that allocation of resources for prevention and treatment of both MRSA and MSSA infections among VLBW infants should be comparable. (Read the full article)

Prenatal methamphetamine exposure has been related to deficits in fetal growth, changes in infant neurobehavior, and fine motor deficits, but little is known about its developmental effects on behavior problems in early childhood.

This is the first prospective study to identify behavior problems associated with prenatal methamphetamine exposure. Mood difficulties and acting-out behavior are increased in exposed children by age 3 years. Early identification and intervention may prevent escalation into delinquency and psychopathology. (Read the full article)

Isolated methylmalonic acidemia, one of the most common inborn errors of organic acid metabolism, is known to be associated with variably impaired intellectual functioning and severe biochemical and clinical abnormalities. However, the neurocognitive outcomes have yet to be fully described.

This research defines the neurocognitive phenotype of isolated methylmalonic acidemia and identifies processing speed as a specific impairment. Clinical, biochemical, and molecular genetic covariates were explored. A history of hyperammonemia at diagnosis was found to correlate with poorer cognitive outcomes. (Read the full article)

Known rates of nonsuicidal self-injury, hurting oneself without the intent to die, are between ~7% and 24% in samples of early adolescents and older adolescents, yet research has not reported rates for youth younger than 11 years old.

Children as young as 7 years old report engaging in nonsuicidal self-injury. There is a grade by gender interaction for nonsuicidal self-injury, such that ninth-grade girls report the greatest rates of engagement and do so by cutting themselves. (Read the full article)

Evaluation of neonatal surgical outcomes is necessary to guide improvements in the quality of care. Meaningful comparisons must adjust for factors that alter outcomes independent of the surgical procedures.

Herein is described a method that permits risk adjustment for the broad range of noncardiac neonatal surgery, regardless of gestational age, to permit useful comparisons for quality improvement. (Read the full article)

In adolescents with eating disorders, percent expected body weight (EBW) is used for diagnosis and to make clinical decisions. The assumption is that the weight-for-stature (WFS) and BMI methods of determining EBW are equivalent, but that may not be true.

This study demonstrates that EBW_WFS is ~3.5% higher than EBW_BMI. Differences are most pronounced at extremes of height. Compared with the EBW_WFS method, sensitivity of EBW_BMI to detect those <75% EBW is low. (Read the full article)

Antimicrobials are a medication class frequently implicated in pediatric adverse drug reactions (ADRs). Trimethoprim-sulfamethoxazole (TMP-SMX) is long recognized as a contributor to the burden of these undesired and unpredictable events.

TMP-SMX ADRs increased from 2000 to 2009, with the majority of children taking the antibiotic for skin and soft tissue infections. The significant increase in TMP-SMX prescribing for these infections may result in a continued increase of associated ADRs. (Read the full article)

Impaired visual development has been reported in infants born to mothers prescribed methadone in pregnancy. Immature visual evoked potentials have been reported in this population, but data were confounded by gestation, growth restriction, and illicit drug use.

Visual evoked potentials are small and immature in infants exposed to methadone and other drugs of misuse in utero. These changes are independently associated with methadone exposure and persist after controlling for gestation, socioeconomic deprivation, alcohol consumption, and cigarette smoking. (Read the full article)

Some infants presenting with bronchiolitis are later diagnosed with asthma. Corticosteroid treatment of all infants with bronchiolitis is not clearly efficacious.

We used infant eczema or asthma history in a first-degree relative to select patients with bronchiolitis for dexamethasone or placebo blinded treatment. Dexamethasone treatment of 5 days led to significantly earlier readiness for discharge from infirmary treatment. (Read the full article)

Invasive methicillin-resistant Staphylococcus aureus (MRSA) in children is associated with high morbidity and mortality. Although reductions in health care–associated MRSA infection among adults are documented, it is unclear if a similar trend is occurring among children.

Data from population-based surveillance were analyzed to assess changes in invasive MRSA infection incidence over time. This analysis describes the epidemiology and trends of invasive MRSA infections among children in 9 US metropolitan areas and estimates national burden. (Read the full article)

Viral wheezing is common in preschool-aged children. The efficacy of inhaled steroids in preventing viral wheezing is debated. Despite this debate, nebulized beclomethasone is widely prescribed (particularly in a few countries) to children with upper respiratory tract infections.

