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Motivation Data normalization is essential to ensure accurate inference and comparability of gene expression measures across samples or conditions. Ideally, gene expression data should be rescaled based on consistently expressed reference genes. However, to normalize biologically diverse samples, the most commonly used reference genes exhibit striking expression variability and size-factor or distribution-based normalization methods can be problematic when the amount of asymmetry in differential expression is significant. Results We report an efficient and accurate data-driven method—Cosine score-based iterative normalization (Cosbin)—to normalize biologically diverse samples. Based on the Cosine scores of cross-condition expression patterns, the Cosbin pipeline iteratively eliminates asymmetric differentially expressed genes, identifies consistently expressed genes, and calculates sample-wise normalization factors. We demonstrate the superior performance and enhanced utility of Cosbin compared with six representative peer methods using both simulation and real multi-omics expression datasets. Implemented in open-source R scripts and specifically designed to address normalization bias due to significant asymmetry in differential expression across multiple conditions, the Cosbin tool complements rather than replaces the existing methods and will allow biologists to more accurately detect true molecular signals among diverse phenotypic groups. Availability and implementation The R scripts of Cosbin pipeline are freely available at https://github.com/MinjieSh/Cosbin. Supplementary information Supplementary data are available at Bioinformatics Advances online. [ABSTRACT FROM AUTHOR]

Objectives: During 2010-2018, the Arkansas Department of Health reported 21 genotype-matched cases of tuberculosis (TB) among residents of a rural county in Arkansas with a low incidence of TB and in nearby counties. The Arkansas Department of Health and the Centers for Disease Control and Prevention investigated to determine the extent of TB transmission and provide recommendations for TB control. Methods: We reviewed medical and public health records, interviewed patients, and reviewed patients' social media posts to describe patient characteristics, identify epidemiologic links, and establish likely chains of transmission. Results: We identified 21 cases; 11 reported during 2010-2013 and 10 during 2016-2018. All case patients were US-born non-Hispanic Black people. Eighteen case patients had the outbreak genotype, and 3 clinically diagnosed (non–culture-confirmed) case patients had epidemiologic links to patients with the outbreak genotype. Social media reviews revealed epidemiologic links among 10 case patients not previously disclosed during interviews. Eight case patients (38%) had ≥1 health care visit during their infectious period, and 7 patients had estimated infectious periods of >12 months. Conclusions: Delayed diagnoses and prolonged infectiousness led to TB transmission in this rural community. TB education and awareness is critical to reducing transmission, morbidity, and mortality, especially in areas where health care providers have limited TB experience. Use of social media can help elucidate people at risk, especially when traditional TB investigation techniques are insufficient. [ABSTRACT FROM AUTHOR]

Background: Species of Trichinella are globally important foodborne parasites infecting a number of domestic and wild vertebrates, including humans. Free-ranging carnivores can act as sentinel species for detection of Trichinella spp. Knowledge of the epidemiology of these parasites may help prevent Trichinella spp. infections in northern Canadian animals and people. Previous research on Trichinella spp. in wildlife from Yukon did not identify risk factors associated with infection, or the diversity and identity of species of Trichinella in regional circulation, based on geographically extensive sampling with large sample sizes. Methods: In a cross-sectional study, we determined the prevalence, infection intensity, risk factors, and species or genotypes of Trichinella in wolverine (Gulo gulo) in two regions of Yukon, Canada, from 2013–2017. A double separatory funnel digestion method followed by mutiplex PCR and PCR-RFLP were used to recover and identify species of Trichinella, respectively. Results: We found larvae of Trichinella in the tongues of 78% (95% CI 73–82) of 338 wolverine sampled. The odds of adult (≥ 2 years) and yearling (1 year) wolverine being Trichinella spp.-positive were four and two times higher, respectively, compared to juveniles (<1 year). The odds of Trichinella spp. presence were three times higher in wolverine from southeast than northwest Yukon. The mean intensity of infection was 22.6 ± 39 (SD, range 0.1–295) larvae per gram. Trichinella T6 was the predominant genotype (76%), followed by T. nativa (8%); mixed infections with Trichinella T6 and T. nativa (12%) were observed. In addition, T. spiralis was detected in one wolverine. Out of 22 isolates initially identified as T. nativa in multiplex PCR, 14 were analyzed by PCR-RFLP to distinguish them from T. chanchalensis, a recently discovered cryptic species, which cannot be distinguished from the T. nativa on multiplex PCR. Ten isolates were identified either as T. chanchalensis alone (n = 7), or mixed infection with T. chanchalensis and T. nativa (n = 2) or T. chanchalensis and Trichinella T6 (n = 1)]. Conclusions: Wolverine hosted high prevalence, high larval intensity, and multiple species of Trichinella, likely due to their scavenging habits, apex position in the food chain, and wide home range. Wolverine (especially adult males) should be considered as a sentinel species for surveys for Trichinella spp. across their distributional range. [ABSTRACT FROM AUTHOR]

Abnormal processing of TAR DNA binding protein 43 (TDP-43) has been identified as a major factor in neuronal degeneration during amyotrophic lateral sclerosis (ALS) or frontotemporal lobar degeneration (FTLD). It is unclear how changes to TDP-43, including nuclear to cytosolic translocation and subsequent accumulation, are controlled in these diseases. TDP-43 is a member of the heterogeneous ribonucleoprotein (hnRNP) RNA binding protein family and is known to associate with cytosolic RNA stress granule proteins in ALS and FTLD. hnRNP trafficking and accumulation is controlled by the action of specific kinases including members of the mitogen-activated protein kinase (MAPK) pathway. However, little is known about how kinase pathways control TDP-43 movement and accumulation. In this study, we used an in vitro model of TDP-43-positve stress granule formation to screen for the effect of kinase inhibitors on TDP-43 accumulation. We found that while a number of kinase inhibitors, particularly of the MAPK pathways modulated both TDP-43 and the global stress granule marker, human antigen R (HuR), multiple inhibitors were more specific to TDP-43 accumulation, including inhibitors of cyclin-dependent kinases (CDKs) and glycogen synthase kinase 3 (GSK3). Close correlation was observed between effects of these inhibitors on TDP-43, hnRNP K and TIAR, but often with different effects on HuR accumulation. This may indicate a potential interaction between TDP-43, hnRNP K and TIAR. CDK inhibitors were also found to reverse pre-formed TDP-43-positive stress granules and both CDK and GSK3 inhibitors abrogated the accumulation of C-terminal TDP-43 (219–414) in transfected cells. Further studies are required to confirm the specific kinases involved and whether their action is through phosphorylation of the TDP-43 binding partner hnRNP K. This knowledge provides a valuable insight into the mechanisms controlling abnormal cytoplasmic TDP-43 accumulation and may herald new opportunities for kinase modulation-based therapeutic intervention in ALS and FTLD. [ABSTRACT FROM AUTHOR]

