Financial Distress in Genitourinary Cancer: Insights From CDC National Health Interview Survey.

PURPOSE: This study leverages CDC National Health Interview Survey data to examine Financial Distress (FD) among genitourinary (GU) cancer survivors, specifically prostate cancer (PC), kidney cancer (KC), and bladder cancer (BC). It investigates the economic impacts faced by these patients, especially in relation to disparities in insurance coverage and its effects on material, psychological, and behavioral aspects of FD. METHODS: We retrospectively analyzed responses from GU cancer survivors, stratifying by cancer status and age (18-64 years, ≥65 years). Medical financial hardship was divided into three domains: material, psychological, and behavioral. Associations between cancer history, hardship, and clinical factors were assessed using generalized ordinal logistic regressions. RESULTS: Significant health care access disparities were found, particularly for mental health services, with 25% of younger BC survivors and 4.7% of younger KC survivors reporting affordability issues, in contrast to 2.7% of noncancer individuals. Dental care was also problematic, with higher avoidance rates among younger BC (27%) and KC (15%) survivors compared with the general population. Surprisingly, noncancer individuals reported more difficulty in affording prescriptions than BC survivors across both age groups. PC survivors, however, showed lower FD across all domains versus noncancer controls, indicating fewer concerns about medical bills and a lesser tendency to forgo care. CONCLUSION: The study underscores significant gaps in the financial support system for GU cancer survivors, with urgent needs in mental and dental health care access. Policy interventions, including comprehensive insurance reforms, are imperative to alleviate the financial burdens on these individuals.

Differential effects of ecosystem engineering by the superb lyrebird Menura novaehollandiae and herbivory by large mammals on floristic regeneration and structure in wet eucalypt forests.

Ecosystem engineers that modify the soil and ground-layer properties exert a strong influence on vegetation communities in ecosystems worldwide. Understanding the interactions between animal engineers and vegetation is challenging when in the presence of large herbivores, as many vegetation communities are simultaneously affected by both engineering and herbivory. The superb lyrebird Menura novaehollandiae, an ecosystem engineer in wet forests of south-eastern Australia, extensively modifies litter and soil on the forest floor. The aim of this study was to disentangle the impacts of engineering by lyrebirds and herbivory by large mammals on the composition and structure of ground-layer vegetation. We carried out a 2-year, manipulative exclusion experiment in the Central Highlands of Victoria, Australia. We compared three treatments: fenced plots with simulated lyrebird foraging; fenced plots excluding herbivores and lyrebirds; and open controls. This design allowed assessment of the relative impacts of engineering and herbivory on germination rates, seedling density, vegetation cover and structure, and community composition. Engineering by lyrebirds enhanced the germination of seeds in the litter layer. After 2 years, more than double the number of germinants were present in "engineered" than "non-engineered" plots. Engineering did not affect the density of seedlings, but herbivory had strong detrimental effects. Herbivory also reduced the floristic richness and structural complexity (<0.5 m) of forest vegetation, including the cover of herbs. Neither process altered the floristic composition of the vegetation within the 2-year study period. Ecosystem engineering by lyrebirds and herbivory by large mammals both influence the structure of forest-floor vegetation. The twofold increase in seeds stimulated to germinate by engineering may contribute to the evolutionary adaptation of plants by allowing greater phenotypic expression and selection than would otherwise occur. Over long timescales, engineering and herbivory likely combine to maintain a more-open forest floor conducive to ongoing ecosystem engineering by lyrebirds.

Embryonic and early postnatal cranial bone volume and tissue mineral density values for C57BL/6J laboratory mice.