Findings from this study confirm that inhaled steroids are not effective in preventing viral wheezing. Moreover, no differences were found in the persistence of symptoms (eg, runny nose, sore throat) or in the parental perception of asthma-like symptom severity. (Read the full article)

Quality measures developed by the Pediatric Quality Measures Program are required to assess disparities in performance according to special health care need status. Methods are needed to identify children according to level of medical complexity in administrative data.

The Pediatric Medical Complexity Algorithm is a new, publicly available algorithm that identifies the small proportion of children with complex chronic disease in Medicaid claims and hospital discharge data with good sensitivity and good to excellent specificity. (Read the full article)

Corrosive substance ingestion is a public health issue in developing countries. Stricture formation is a late complication of corrosive substance ingestion. The role of corticosteroids in preventing corrosive-induced strictures is controversial.

High doses of methylprednisolone therapy lead to less frequent stricture formation in grade IIb esophageal burns in children who ingested caustic substances and may improve prognosis. (Read the full article)

Quality improvement (QI) studies generally do not account for concurrent trends of improvement and it is difficult to distinguish the impact of a multihospital collaborative QI project without a contemporary control group.

A multihospital collaborative QI model led to greater declines in hypothermia and invasive ventilation rates in the delivery room compared with an individual NICU QI model and NICUs that did not participate in formal QI activities. (Read the full article)

Prophylactic indomethacin in extremely low birth weight infants decreases severe intraventricular hemorrhage and patent ductus arteriosus but it is unknown whether concurrent enteral feeding and prophylactic indomethacin is associated with increased risk of spontaneous intestinal perforation.

The combination of prophylactic indomethacin and enteral feeding during the first 3 days after birth does not increase the risk of spontaneous intestinal perforation. (Read the full article)

Children and adolescents with attention-deficit/hyperactivity disorder are prone to sustaining trauma that requires emergency department (ED) admission. Methylphenidate can reduce attention-deficit/hyperactivity disorder symptoms and thus theoretically may reduce the risk of trauma-related ED admission, but previous studies did not provide a clear association.

For patients treated with methylphenidate, on-medication periods were associated with lower rates of trauma-related ED admission compared with off-medication periods. A similar protective association was found in both genders. Potential treatment benefit was greater for age ≥16 years. (Read the full article)

Blood cultures are the most widely available diagnostic tool to identify bacterial pathogens in community-acquired pneumonia (CAP). Despite a recent national guideline recommendation for blood culture performance in children with moderate/severe CAP, there is still wide variation across institutions.

Using improvement methodology, we demonstrated that blood cultures can be routinely performed in children admitted for CAP, in accordance with a recent national guideline, without increasing length of stay in a setting with a low false-positive blood culture rate. (Read the full article)

Two prospective studies of children with septic arthritis have shown that the addition of dexamethasone to antibiotic therapy contributes to clinical and laboratory improvement. Nevertheless, the mainstay of treatment remains antibiotics alone.

This study, which was conducted outside a randomized controlled trial, demonstrates that children with septic arthritis treated early with a short course of adjuvant dexamethasone show earlier improvement in clinical and laboratory parameters than children treated with antibiotics alone. (Read the full article)

Leishmania major is the causative agent of cutaneous leishmaniasis (CL). No human vaccine is available for CL and current drug regimens present several drawbacks such as emerging resistance, severe toxicity, medium effectiveness, and/or high cost. Thus, the need for better treatment options against CL is a priority. In the present study, we validate the enzyme methionine aminopeptidase-1 (MetAP1), a metalloprotease that catalyzes the removal of N-terminal methionine from peptides and proteins, as a chemotherapeutic target against CL infection. The in vitro antileishmanial activity of eight novel MetAP1 inhibitors (OJT001-OJT008) were investigated. Three compounds OJT006, OJT007, and OJT008 demonstrated potent anti-proliferative effect in macrophages infected with L. major amastigotes and promastigotes at submicromolar concentrations, with no cytotoxicity against host cells. Importantly, the leishmanicidal effect was diminished by almost 10-fold in transgenic L. major promastigotes overexpressing MetAP1_LM in comparison to wild-type promastigotes. Furthermore, the in vivo activity of OJT006, OJT007, and OJT008 were investigated in L. major-infected BALB/c mice. In comparison to the control group, OJT008 significantly decreased footpad parasite load by 86%, and exhibited no toxicity against in treated mice. We propose MetAP1 inhibitor OJT008 as a potential chemotherapeutic candidate against CL infection caused by L. major infection.