Abstract: Five on-farm practices for reduction of Salmonella shedding or sero-prevalence in grow-finish swine were selected through scoping study and expert consultation. Specific examples were selected based on supporting evidence from at least one controlled trial (CT), and availability to Canadian swine producers. Efficacy was evaluated using systematic review and meta-analysis (SR-MA) methodology. A modified Grading of Recommendations, Assessment, and Evaluation (GRADE) approach was applied to assess the quality of evidence for each intervention, and a ‘summary of findings’ table was developed to present findings ‘at-a-glance’. MA of the small dataset of CTs investigating feeding meal, and measuring serology, yielded a significant summary estimate of efficacy (odds ratio (OR)=0.21; 95% confidence intervals (CI): 0.14, 0.31) with non-significant heterogeneity (P >0.10). MA of the dataset investigating inclusion of organic acids in the ration, measuring serology, yielded a significant summary estimate with significant heterogeneity across studies (P <0.001, I 2 =91%) precluding presentation of a single summary estimate; a range of results were reported (OR Range: 28 (1.6, 498); 0.07 (CI: 0.042, 0.33)). Pen disinfection between batches of finishers was studied in one large CT measuring both fecal culture (OR 0.84 (0.68, 1.1)) and serology (OR 0.48 (0.40, 0.58)) outcomes. The dataset investigating Salmonella spp. vaccination contained inconsistent findings (OR Range: 4.5 (1.3, 15); 0.07 (0.008, 0.68)), with significant heterogeneity across studies (P =0.005, I 2 =82), assessed measuring fecal culture. MA of the dataset investigating inclusion of in-feed tetracyclines yielded a significant OR indicating a potential harmful effect, measuring fecal culture, (OR Range: 14 (1.9, 108); 1.0 (0.43, 2.5)) with significant heterogeneity (P =0.003, I 2 =82%) across studies, suggesting some potential for withdrawal of in-feed tetracyclines to reduce Salmonella shedding. Therefore our ranking of intervention efficacy is: feeding meal>inclusion of acids in ration, feeder pen disinfection or Salmonella spp. vaccination>in-feed tetrayclines. Study design characteristics increasing risk of bias, including failure to justify sample size (19 of 31 studies) and failure to report random or systematic sampling (13 of 31studies), resulted in modified GRADE evidence rankings of ‘low’ for these interventions. This suggests that further research is likely to affect our findings. Field CTs investigating herd-level interventions with measurements at the herd- and individual-levels are recommended. Overall, SR-MA was a useful approach for ranking efficacy, and GRADE offered a transparent method for ranking quality of evidence, although both were limited by the small number of comparable studies available. [Copyright &y& Elsevier]

Abstract: The larval stage (syn Cysticercus bovis) of the human tapeworm Taenia saginata causes cysticercosis in cattle, which has both aesthetic and food safety implications to consumers of beef. A monoclonal antibody-based immunohistochemical (IHC) assay developed to improve postmortem diagnosis of this parasite and a standard histological method were assessed to determine their fitness for intended use. Sections from 169 known-positive specimens of T. saginata from experimentally or naturally infected cattle, and from 30 known-negative specimens and lesions of various etiologies from non-infected cattle, were tested. The IHC assay identified significantly more known positive bovine cysticerci than the histological method (91.7% and 38.5%, respectively). Positive IHC staining occurred on sections from other cestode species, but should not affect the diagnostic specificity of this assay for bovine cysticercosis, due to the different host and/or tissue preferences amongst these parasites. Use of the IHC assay should improve the reliability of diagnosing lesions caused by degenerated cysticerci, facilitating more effective and efficient control of bovine cysticercosis. [Copyright &y& Elsevier]

Abstract: Copper (Cu) has a critical role in the generation of oxidative stress during neurodegeneration and cancer. Reactive oxygen species generated through abnormal elevation or deficiency of Cu can lead to lipid, protein, and DNA damage. Oxidation of DNA can induce strand breaks and is associated with altered cell fate including transformation or death. DNA repair is mediated through the action of the multimeric DNA–PK repair complex. The components of this complex are the Ku autoantigens, XRCC5 and XRCC6 (Ku80 and Ku70, respectively). How this repair complex responds to perturbed Cu homeostasis and Cu-mediated oxidative stress has not been investigated. We previously reported that XRCC5 expression is altered in response to cellular Cu levels, with low Cu inhibiting XRCC5 expression and high Cu levels enhancing expression. In this study we further investigated the interaction between XRCC5 and Cu. We report that cytosolic XRCC5 is increased in response to Cu, but not zinc, iron, or nickel, and the level of cytosolic XRCC5 correlates with protection against oxidative damage to DNA. These observations were made in both HeLa cells and fibroblasts. Cytosolic XRCC5 interacted with the Cu chaperone and detoxification protein human Atox1 homologue (HAH), and down regulation of XRCC5 expression using siRNA led to enhanced HAH expression when cells were exposed to Cu. XRCC5 could also be purified from cytosolic extracts using a Cu-loaded column. These findings provide further evidence that cytosolic XRCC5 has a key role in protection against DNA oxidation from Cu, through either direct sequestration or signaling through other Cu-detoxification molecules. Our findings have important implications for the development of therapeutic treatments targeting Cu in neurodegeneration and/or cancer. [Copyright &y& Elsevier]