BACKGROUND: Laboratory mice are routinely used in craniofacial research based on the relatively close genetic relationship and conservation of developmental pathways between humans and mice. Since genetic perturbations and disease states may have localized effects, data from individual cranial bones are valuable for the interpretation of experimental assays. We employ high-resolution microcomputed tomography to characterize cranial bones of C57BL/6J mice at embryonic day (E) 15.5 and E17.5, day of birth (P0), and postnatal day 7 (P7) and provide estimates of individual bone volume and tissue mineral density (TMD). RESULTS: Average volume and TMD values are reported for individual bones. Significant differences in volume and TMD during embryonic ages likely reflect early mineralization of cranial neural crest-derived and intramembranously forming bones. Although bones of the face and vault had higher TMD values during embryonic ages, bones of the braincase floor had significantly higher TMD values by P7. CONCLUSIONS: These ontogenetic data on cranial bone volume and TMD serve as a reference standard for future studies using mice bred on a C57BL/6J genetic background. Our findings also highlight the importance of differentiating "control" data from mice that are presented as "unaffected" littermates, particularly when carrying a single copy of a cre-recombinase gene.

Cells of the human intestinal tract mapped across space and time.

The cellular landscape of the human intestinal tract is dynamic throughout life, developing in utero and changing in response to functional requirements and environmental exposures. Here, to comprehensively map cell lineages, we use single-cell RNA sequencing and antigen receptor analysis of almost half a million cells from up to 5 anatomical regions in the developing and up to 11 distinct anatomical regions in the healthy paediatric and adult human gut. This reveals the existence of transcriptionally distinct BEST4 epithelial cells throughout the human intestinal tract. Furthermore, we implicate IgG sensing as a function of intestinal tuft cells. We describe neural cell populations in the developing enteric nervous system, and predict cell-type-specific expression of genes associated with Hirschsprung's disease. Finally, using a systems approach, we identify key cell players that drive the formation of secondary lymphoid tissue in early human development. We show that these programs are adopted in inflammatory bowel disease to recruit and retain immune cells at the site of inflammation. This catalogue of intestinal cells will provide new insights into cellular programs in development, homeostasis and disease.

Somatic mutation landscapes at single-molecule resolution.

Somatic mutations drive the development of cancer and may contribute to ageing and other diseases1,2. Despite their importance, the difficulty of detecting mutations that are only present in single cells or small clones has limited our knowledge of somatic mutagenesis to a minority of tissues. Here, to overcome these limitations, we developed nanorate sequencing (NanoSeq), a duplex sequencing protocol with error rates of less than five errors per billion base pairs in single DNA molecules from cell populations. This rate is two orders of magnitude lower than typical somatic mutation loads, enabling the study of somatic mutations in any tissue independently of clonality. We used this single-molecule sensitivity to study somatic mutations in non-dividing cells across several tissues, comparing stem cells to differentiated cells and studying mutagenesis in the absence of cell division. Differentiated cells in blood and colon displayed remarkably similar mutation loads and signatures to their corresponding stem cells, despite mature blood cells having undergone considerably more divisions. We then characterized the mutational landscape of post-mitotic neurons and polyclonal smooth muscle, confirming that neurons accumulate somatic mutations at a constant rate throughout life without cell division, with similar rates to mitotically active tissues. Together, our results suggest that mutational processes that are independent of cell division are important contributors to somatic mutagenesis. We anticipate that the ability to reliably detect mutations in single DNA molecules could transform our understanding of somatic mutagenesis and enable non-invasive studies on large-scale cohorts.

Foraging by an avian ecosystem engineer extensively modifies the litter and soil layer in forest ecosystems.