Malaria parasites invade and replicate within red blood cells (RBCs), extensively modifying their structure and gaining access to the extracellular environment by placing the plasmodial surface anion channel (PSAC) into the RBC membrane. Expression of members of the cytoadherence linked antigen gene 3 (clag3) family is required for PSAC activity, a process that is regulated epigenetically. PSAC is a well-established route of uptake for large, hydrophilic antimalarial compounds and parasites can acquire resistance by silencing clag3 gene expression, thereby reducing drug uptake. We found that exposure to sub-IC50 concentrations of the histone methyltransferase inhibitor chaetocin caused substantial changes in both clag3 gene expression and RBC permeability, reversing acquired resistance to the antimalarial compound blasticidin S that is transported through PSAC. Chaetocin treatment also altered progression of parasites through their replicative cycle, presumably by changing their ability to modify chromatin appropriately to enable DNA replication. These results indicate that targeting histone modifiers could represent a novel tool for reversing epigenetically acquired drug resistance in P. falciparum.

KBP-7072 is a semi-synthetic aminomethylcycline with broad-spectrum activity against Gram-positive and Gram-negative pathogens including multidrug resistant bacterial strains. The pharmacokinetics (PK) of KBP-7072 after oral and intravenous (IV) administration of single and multiple doses were investigated in animal models including during fed and fasted states and also evaluated the protein binding and excretion characteristics. In Sprague-Dawley (SD) rats, Beagle dogs, and CD-1 mice, KBP-7072 demonstrated a linear PK profile after administration of single oral and IV and multiple oral doses. Oral bioavailability ranged from 12% to 32%. Mean T_max ranged from 0.5 to 4 hours, and mean half-life ranged from approximately 6 to 11 hours. Administration of oral doses in the fed state resulted in a marked reduction in C_max and AUC compared with dosing in fasted animals. The mean bound fractions of KBP-7072 were 77.5%, 69.8%, 64.5%, 69.3%, and 69.2% in mouse, rat, dog, monkey, and human plasma, respectively. Following a single 22.5 mg/kg oral dose of KBP-7072 in SD rats, cumulative excretion in feces was 64% and in urine was 2.5% of the administered dose. The PK results in animal models are consistent with single and multiple ascending dose studies in healthy volunteers and confirm the suitability of KBP-7072 for once daily oral and IV administration in clinical studies.

Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI) are associated with substantial morbidity and mortality. Monotherapy with first-line antimicrobials such as vancomycin (VAN; glycopeptide) and daptomycin (DAP; lipopeptide) are inadequate in some cases due to reduced antibiotic susceptibilities or therapeutic failure. In recent years, β-lactam antibiotics have emerged as a potential option for combination therapy with VAN/DAP that may meet an unmet therapeutic need for MRSA BSI. Ceftaroline (CPT), the only commercially available β-lactam in the United States with intrinsic in vitro activity against MRSA, has been increasingly studied in the setting of VAN and DAP failures. Novel combinations of first-line agents (VAN and DAP) with β-lactams have been the subject of many recent investigations due to in vitro findings such as the "see-saw effect", where β-lactam susceptibility may be improved in the presence of decreased glycopeptide and lipopeptide susceptibility. The combination of CPT and DAP, in particular, has become the focus of many scientific evaluations, due to intrinsic anti-MRSA activities and potent in vitro synergistic activity against various MRSA strains. This article reviews the available literature describing these innovative therapeutic approaches for MRSA BSI, focusing on preclinical and clinical studies, and evaluates the potential benefits and limitations of each strategy.

Aspergillus niger, the third species responsible for invasive aspergillosis has been considered as a homogeneous species until DNA-based identification uncovered many cryptic species. These species have been recently reclassified into the Aspergillus section Nigri. However little is yet known among the section Nigri about the species distribution and the antifungal susceptibility pattern of each cryptic species. A total of 112 clinical isolates collected from 5 teaching hospitals in France and phenotypically identified as A. niger were analyzed. Identification to the species level was carried out by nucleotide sequence analysis. The Minimum Inhibitory Concentrations (MICs) of itraconazole, voriconazole, posaconazole, isavuconazole and amphotericin B were determined by both the EUCAST and gradient concentration strips methods. Aspergillus tubingensis (n=51, 45.5%) and A. welwitschiae (n=50, 44.6%) were the most common species while A. niger accounted for only 6.3% (n=7). The MICs of azoles drugs were higher for A. tubingensis than for A. welwitschiae. The MIC of amphotericin B was 2 mg/L or less for all isolates. Importantly, MICs determined by EUCAST showed no correlation with those determined by gradient concentration strips methods, these latter being lower than the former (Spearman's rank correlation tests ranging - depending on the antifungal agent - from 0.01 to 0.25; p>0.4). In conclusion, A. niger should be considered as a minority species in the section Nigri. The differences in MICs between species for different azoles underline the importance of accurate identification. Significant divergences in the determination of MIC between EUCAST and gradient concentration strips methods require further investigation.