Premise of the study: Early reproductive maturity is common in dry and ephemeral habitats and often associated with smaller flowers with increased potential for within-flower (autonomous) self-pollination. We investigated whether populations from locations that differ in moisture availability, known to vary for whole-plant development rate, also varied in the timing of autonomous selfing. This timing is of interest because the modes of selfing (prior, competing, and delayed) have different fitness consequences. Methods: We measured timing of anther dehiscence, stigma receptivity, and herkogamy under pollinator-free conditions for plants from three populations of Collinsia parviflora that differed in annual precipitation, flower size, and time to sexual maturity. Using a manipulative experiment, we determined potential seed production via prior, competing, and delayed autonomous selfing for each population. Key results: Stigma receptivity, anther dehiscence, and selfing ability covaried with whole-plant development and climate. Plants from the driest site, which reached sexual maturity earliest, had receptive stigmas and dehiscent anthers in bud. Most seeds were produced via prior selfing. The population from the wettest site with slowest development was not receptive until after flowers opened. Although competing selfing was possible, all selfing was delayed. The intermediate population was between these extremes, with significant contributions from both competing and delayed selfing. Conclusions: Our results demonstrate that within-species variation in the timing of selfing occurs and is related to both environmental conditions and whole-plant development rates. We suggest that, if these results can be generalized to other species. mating systems may evolve in response to ongoing climatic change. [ABSTRACT FROM AUTHOR]

This paper reports an investigation of the use of Two-Photon Absorption (TPA) of blue laser pulses and production of ultraviolet pulses through Second Harmonic Generation (SHG) to simulate single event effects involving ionization and charge trapping in dielectrics. [ABSTRACT FROM AUTHOR]

Objectives: The diagnostic process is a vital component of safe and effective emergency department (ED) care. There are no standardized methods for identifying or reliably monitoring diagnostic errors in the ED, impeding efforts to enhance diagnostic safety. We sought to identify trigger concepts to screen ED records for diagnostic errors and describe how they can be used as a measurement strategy to identify and reduce preventable diagnostic harm. Methods: We conducted a literature review and surveyed ED directors to compile a list of potential electronic health record (EHR) trigger (e-triggers) and non-EHR based concepts. We convened a multidisciplinary expert panel to build consensus on trigger concepts to identify and reduce preventable diagnostic harm in the ED. Results: Six e-trigger and five non-EHR based concepts were selected by the expert panel. E-trigger concepts included: unscheduled ED return to ED resulting in hospital admission, death following ED visit, care escalation, high-risk conditions based on symptom-disease dyads, return visits with new diagnostic/therapeutic interventions, and change of treating service after admission. Non-EHR based signals included: cases from mortality/morbidity conferences, risk management/ safety office referrals, ED medical director case referrals, patient complaints, and radiology/laboratory misreads and callbacks. The panel suggested further refinements to aid future research in defining diagnostic error epidemiology in ED settings. Conclusions: We identified a set of e-trigger concepts and non-EHR based signals that could be developed further to screen ED visits for diagnostic safety events. With additional evaluation, trigger-based methods can be used as tools to monitor and improve ED diagnostic performance. [ABSTRACT FROM AUTHOR]

Objectives: Few studies describe the impact of antimicrobial stewardship programs (ASPs) on recognizing and preventing diagnostic errors. Handshake stewardship (HS-ASP) is a novel ASP model that prospectively reviews hospital-wide antimicrobial usage with recommendations made in person to treatment teams. The purpose of this study was to determine if HS-ASP could identify and intervene on potential diagnostic errors for children hospitalized at a quaternary care children’s hospital. Methods: Previously self-identified “Great Catch” (GC) interventions by the Children’s Hospital Colorado HS-ASP team from 10/2014 through 5/2018 were retrospectively reviewed. Each GC was categorized based on the types of recommendations from HS-ASP, including if any diagnostic recommendations were made to the treatment team. Each GC was independently scored using the “Safer Dx Instrument” to determine presence of diagnostic error based on a previously determined cut-off score of ≤1.50. Interrater reliability for the instrument was measured using a randomized subset of one third of GCs. Results: During the study period, there were 162 GC interventions. Of these, 65 (40%) included diagnostic recommendations by HS-ASP and 19 (12%) had a Safer Dx Score of ≤1.50, (Κ=0.44; moderate agreement). Of those GCs associated with diagnostic errors, the HS-ASP team made a diagnostic recommendation to the primary treatment team 95% of the time. Conclusions: Handshake stewardship has the potential to identify and intervene on diagnostic errors for hospitalized children. [ABSTRACT FROM AUTHOR]

Medical training as a process of professional socialization has been well explored within the fields of medical education, medical sociology and medical anthropology. Our contribution is to outline a bio-power, more specifically an anatomo-politics, of medical education. The current research aimed to explore perspectives on what is commonly termed the ‘hidden curriculum’. We conducted interviews with pre-clinical medical students, clinical teachers and medical educators within a New Zealand medical school. In this paper, we outline ways that respondents described the juxtaposition of the undeclared or hidden aspects of medical education with the formal declared curriculum. Our respondents were aware of incongruencies across these components that resulted in mixed messages to students. Curricula initiatives aim to encourage new forms of subjectivity so that students are often expected to be the kinds of doctors that their teachers are not. However, the success of such initiatives is dependent on the degree of alignment between informal and formal components of the curriculum. [ABSTRACT FROM AUTHOR]