Ecosystem engineers physically modify their environment, thereby altering habitats for other organisms. Increasingly, "engineers" are recognized as an important focus for conservation and ecological restoration because their actions affect a range of ecosystem processes and thereby influence how ecosystems function. The Superb Lyrebird Menura novaehollandiae is proposed as an ecosystem engineer in forests of southeastern Australia due to the volume of soil and litter it turns over when foraging. We measured the seasonal and spatial patterns of foraging by Lyrebirds and the amount of soil displaced in forests in the Central Highlands, Victoria. We tested the effects of foraging on litter, soil nutrients and soil physical properties by using an experimental approach with three treatments: Lyrebird exclusion, Lyrebird exclusion with simulated foraging, and non-exclusion reference plots. Treatments were replicated in three forest types in each of three forest blocks. Lyrebirds foraged extensively in all forest types in all seasons. On average, Lyrebirds displaced 155.7 Mg/ha of litter and soil in a 12-month period. Greater displacement occurred where vegetation complexity (<50 cm height) was low. After two years of Lyrebird exclusion, soil compaction (top 7.5 cm) increased by 37% in exclusion plots compared with baseline measures, while in unfenced plots it decreased by 22%. Litter depth was almost three times greater in fenced than unfenced plots. Soil moisture, pH, and soil nutrients showed no difference between treatments. The enormous extent of litter and soil turned over by the Superb Lyrebird is unparalleled by any other vertebrate soil engineer in terrestrial ecosystems globally. The profound influence of such foraging activity on forest ecosystems is magnified by its year-round pattern and widespread distribution. The disturbance regime that Lyrebirds impose has implications for diverse ecosystem processes including decomposition and nutrient cycling, the composition of litter- and soil-dwelling invertebrate communities, the shaping of ground-layer vegetation patterns, and fire behavior and post-fire ecosystem recovery. Maintaining Lyrebird populations as a key facilitator of ecosystem function is now timely and critical as unprecedented wildfires in eastern Australia in summer 2019-2020 have severely burned ~12 million ha of forest, including ~30% of the geographic range of the Superb Lyrebird.

Single-cell atlas of the first intra-mammalian developmental stage of the human parasite Schistosoma mansoni.

Over 250 million people suffer from schistosomiasis, a tropical disease caused by parasitic flatworms known as schistosomes. Humans become infected by free-swimming, water-borne larvae, which penetrate the skin. The earliest intra-mammalian stage, called the schistosomulum, undergoes a series of developmental transitions. These changes are critical for the parasite to adapt to its new environment as it navigates through host tissues to reach its niche, where it will grow to reproductive maturity. Unravelling the mechanisms that drive intra-mammalian development requires knowledge of the spatial organisation and transcriptional dynamics of different cell types that comprise the schistomulum body. To fill these important knowledge gaps, we perform single-cell RNA sequencing on two-day old schistosomula of Schistosoma mansoni. We identify likely gene expression profiles for muscle, nervous system, tegument, oesophageal gland, parenchymal/primordial gut cells, and stem cells. In addition, we validate cell markers for all these clusters by in situ hybridisation in schistosomula and adult parasites. Taken together, this study provides a comprehensive cell-type atlas for the early intra-mammalian stage of this devastating metazoan parasite.

Animal movements in fire-prone landscapes.

Movement is a trait of fundamental importance in ecosystems subject to frequent disturbances, such as fire-prone ecosystems. Despite this, the role of movement in facilitating responses to fire has received little attention. Herein, we consider how animal movement interacts with fire history to shape species distributions. We consider how fire affects movement between habitat patches of differing fire histories that occur across a range of spatial and temporal scales, from daily foraging bouts to infrequent dispersal events, and annual migrations. We review animal movements in response to the immediate and abrupt impacts of fire, and the longer-term successional changes that fires set in train. We discuss how the novel threats of altered fire regimes, landscape fragmentation, and invasive species result in suboptimal movements that drive populations downwards. We then outline the types of data needed to study animal movements in relation to fire and novel threats, to hasten the integration of movement ecology and fire ecology. We conclude by outlining a research agenda for the integration of movement ecology and fire ecology by identifying key research questions that emerge from our synthesis of animal movements in fire-prone ecosystems.

Copy number variation arising from gene conversion on the human Y chromosome.

We describe the variation in copy number of a ~ 10 kb region overlapping the long intergenic noncoding RNA (lincRNA) gene, TTTY22, within the IR3 inverted repeat on the short arm of the human Y chromosome, leading to individuals with 0-3 copies of this region in the general population. Variation of this CNV is common, with 266 individuals having 0 copies, 943 (including the reference sequence) having 1, 23 having 2 copies, and two having 3 copies, and was validated by breakpoint PCR, fibre-FISH, and 10× Genomics Chromium linked-read sequencing in subsets of 1234 individuals from the 1000 Genomes Project. Mapping the changes in copy number to the phylogeny of these Y chromosomes previously established by the Project identified at least 20 mutational events, and investigation of flanking paralogous sequence variants showed that the mutations involved flanking sequences in 18 of these, and could extend over > 30 kb of DNA. While either gene conversion or double crossover between misaligned sister chromatids could formally explain the 0-2 copy events, gene conversion is the more likely mechanism, and these events include the longest non-allelic gene conversion reported thus far. Chromosomes with three copies of this CNV have arisen just once in our data set via another mechanism: duplication of 420 kb that places the third copy 230 kb proximal to the existing proximal copy. Our results establish gene conversion as a previously under-appreciated mechanism of generating copy number changes in humans and reveal the exceptionally large size of the conversion events that can occur.