One of the reasons for the lengthy tuberculosis (TB) treatment is the difficult to treat non-multiplying mycobacterial subpopulation. In order to assess the ability of (new) TB drugs to target this subpopulation, we need to incorporate dormancy models in our pre-clinical drug development pipeline. In most available dormancy models it takes a long time to create a dormant state and it is difficult to identify and quantify this non-multiplying condition.

The Mycobacterium tuberculosis 18b strain might overcome some of these problems, because it is dependent on streptomycin for growth and becomes non-multiplying after 10 days of streptomycin starvation, but still can be cultured on streptomycin-supplemented culture plates. We developed our 18b dormancy time-kill kinetic model to assess the difference in the activity of isoniazid, rifampicin, moxifloxacin and bedaquiline against log-phase growth compared to the non-multiplying M. tuberculosis subpopulation by CFU counting including a novel AUC-based approach as well as time-to-positivity (TTP) measurements.

We observed that isoniazid and moxifloxacin were relatively more potent against replicating bacteria, while rifampicin and high dose bedaquiline were equally effective against both subpopulations. Moreover, the TTP data suggest that including a liquid culture-based method could be of additional value as it identifies a specific mycobacterial subpopulation that is non-culturable on solid media.

In conclusion, the results of our study underline that the time-kill kinetics 18b dormancy model in its current form is a useful tool to assess TB drug potency and thus has its place in the TB drug development pipeline.

Background: MRSA pose significant therapeutic challenges, related to their: frequency in clinical infections; innate virulence properties; and propensity for multi-antibiotic resistance. MRSA are among the most common causes of endovascular infections, including infective endocarditis (IE).

Objective: To employ transthoracic echocardiography (TTE) to evaluate the effect of exebacase, a novel direct lytic agent, in experimental aortic valve MRSA IE.

Study Design: TTE was utilized to evaluate the in vivo effect of exebacase on MRSA-infected vegetation progression when combined with daptomycin (vs daptomycin alone). Primary intravegetation outcomes were: maximum size; weights at sacrifice; and MRSA counts at infection baseline vs after 4 days of daptomycin treatment (alone or in addition to exebacase administered once on treatment Day 1).

Results: A single dose of exebacase in addition to daptomycin cleared significantly more intravegetation MRSA than daptomycin alone. This was associated with a statistical trend toward reduced maximum vegetation size in the exebacase + daptomycin vs the daptomycin-alone therapy groups (p = 0.07). Also, mean vegetation weights in the exebacase-treated group were significantly lower vs daptomycin-alone (p < 0.0001). Maximum vegetation size by TTE correlated with vegetation weight (p = 0.005). In addition, intravegetation MRSA counts in the combination group were significantly lower vs untreated controls (p<0.0001) and the daptomycin-alone group (p<0.0001).

Conclusion: This study suggests that exebacase has a salutary impact on MRSA-infected vegetation progression when combined with daptomycin, especially in terms of vegetation MRSA burden, size and weight. Moreover, TTE appears to be an efficient non-invasive tool to assess therapeutic efficacies in experimental MRSA IE.

Methicillin-resistant Staphylococcus aureus (MRSA) has grown to become a major burden on healthcare systems. The cumulation of limited therapeutic options and worsened patient outcomes with persistent MRSA bacteremia has driven research in optimizing its initial management. The guidelines published by the Infectious Disease of America currently recommend combination therapy for refractory MRSA bacteremia, but the utility of combining antibiotics from the start of therapy is under investigation. The alternative strategy of early use of a β-lactam antibiotics in combination with vancomycin upon initial MRSA bacteremia detection has shown promise. While this concept has gained international attention, providers should give this strategy serious consideration prior to implementation. The objective of this review is to examine retrospective and prospective evidence for early combination with vancomycin and β-lactam antibiotics, as well as explore potential consequences of combination therapy.

T. Michael O'Shea
Jul 1, 1999; 104:15-21
ARTICLES

Robert Guthrie
Sep 1, 1963; 32:338-343
ARTICLES

Facebook's policy on political ads is no different than those of campaign commercials, but the social network's size and scale makes the debate more serious.