Group A Streptococcus (GAS) is an important human pathogen that causes many types of infections, including pharyngitis and severe invasive diseases. We recently sequenced the genome of a serotype M3 strain and identified a prophage-encoded secreted phospholipase A2 designated SlaA. To study SlaA structure-activity relationships, 20 site-specific mutants were constructed by alanine-replacement mutagenesis and purified to apparent homogeneity. Enzymatic activity was greatly reduced by alanine replacement of amino acid residues previously described as crucial in the catalytic mechanism of secreted phospholipase A2. Similarly, substitution of five residues in an inferred Ca2+binding loop and three residues in the inferred active site region resulted in loss of activity of 76.5% or greater relative to the wild-type enzyme. Analysis of enzyme substrate specificity confirmed SlaA as a phospholipase A2, with activity against multiple phospholipid head groups and acyl chains located at the sn-2 position. PCR analysis of 1,189 GAS strains representing 48 M protein serotypes commonly causing human infections identified the slaA gene in 129 strains of nine serotypes (M1, M2, M3, M4, M6, M22, M28, M75, and st3757). Expression of SlaA by strains of these serotypes was confirmed by Western immunoblot. SlaA production increased rapidly and substantially on co-culture with Detroit 562 human pharyngeal epithelial cells. Together, these data provide new information about a novel extracellular enzyme that participates in GAS-human interactions. [ABSTRACT FROM AUTHOR]

Sixty four members of the public were exposed to the same staged conversation either while waiting in a bus station or travelling on a train. Half of the conversations were by mobile phone, so that only one end of the conversation was heard, and half were co present face-to-face conversations. The volume of the conversations was controlled at one of two levels: the actors' usual speech level and exaggeratedly loud. Following exposure to the conversation participants were approached and asked to give verbal ratings on six scales. Analysis of variance showed that mobile phone conversations were significantly more noticeable and annoying than face-to-face conversations at the same volume when the content of the conversation is controlled. Indeed this effect of medium was as large as the effect of loudness. Various explanations of this effect are explored, with their practical implications. [ABSTRACT FROM AUTHOR]

Summary In this report we describe the 1500-fold purification and characterization of the haemolytic phospholipase C (PLC) of Pseudomonas aeruginosa , the paradigm member of a novel PLC/phosphatase superfamily. Members include proteins from Mycobacterium tuberculosis, Bordetella spp., Francisella tularensis and Burkholderia pseudomallei . Purification involved overexpression of the plcHR 1,2 operon, ion exchange chromatography and native preparative polyacrylamide gel electrophoresis. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry confirmed the presence of two proteins in the purified sample with sizes of 17 117.2 Da (PlcR2 ) and 78 417 Da (PlcH). Additionally, liquid chromatography electrospray mass spectrometry (LCMS) revealed that PlcH and PlcR2 are at a stoichiometry of 1 : 1. Western blot analysis demonstrated that the enzyme purifies as a heterodimeric complex, PlcHR2 . PlcHR2 is only active on choline-containing phospholipids. It is equally active on phosphatidylcholine (PC) and sphingomyelin (SM) and is able to hydrolyse plasmenylcholine phospholipids (plasmalogens). Neither PlcHR2 nor the M. tuberculosis homologues are inhibited by D609 a widely used, competitive inhibitor of the Bacillus cereus PLC. PlcH, PlcR2 , and the PlcHR2 complex bind calcium. While calcium has no detectable effect on enzymatic activity, it inhibits the haemolytic activity of PlcHR2 . In addition to being required for the secretion of PlcH, the chaperone PlcR2 affects both the enzymatic and haemolytic properties of PlcH. Inclusive in these data is the con-clusion that the members of this PC-PLC and phosphatase family possess a novel mechanism for the recognition and hydrolysis of their respective substrates. [ABSTRACT FROM AUTHOR]

Surgical training includes the development of technical and nontechnical skills. While technical skills are more easily quantified, nontechnical skills such as situation awareness (SA) are more difficult to measure and quantify. This study investigated the relationships between different SA elements and expertise. Twenty attending and resident surgeons rated their anticipation of an impending adverse event while watching 20 videos of laparoscopic cholecystectomies with and without adverse events. After watching each video, they assessed surgeon skills and self-assessed their anticipation ratings. All participants answered a general confidence questionnaire before and after the study. Videos with adverse events led to significantly higher anticipation of adverse events (P < 0.001), lower surgeon skill rating (P < 0.001), and higher self-assessment in their anticipation ratings (P < 0.001) across both participant groups. General confidence was significantly lower for residents than that for attending surgeons (P < 0.001). Compared with the residents, attendings exhibited stronger and more stable correlations between measurements of SA. When viewing videos with adverse events, attendings showed significantly higher correlation between anticipation of an impending adverse event and skill assessment of the surgeon (P = 0.005). This study investigated how different elements of SA and their relationships were influenced by experience. The results indicated that attendings had stronger and more stable correlations between SA elements than residents, demonstrating how measurement correlations could be meaningful and sensitive indicators of expertise and autonomy readiness. [ABSTRACT FROM AUTHOR]

Background: Species of Trichinella are globally important foodborne parasites infecting a number of domestic and wild vertebrates, including humans. Free-ranging carnivores can act as sentinel species for detection of Trichinella spp. Knowledge of the epidemiology of these parasites may help prevent Trichinella spp. infections in northern Canadian animals and people. Previous research on Trichinella spp. in wildlife from Yukon did not identify risk factors associated with infection, or the diversity and identity of species of Trichinella in regional circulation, based on geographically extensive sampling with large sample sizes. Methods: In a cross-sectional study, we determined the prevalence, infection intensity, risk factors, and species or genotypes of Trichinella in wolverine (Gulo gulo) in two regions of Yukon, Canada, from 2013–2017. A double separatory funnel digestion method followed by mutiplex PCR and PCR-RFLP were used to recover and identify species of Trichinella, respectively. Results: We found larvae of Trichinella in the tongues of 78% (95% CI 73–82) of 338 wolverine sampled. The odds of adult (≥ 2 years) and yearling (1 year) wolverine being Trichinella spp.-positive were four and two times higher, respectively, compared to juveniles (<1 year). The odds of Trichinella spp. presence were three times higher in wolverine from southeast than northwest Yukon. The mean intensity of infection was 22.6 ± 39 (SD, range 0.1–295) larvae per gram. Trichinella T6 was the predominant genotype (76%), followed by T. nativa (8%); mixed infections with Trichinella T6 and T. nativa (12%) were observed. In addition, T. spiralis was detected in one wolverine. Out of 22 isolates initially identified as T. nativa in multiplex PCR, 14 were analyzed by PCR-RFLP to distinguish them from T. chanchalensis, a recently discovered cryptic species, which cannot be distinguished from the T. nativa on multiplex PCR. Ten isolates were identified either as T. chanchalensis alone (n = 7), or mixed infection with T. chanchalensis and T. nativa (n = 2) or T. chanchalensis and Trichinella T6 (n = 1)]. Conclusions: Wolverine hosted high prevalence, high larval intensity, and multiple species of Trichinella, likely due to their scavenging habits, apex position in the food chain, and wide home range. Wolverine (especially adult males) should be considered as a sentinel species for surveys for Trichinella spp. across their distributional range. [ABSTRACT FROM AUTHOR]