The Activity of Antimicrobial Surfaces Varies by Testing Protocol Utilized.

BACKGROUND: Contaminated hospital surfaces are an important source of nosocomial infections. A major obstacle in marketing antimicrobial surfaces is a lack of efficacy data based on standardized testing protocols. AIM: We compared the efficacy of multiple testing protocols against several "antimicrobial" film surfaces. METHODS: Four clinical isolates were used: one Escherichia coli, one Klebsiella pneumoniae, and two Staphylococcus aureus strains. Two industry methods (modified ISO 22196 and ASTM E2149), a "dried droplet", and a "transfer" method were tested against two commercially available antimicrobial films, one film in development, an untreated control, and a positive (silver) control film. At 2 (only ISO) and 24 hours following inoculation, bacteria were collected from film surfaces and enumerated. RESULTS: Compared to untreated films in all protocols, there were no significant differences in recovery on either commercial brand at 2 or 24 hours after inoculation. The silver surface demonstrated significant microbicidal activity (mean loss 4.9 Log10 CFU/ml) in all methods and time points with the exception of 2 hours in the ISO protocol and the transfer method. Using our novel droplet method, no differences between placebo and active surfaces were detected. The surface in development demonstrated variable activity depending on method, organism, and time point. The ISO demonstrated minimal activity at 2 hours but significant activity at 24 hours (mean 4.5 Log10 CFU/ml difference versus placebo). The ASTEM protocol exhibited significant differences in recovery of staphylococci (mean 5 Log10 CFU/ml) but not Gram-negative isolates (10 fold decrease). Minimal activity was observed with this film in the transfer method. CONCLUSIONS: Varying results between protocols suggested that efficacy of antimicrobial surfaces cannot be easily and reproducibly compared. Clinical use should be considered and further development of representative methods is needed.

Isoetes mississippiensis: A new quillwort from Mississippi, USA.

Isoetes mississippiensis S.W. Leonard, W.C. Taylor, L.J. Musselman and R.D. Bray (Isoetaceae, Lycopodiophyta) is a new species known from two sites along tributaries of the Pearl River in southern Mississippi. This species is distinguished from other species in the southeastern United States by a combination of character states including a basic diploid (2n=22) chromosome count, laevigate megaspores, and a narrow velum covering less than one-third of the adaxial sporangium wall.

High-throughput and quantitative genome-wide messenger RNA sequencing for molecular phenotyping.

BACKGROUND: We present a genome-wide messenger RNA (mRNA) sequencing technique that converts small amounts of RNA from many samples into molecular phenotypes. It encompasses all steps from sample preparation to sequence analysis and is applicable to baseline profiling or perturbation measurements. RESULTS: Multiplex sequencing of transcript 3' ends identifies differential transcript abundance independent of gene annotation. We show that increasing biological replicate number while maintaining the total amount of sequencing identifies more differentially abundant transcripts. CONCLUSIONS: This method can be implemented on polyadenylated RNA from any organism with an annotated reference genome and in any laboratory with access to Illumina sequencing.

Surface microbiology of the iPad tablet computer and the potential to serve as a fomite in both inpatient practice settings as well as outside of the hospital environment.