The mecA gene is commonly used to identify resistance in Staphylococcus aureus , but historically is not used for coagulase-negative staphylococci (CoNS). Analysis of 412 staphylococcal blood cultures (2014–2018) revealed that the absence of mecA had high concordance (100%) with oxacillin susceptibility for S. aureus and CoNS alike. [ABSTRACT FROM AUTHOR]

Purpose: At Children's Hospital Colorado (CHCO), there are approximately 40 000 inpatient anti-infective orders every year resulting over 100 000 dispenses. Significant quantities of anti-infectives are wasted, incurring roughly $100 000 in waste annually. Identifying areas for improvement will result in cost savings and ameliorate the impact of drug shortages. Summary: This descriptive report discusses the reasons for anti-infective waste at a free-standing, quaternary-care, pediatric hospital. The anti-infectives with the highest cost in waste ($) included meropenem ($38 084), micafungin ($21 690), amphotericin B liposome ($15 913). An internal audit of CHCO anti-infective waste revealed that drugs are wasted for the following reasons: patient discharge, medication order discontinuation or change, and misplaced doses. Conclusion: The CHCO Antimicrobial Stewardship Program and the Pharmacy have proposed 4 process improvement measures that will target anti-infective waste to reduce pharmaceutical waste and hospital costs. These measures may be applicable to other drug classes that likely suffer from a similar proportion of waste. [ABSTRACT FROM AUTHOR]

Background Children's Hospital Colorado created a unique method of antimicrobial stewardship, called handshake stewardship, that effectively decreased hospital anti-infective use and costs in its pilot year (2013). Handshake stewardship is distinguished by: (1) the lack of prior authorization; (2) a review of all prescribed anti-infectives; (3) a shared review by the physician and the pharmacist; and (4) a daily, rounding-based, in-person approach to supporting providers. We sought to reevaluate the outcomes of the program after 5 years of experience, totaling 8 years of data. Methods We retrospectively measured anti-infective (antibiotic, antiviral, antifungal) use hospital-wide by unit and by drug for an 8-year period spanning October 2010 to October 2018. Aggregated monthly use was measured in days of therapy per thousand patient days (DOT/1000 PD). The percentage of children admitted ever receiving an anti-infective was also measured, as well as severity-adjusted mortality, readmissions, and lengths of stay. Results Hospital-wide mean anti-infective use significantly decreased, from 891 (95% confidence interval [CI] 859–923) in the pre-implementation phase to 655 (95% CI 637–694) DOT/1000 PD in post-implementation Year 5; in a segmented regression time series analysis, this was a rate of -2.6 DOT/1000 PD (95% CI -4.8 to -0.4). This is largely attributable to decreased antibacterial use, from 704 (95% CI 686–722) to 544 (95% CI 525 –562) DOT/1000 PD. The percentage of children ever receiving an anti-infective during admission likewise declined, from 65% to 52% (95% CI 49–54). There were no detrimental effects on severity adjusted mortality, readmissions, or lengths of stay. Conclusions The handshake method is an effective and sustainable approach to stewardship. [ABSTRACT FROM AUTHOR]

Mitochondria are the major source of cellular energy (ATP), as well as critical mediators of widespread functions such as cellular redox balance, apoptosis, and metabolic flux. The organelles play an especially important role in the maintenance of cardiac homeostasis; their inability to generate ATP following impairment due to ischemic damage has been directly linked to organ failure. Methods to quantify mitochondrial content are limited to low throughput immunoassays, measurement of mitochondrial DNA, or relative quantification by untargeted mass spectrometry. Here, we present a high throughput, reproducible and quantitative mass spectrometry multiple reaction monitoring based assay of 37 proteins critical to central carbon chain metabolism and overall mitochondrial function termed 'MitoPlex'. We coupled this protein multiplex with a parallel analysis of the central carbon chain metabolites (219 metabolite assay) extracted in tandem from the same sample, be it cells or tissue. In tests of its biological applicability in cells and tissues, "MitoPlex plus metabolites" indicated profound effects of HMG-CoA Reductase inhibition (e.g., statin treatment) on mitochondria of i) differentiating C2C12 skeletal myoblasts, as well as a clear opposite trend of statins to promote mitochondrial protein expression and metabolism in heart and liver, while suppressing mitochondrial protein and ii) aspects of metabolism in the skeletal muscle obtained from C57Bl6 mice. Our results not only reveal new insights into the metabolic effect of statins in skeletal muscle, but present a new high throughput, reliable MS-based tool to study mitochondrial dynamics in both cell culture and in vivo models. • Common methods for quantifying mitochondrial mass and function are incomplete. • MitoPlex is a highly sensitive assay of mouse mitochondrial proteins. • Our method combines proteomic and metabolomic analysis from the same sample. • MitoPlex is a novel way to assay cell and tissue metabolism in mouse experiments. [ABSTRACT FROM AUTHOR]

Enterococcus gallinarum and casseliflavus have inherent vancomycin resistance and, though known as pathogens, have not been well characterized in pediatric patients. We identified a significant prevalence of these enterococcal species among immunocompromised patients at a large pediatric institution and describe the impact on patient care, antibiotic stewardship, and infection control. [ABSTRACT FROM AUTHOR]