BACKGROUND: The use of tablet computers and other touch screen technology within the healthcare system has rapidly expanded. It has been reported that these devices can harbor pathogens in hospitals; however, much less is known about what pathogens they can harbor when used outside the hospital environment compared to hospital practice. METHODS: Thirty iPads belonging to faculty with a variety of practice settings were sampled to determine the presence and quantity of clinically-relevant organisms. Flocked nylon swabs and neutralizer solution were used to sample the surface of each iPad. Samples were then plated on a variety of selective agars for presence and quantity of selected pathogens. In addition, faculty members were surveyed to classify the physical location of their practice settings and usage patterns. Continuous variables were compared via an unpaired Student's t test with two-tailed distribution; categorical variables were compared with the Fisher's exact test. RESULTS: Of the iPads sampled, 16 belonged to faculty practicing within a hospital and 14 belonged to a faculty member practicing outside a hospital. More faculty within the hospital group used their iPads at their practice sites (78.6% vs. 31.3%; p = 0.014) and within patient care areas (71.4% vs. 18.8%; p = 0.009) than the non-hospital group. There were no differences in the presence, absence, or quantity of, any of the pathogens selectively isolated between groups. Problematic nosocomial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and P. aeruginosa were isolated from both hospital and non-hospital faculty iPads. CONCLUSIONS: Gram positive and Gram negative organisms were recovered from the surfaces of iPads regardless of practice setting; these included problematic multidrug-resistant pathogens like MRSA, VRE, and Pseudomonas aeruginosa. Healthcare personnel in all settings should be aware of the potential for tablet computers to serve as a nidus for microorganism transmission.

SASI-Seq: sample assurance Spike-Ins, and highly differentiating 384 barcoding for Illumina sequencing.

BACKGROUND: A minor but significant fraction of samples subjected to next-generation sequencing methods are either mixed-up or cross-contaminated. These events can lead to false or inconclusive results. We have therefore developed SASI-Seq; a process whereby a set of uniquely barcoded DNA fragments are added to samples destined for sequencing. From the final sequencing data, one can verify that all the reads derive from the original sample(s) and not from contaminants or other samples. RESULTS: By adding a mixture of three uniquely barcoded amplicons, of different sizes spanning the range of insert sizes one would normally use for Illumina sequencing, at a spike-in level of approximately 0.1%, we demonstrate that these fragments remain intimately associated with the sample. They can be detected following even the tightest size selection regimes or exome enrichment and can report the occurrence of sample mix-ups and cross-contamination.As a consequence of this work, we have designed a set of 384 eleven-base Illumina barcode sequences that are at least 5 changes apart from each other, allowing for single-error correction and very low levels of barcode misallocation due to sequencing error. CONCLUSION: SASI-Seq is a simple, inexpensive and flexible tool that enables sample assurance, allows deconvolution of sample mix-ups and reports levels of cross-contamination between samples throughout NGS workflows.

Clinical Outcomes in Patients with Heterogeneous Vancomycin-Intermediate Staphylococcus aureus Bloodstream Infection.

The prevalence of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) infections varies in the literature, a problem complicated by the lack of routine screening procedures; however, limited data suggest that hVISA has been associated with persistent bloodstream infections (BSI) and vancomycin failure, yet these studies have been confounded by design issues. We conducted this study to compare the characteristics of patients with BSI caused by hVISA with those with vancomycin-susceptible Staphylococcus aureus (VSSA) treated with vancomycin. This retrospective, multicenter matched (1:1) cohort study compared the clinical characteristics and outcomes of hVISA and VSSA. Patients with hVISA methicillin-resistant Staphylococcus aureus (MRSA) BSI from 2004 to 2012 were matched to VSSA-MRSA BSI patients. The primary outcome was failure of vancomycin treatment, defined as a composite of persistent bacteremia (≥7 days), persistent signs and symptoms, change of MRSA antibiotic, recurrent BSI, or MRSA-related mortality. We identified 122 matched cases. The overall vancomycin failure rate was 57% (82% hVISA versus 33% VSSA; P < 0.001). The individual components of failure in hVISA versus VSSA were persistent bacteremia, 59% versus 21% (P < 0.001); change in MRSA therapy, 54% versus 25% (P = 0.001); MRSA-related mortality, 21% versus 10% (P = 0.081); and recurrence of BSI, 26% versus 2% (P < 0.001). Using logistic regression analysis and adjusting for covariates, hVISA (adjusted odds ratio [aOR], 11.1; 95% confidence interval [CI], 4.3 to 28.7) and intensive care unit (ICU) admission (aOR, 4.5; 95% CI, 1.8 to 11.6) were still independently associated with vancomycin failure. Relative to VSSA BSI, patients with hVISA were more likely to experience failure of vancomycin treatment, including persistent bacteremia and recurrence. Our results indicate that hVISA was responsible for considerable morbidity.

Comparative activities of telavancin combined with nafcillin, imipenem, and gentamicin against Staphylococcus aureus.

Beta-lactams enhance the killing activity of vancomycin. Due to structural and mechanistic similarities between vancomycin and telavancin, we investigated the activity of telavancin combined with nafcillin and imipenem compared to the known synergistic combination of telavancin and gentamicin. Thirty strains of Staphylococcus aureus, 10 methicillin-susceptible S. aureus (MSSA), 10 methicillin-resistant S. aureus (MRSA), and 10 heterogeneously vancomycin-intermediate S. aureus (hVISA), were tested for synergy by time-kill methodology. Six strains (2 each of MSSA, MRSA, and hVISA) were further evaluated in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model with simulated regimens of 10 mg/kg of body weight of telavancin once daily alone and combined with 2 g nafcillin every 4 h, 500 mg imipenem every 6 h, or 5 mg/kg gentamicin once daily over 72 h. In the synergy test, 67% of strains displayed synergy with the combination of telavancin and gentamicin, 70% with telavancin and nafcillin, and 63% with telavancin and imipenem. In the PK/PD model, the activities of all three combinations against MRSA and hVISA were superior to all individual drugs alone (P ≤ 0.002) and were similar to each other (P ≥ 0.187). The activities of all three combinations against MSSA were generally similar to each other except for one strain where the combination of telavancin and imipenem was superior to all other regimens (P ≤ 0.011). The activity of the combination of telavancin and beta-lactam agents was similar to that of telavancin and gentamicin against S. aureus, including resistant strains. Because beta-lactam combinations are less likely to be nephrotoxic than telavancin plus gentamicin, these beta-lactam combinations may have clinical utility.

Evaluation of the combination of daptomycin and nafcillin against vancomycin-intermediate Staphylococcus aureus.

OBJECTIVES: Continued selective pressure from glycopeptide use has led to non-susceptible strains of Staphylococcus aureus, including vancomycin-intermediate S. aureus (VISA). Though relatively uncommon, VISA presents a particularly difficult clinical challenge when it arises. Pertinent to this investigation is the correlation between vancomycin intermediacy and daptomycin non-susceptibility. The aim of this study was to evaluate the potential for synergy between daptomycin and nafcillin against VISA. METHODS: Twenty VISA strains were evaluated for daptomycin and nafcillin MICs by broth microdilution in duplicate. Potential for synergy was assessed by time-kill at 0.5× MIC in triplicate. Four strains displaying synergy in time-kill analysis were analysed in an in vitro pharmacokinetic (PK)/pharmacodynamic (PD) model in duplicate over 72 h. RESULTS: In time-kill experiments, 55% of strains (11/20) displayed synergy with the combination. In the PK/PD model, no differences between daptomycin-alone and combination regimens were observed for the strain with the lowest daptomycin MIC (0.5 mg/L). For the strain with a daptomycin MIC of 1 mg/L, 6 mg/kg daptomycin+nafcillin was superior to 6 mg/kg daptomycin alone (P=0.002) and 10 mg/kg daptomycin+nafcillin was superior to all other regimens (P ≤ 0.004). When the daptomycin MIC increased to 2 mg/L, 10 mg/kg daptomycin+nafcillin was superior to 6 mg/kg daptomycin+nafcillin, which was superior to both 6 and 10 mg/kg daptomycin alone (P ≤ 0.019). CONCLUSIONS: Daptomycin and nafcillin in combination significantly improved antibacterial activity against VISA. This effect was more pronounced as the daptomycin susceptibility of the strain declined.