The human body absorption cross section (ACS) is important in nonionizing radiation dosimetry, but it is always hard to accurately evaluate the ACS of an individual from his or her morphological parameters, such as height and weight. To obtain an empirical formula that can evaluate the ACS from morphological parameters, 48 subjects with different morphological parameters were measured from 1 to 16 GHz in a reverberation chamber. The ACS was extracted from the power delay profile. This has the advantage of not requiring antenna radiation efficiency, and it has not been previously used in a wideband group study like this. The accuracy of the ACS measurement is demonstrated by comparison with the ACS of a spherical model with known structure and material, and the mean absolute percentage error of the sphere measurement is just 3.4%. Statistical analysis shows that the body surface area (BSA) has the strongest correlation with the ACS among all the morphological parameters; therefore, we present a new empirical ACS formula as a function of BSA and frequency. This will be of interest to those considering dosimetry, and in computing the effect of human body absorption on radio propagation in vehicles and other structures. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme (ACE) affects blood pressure. In addition, ACE overexpression in myeloid cells increases their immune function. Using MS and chemical analysis, we identified marked changes of intermediate metabolites in ACEoverexpressing macrophages and neutrophils, with increased cellular ATP (1.7-3.0-fold) and Krebs cycle intermediates, including citrate, isocitrate, succinate, and malate (1.4 -3.9- fold). Increased ATP is due to ACE C-domain catalytic activity; it is reversed by an ACE inhibitor but not by an angiotensin II AT1 receptor antagonist. In contrast, macrophages from ACE knockout (null) mice averaged only 28% of the ATP levels found in WT mice. ACE overexpression does not change cell or mitochondrial size or number. However, expression levels of the electron transport chain proteinsNDUFB8(complex I), ATP5A, and ATP5β (complex V) are significantly increased in macrophages and neutrophils, and COX1 and COX2 (complex IV) are increased in macrophages overexpressing ACE. Macrophages overexpressing ACE have increased mitochondrial membrane potential (24% higher), ATP production rates (29% higher), and maximal respiratory rates (37% higher) compared with WT cells. Increased cellular ATP underpins increased myeloid cell superoxide production and phagocytosis associated with increased ACE expression. Myeloid cells overexpressing ACE indicate the existence of a novel pathway in which myeloid cell function can be enhanced, with a key feature being increased cellular ATP. [ABSTRACT FROM AUTHOR]

Background Metronidazole is traditionally dosed every 6–8 hours even though in adults it has a long half-life, concentration-dependent killing, and 3-hour postantibiotic effect. Based on this logic, some pediatric hospitals adopted once-daily dosing for appendicitis, despite limited pharmacokinetics-pharmacodynamics (PK/PD) in children. We studied pediatric patients with appendicitis given metronidazole once daily to determine whether this dosing would meet target area under the curve (AUC)/minimum inhibitory concentration (MIC) ratio of ≥70 for Bacteroides fragilis. Methods One hundred pediatric patients aged 4–17 years had an average of 3 blood draws per patient during the first 24 hours after a 30 mg/kg per dose of intravenous metronidazole. Concentrations of drug were determined using validated liquid chromatography and tandem mass spectrometry. A NONMEM model was constructed for determining PK, followed by Monte Carlo simulations to generate a population of plasma concentration-time AUC of metronidazole and hydroxy-metronidazole. Results Simulated AUC values met target attainment (AUC/MIC ratio of ≥70 to B fragilis MICs) for 96%–100% of all patients for an MIC of 2 mcg/mL. For MICs of 4 and 8 mcg/mL, target attainment ranged from 61% to 97% and 9% to 71%, respectively. Areas under the curve were similar to that of adults receiving 1000 mg and 1500 mg q24, or 500 mg q8 hours. Conclusions Metronidazole, 30 mg/kg per dose, once daily achieved AUC target attainment for B fragilis with an MIC of 2 mcg/mL or less in pediatric appendicitis patients. Based on this and studies in adults, there does not seem to be any PK/PD advantage of more frequent dosing in this population. [ABSTRACT FROM AUTHOR]

Otopathogens in acute otitis media (AOM) have implications for care because the likelihood of resolution without antibiotics and optimal antibiotic agent varies by microorganism. We aimed to determine the sensitivity, specificity, positive predictive value, and negative predictive value of nasopharyngeal (NP) qualitative polymerase chain reaction (PCR) for common bacterial otopathogens in children with AOM compared to NP culture. NP flocked swabs collected from enrolled children aged 6 to 35 months with uncomplicated AOM in Denver, CO were tested by culture and multiplex PCR. The sensitivity and negative predictive value of PCR using culture as a reference were high (H. influenzae 93.3%, 98.0%; S. pneumoniae 94.2%, 95.1%; M. catarrhalis 92.3%, 86.4%); whereas the specificity and positive predictive value were lower and varied by organism (54.2%–84.1%, 55.1%–69.2%, respectively). PCR detected 1.5 times more organisms than culture. NP PCR has a high predictive value for excluding otopathogens compared to culture and warrants exploration as a diagnostic tool. [ABSTRACT FROM AUTHOR]

Introduction and hypothesis: To study mitochondrial turnover in the heart, we developed MitoTimer, a fluorescent protein targeted to the mitochondrial matrix that matures from green to red fluorescence over time. We generated a mouse line where MitoTimer is expressed under the cardiac-restricted promoter and were able to observe newly-synthesized and quiescent mitochondria in cardiomyocytes. Surprisingly, the hearts exhibit considerable heterogeneity in green-to-red MitoTimer fluorescence at the level of cardiomyocytes as well as between the mitochondria within individual cells. We hypothesized that these discrete subpopulations of cells represent fibers engaged in specialized functions. Methods: To isolate cells from the heart for proteomic and biochemical analysis, we developed an isolation strategy utilizing flow-cytometry followed by sequential processing to separate cytosolic, myofilament and insoluble protein fractions for liquid chromatography/mass spectrometry. Results of the analysis were validated by biochemical techniques. Results: Analysis of cardiomyocyte sub-populations revealed substantial differences in their protein compositions. Green cells display a profile consistent with an upregulation of PPARA and KLF15 signaling pathways and a downregulation of insulin receptor signaling, suggesting a preference for fatty acid oxidation (FAO). Consistent with this analysis, Western blots revealed that green cells express higher levels of CD36 and Cpt1b proteins compared to red cells. Interestingly, maturation of Timer protein fluorescence to red is sensitive to changes in molecular oxygen concentration. Cells that exhibit higher utilization of FAO and thus a lower oxygen tension will have a decrease in MitoTimer protein maturation, resulting in a greater green fluorescence. These results suggest MitoTimer may be a useful not only as a marker of mitochondrial age, but also as a marker of metabolic substrate preference. Conclusion: Cardiomyocytes in the heart present a highly heterogeneous population, arranged in discrete fibers that have a higher preference for one metabolic substrate over another. We are currently investigating the physiological roles these fibers play in the heart. [ABSTRACT FROM AUTHOR]