Use of the cardioprotectants thymosin ß4 and dexrazoxane during congenital heart surgery: proposal for a randomized, double-blind, clinical trial.

Neonates and infants undergoing heart surgery with cardioplegic arrest experience both inflammation and myocardial ischemia-reperfusion (IR) injury. These processes provoke myocardial apoptosis and oxygen-free radical formation that result in cardiac injury and dysfunction. Thymosin ß4 (Tß4) is a naturally occurring peptide that has cardioprotective and antiapoptotic effects. Similarly, dexrazoxane provides cardioprotection by reduction of toxic reactive oxygen species (ROS) and suppression of apoptosis. We propose a pilot pharmacokinetic/safety trial of Tß4 and dexrazoxane in children less than one year of age, followed by a randomized, double-blind, clinical trial of Tß4 or dexrazoxane versus placebo during congenital heart surgery. We will evaluate postoperative time to resolution of organ failure, development of low cardiac output syndrome, length of cardiac ICU and hospital stays, and echocardiographic indices of cardiac dysfunction. Results could establish the clinical utility of Tß4 and/or dexrazoxane in ameliorating ischemia-reperfusion injury during congenital heart surgery.

An introductory review module for an anti-infectives therapeutics course.

OBJECTIVE: To determine whether an introductory review module using a hybrid-learning approach helped students learn infectious disease management in an anti-infectives therapeutics course. DESIGN: An introductory module consisting of an online pharmacology review, pre-class assignment, 2 classroom lectures, and 1 case-based lecture was developed and implemented. ASSESSMENT: Among the 110 students who completed pre- and post-tests on the material covered, average scores increased from 71% to 83% (p<0.0001). Performance on knowledge-based question improved for 8 out of 10 questions (p<0.05) and student confidence increased from the first lecture to completion of the module (p<0.001 for all comparisons). Of the 129 students who completed an evaluation of the introductory module, 98% strongly agreed or agreed that the content was essential for course success. CONCLUSION: The addition of an introductory module using a hybrid-learning approach to review and solidify concepts of medical microbiology and pharmacology provided the foundation necessary for success in an infectious diseases module.

Synergy between vancomycin and nafcillin against Staphylococcus aureus in an in vitro pharmacokinetic/pharmacodynamic model.

INTRODUCTION: Continued pressure from glycopeptide use has led to non-susceptible strains of Staphylococcus aureus including heterogeneously vancomycin-intermediate S. aureus (hVISA). Infections with hVISA are associated with poor patient outcomes, thus incentivizing novel treatments. Evidence suggests that vancomycin and anti-staphylococcal penicillin susceptibility are inversely related which indicates that the use of this combination may be particularly useful against methicillin-resistant S. aureus with reduced susceptibility to vancomycin, such as hVISA. The aim of this study was to evaluate the potential for synergy between vancomycin and nafcillin against hVISA. METHODS: Twenty-five hVISA strains were evaluated for vancomycin and nafcillin minimum inhibitory concentration (MIC) by broth microdilution in duplicate. Potential for synergy was assessed by time-kill at 1/2x MIC in triplicate. Five strains were chosen, representing the range nafcillin MIC's available in the cohort -4, 16, 64, 128, and 256 µg/mL, and were run in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model in duplicate over 72 hours to evaluate the potential of the combination with simulated human pharmacokinetics. In addition, 4 fully glycopeptide susceptible strains of S. aureus including 2 methicillin-susceptible (MSSA) and 2 methicillin-resistant (MRSA) were run in the PK/PD model for comparison. RESULTS: In the time-kill, 92% of strains (23 of 25) displayed synergy with the combination of vancomycin and nafcillin. In the PK/PD model, all five strains of hVISA showed an improvement in overall activity (P≤0.004) and organism burden at 72 hours (P≤0.001) with the combination compared to either drug alone. The combination was also successful against both MRSA and MSSA in overall activity (P≤0.009) and organism burden at 72 hours (P≤0.016), though the magnitude of the effect was diminished against MSSA. CONCLUSIONS: The combination of vancomycin and nafcillin significantly improved antibacterial activity against hVISA, MRSA, and MSSA compared to either drug alone.