Background: Eye-gaze metrics derived from areas of interest (AOIs) have been suggested to be effective for surgical skill assessment. However, prior research is mostly based on static images and simulated tasks that may not translate to complex and dynamic surgical scenes. Therefore, eye-gaze metrics must advance to account for changes in the location of important information during a surgical procedure.Methods: We developed a dynamic AOI generation technique based on eye gaze collected from an expert viewing surgery videos. This AOI updated as the gaze of the expert moved with changes in the surgical scene. This technique was evaluated through an experiment recruiting a total of 20 attendings and residents to view 10 videos associated with and another 10 without adverse events.Results: Dwell time percentage (i.e., gaze duration) inside the AOI differentiated video type (U = 13508.5, p < 0.001) between videos with the presence (Mdn = 16.75) versus absence (Mdn = 19.95) of adverse events. This metric also differentiated participant group (U = 14029.5, p < 0.001) between attendings (Mdn = 15.45) and residents (Mdn = 19.80). This indicates that our dynamic AOIs reflecting the expert eye gaze was able to differentiate expertise, and the presence of unexpected adverse events.Conclusion: This dynamic AOI generation technique produced dynamic AOIs for deriving eye-gaze metrics that were sensitive to expertise level and event characteristics. [ABSTRACT FROM AUTHOR]

The extremely limited regenerative potential of adult mammalian hearts has prompted the need for novel cell-based therapies that can restore contractile function in heart disease. We have previously shown the regenerative potential of mixed fetal cells that were naturally found migrating to the injured maternal heart. Exploiting this intrinsic mechanism led to the current hypothesis that Caudal-type homeobox-2 (Cdx2) cells in placenta may represent a novel cell type for cardiac regeneration. Using a lineagetracing strategy, we specifically labeled fetal-derived Cdx2 cells with enhanced green fluorescent protein (eGFP). Cdx2-eGFP cells from end-gestation placenta were assayed for cardiac differentiation in vitro and in vivo using a mouse model of myocardial infarction. We observed that these cells differentiated into spontaneously beating cardiomyocytes (CMs) and vascular cells in vitro, indicating multipotentiality. When administered via tail vein to infarcted wild-type male mice, they selectively and robustly homed to the heart and differentiated to CMs and blood vessels, resulting in significant improvement in contractility as noted by MRI. Proteomics and immune transcriptomics studies of Cdx2-eGFP cells compared with embryonic stem (ES) cells reveal that they appear to retain "stem"-related functions of ES cells but exhibit unique signatures supporting roles in homing andsurvival, with an ability toevade immune surveillance,which is critical for cell-based therapy. Cdx2-eGFP cells may potentially represent a therapeutic advance in allogeneic cell therapy for cardiac repair. [ABSTRACT FROM AUTHOR]

Abstract Background Pathogen detection in pediatric patients with musculoskeletal infections relies on conventional bacterial culture, which is slow and can delay antimicrobial optimization. The ability to rapidly identify causative agents and antimicrobial resistance genes in these infections may improve clinical care. Methods Convenience specimens from bone and joint samples submitted for culture to Children's Hospital Colorado (CHCO) from June 2012 to October 2016 were evaluated using a "Musculoskeletal Diagnostic Panel" (MDP) consisting of the Xpert MRSA/SA SSTI real-time PCR (qPCR, Cepheid) and laboratory-developed qPCRs for Kingella kingae detection and erm genes A, B, and C which confer clindamycin resistance. Results from the MDP were compared to culture and antimicrobial susceptibility testing (AST) results. Results A total of 184 source specimens from 125 patients were tested. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the Xpert MRSA/SA SSTI compared to culture and AST results were 85%, 98%, 93%, and 95% respectively for MSSA and 82%, 100%, 100%, and 99% for MRSA. Compared to phenotypic clindamycin resistance in S. aureus isolates, the erm A, B, and C gene PCRs collectively demonstrated a sensitivity, specificity, PPV, and NPV of 80%, 96%, 67%, and 98%. In comparison to clinical truth, Kingella PCR had a sensitivity, specificity, PPV, and NPV of 100%, 99.5%, 100%, and 100%. Conclusions This novel MDP offers a rapid, sensitive, and specific option for pathogen detection in pediatric patients with musculoskeletal infections. [ABSTRACT FROM AUTHOR]

Heaviside, in volume 1 of Electromagnetic theory, considered shielding of conducting materials in the form of attenuation. This treatment is still significant in the understanding of shielding effectiveness. He also considered propagation of electromagnetic waves in free-space. What Heaviside (1850-1925) could never have imagined is that 125 years later, there would be devices we know as mobile phones (or cell phones, handies, etc.) with capabilities beyond the dreams of the great science fiction writers of the day like H. G. Wells (1866-1949) or Jules Verne (1828-1905). More than this, that there would be a need for law enforcement agencies, among others, to use electromagnetically shielded enclosures to protect electronic equipment from communicating with the 'outside world'. Nevertheless, Heaviside's work is still fundamental to the developments discussed here. This paper provides a review of Heaviside's view of shielding and propagation provided in volume 1 of Electromagnetic theory and develops that to the design of new experiments to test the shielding of these portable enclosures in a mode-stirred reverberation chamber, a test environment that relies entirely on reflections from conducting surfaces for its operation. [ABSTRACT FROM AUTHOR]

Age-related thymic involution is characterized by a decrease in thymic epithelial cell (TEC) number and function parallel to a disruption in their spatial organization, resulting in defective thymocyte development and proliferation as well as peripheral T cell dysfunction. Deficiency of Klotho, an antiaging gene and modifier of fibroblast growth factor signaling, causes premature aging. To investigate the role of Klotho in accelerated age-dependent thymic involution, we conducted a comprehensive analysis of thymopoiesis and peripheral T cell homeostasis using Klotho-deficient (Kl/Kl) mice. At 8 wk of age, Kl/Kl mice displayed a severe reduction in the number of thymocytes (10-100-fold reduction), especially CD4 and CD8 double-positive cells, and a reduction of both cortical and medullary TECs. To address a cell-autonomous role for Klotho in TEC biology, we implanted neonatal thymi from Klotho-deficient and -sufficient mice into athymic hosts. Kl/Kl thymus grafts supported thymopoiesis equivalently to Klothosufficient thymus transplants, indicating that Klotho is not intrinsically essential for TEC support of thymopoiesis. Moreover, lethally irradiated hosts given Kl/Kl or wild-type bone marrow had normal thymocyte development and comparably reconstituted T cells, indicating that Klotho is not inherently essential for peripheral T cell reconstitution. Because Kl/Kl mice have higher levels of serum phosphorus, calcium, and vitamin D, we evaluated thymus function in Kl/Kl mice fed with a vitamin D-deprived diet. We observed that a vitamin D-deprived diet abrogated thymic involution and T cell lymphopenia in 8-wk-old Kl/Kl mice. Taken together, our data suggest that Klotho deficiency causes thymic involution via systemic effects that include high active vitamin D levels. [ABSTRACT FROM AUTHOR]

Highlights • We developed and evaluated an individual-based model for a temperate fish species. • Seasonal growth and density dependence are key drivers in the model. • Realistic and worst-case pesticide exposure regimes were simulated. • Density dependent parameters were evaluated to assess population resilience. • The model is suitable for use in chemical risk assessments. Abstract The effects of toxicant exposure on individuals captured in standard environmental risk assessments (ERA) do not necessarily translate proportionally into effects at the population-level. Population models can incorporate population resilience, physiological susceptibility, and likelihood of exposure, and can therefore be employed to extrapolate from individual- to population-level effects in ERA. Here, we present the development of an individual-based model (IBM) for the three-spined stickleback (Gasterosteus aculeatus) and its application in assessing population-level effects of disrupted male breeding behaviour after exposure to the anti-androgenic pesticide, fenitrothion. The stickleback is abundant in marine, brackish, and freshwater systems throughout Europe and their complex breeding strategy makes wild populations potentially vulnerable to the effects of endocrine disrupting chemicals (EDCs). Modelled population dynamics matched those of a UK field population and the IBM is therefore considered to be representative of a natural population. Literature derived dose-response relationships of fenitrothion-induced disruption of male breeding behaviours were applied in the IBM to assess population-level impacts. The modelled population was exposed to fenitrothion under both continuous (worst-case) and intermittent (realistic) exposure patterns and population recovery was assessed. The results suggest that disruption of male breeding behaviours at the individual-level cause impacts on population abundance under both fenitrothion exposure regimes; however, density-dependent processes can compensate for some of these effects, particularly for an intermittent exposure scenario. Our findings further demonstrate the importance of understanding life-history traits, including reproductive strategies and behaviours, and their density-dependence, when assessing the potential population-level risks of EDCs. [ABSTRACT FROM AUTHOR]

The prevalence of pediatric antimicrobial stewardship programs (ASPs) is increasing in acute care facilities across the United States. Over the past several years, the evidence base used to inform effective stewardship practices has expanded, and regulatory interest in stewardship programs has increased. Here, we review approaches for established, hospital-based pediatric ASPs to adapt and report standardized metrics, broaden their reach to specialized populations, expand to undertake novel stewardship initiatives, and implement rapid diagnostics to continue their evolution in improving antimicrobial use and patient outcomes. [ABSTRACT FROM AUTHOR]

To achieve this, we measured blood basophils, eosinophils and other type 2 inflammatory cells, before and after 16 weeks of mepolizumab ("Nucala", GlaxoSmithKline) by flow cytometry. Furthermore, there were no mepolizumab-dependent effects on eosinophil/basophil Siglec-8, CD69 or IL-5R expression (not shown), consistent with others[8] or basophil IL-3R (Figure S7), SP . sp and thus, these parameters were not examined for a relationship with ACQ6. [Extracted from the article]

Following the detection of the invasive killer shrimp, Dikerogammarus villosus (Dv) at two sites in the UK in September 2010, an effective biosecurity system is required to prevent further spread. This study investigated the application of several treatments as potential biosecurity measures with a view to their application on Dv-infected fomites. For each treatment, adult Dv were submerged for 15 minutes at different concentrations to determine the maximum lethal concentration, and for each effective treatment for different times to assess a minimal lethal time (LT50). Sodium hypochlorite (50,000 mg/Lmg/L), FAM30® (6 ml/l), Virkon S® (1% solution) and water at high temperature (45 °C) were found to cause 100% mortality within 15-min exposure, while carbonated water caused narcosis in 100% of animals within a few seconds of exposure. Due to various drawbacks in the use of sodium hypochlorite, FAM30® and Virkon S® (e.g. health and safety, legal use) they were not recommended as biosecurity treatments, whereas both water at high temperature and carbonated water showed promise. However, further investigation and field based research are required before these techniques can be fully realised as methods of control. [ABSTRACT FROM AUTHOR]

Trichinella is an important zoonotic parasite found in a range of wildlife species harvested for food and fur in Canada. We compared larval intensity from tongue and diaphragm, the best predilection sites in other animal species, from naturally infected, wild wolverines ( Gulo gulo ) (n = 95). Muscle larvae of Trichinella spp. were recovered by the pepsin/HCl artificial digestion method (gold standard) using double separatory funnels, and species were identified using multiplex PCR. Prevalence was 83% (79/95). Of those positive for Trichinella spp. ( n  = 79), 76 (96.2%) were detected in both tissues, 2 (2.5%) were positive only on diaphragm, and 1 (1.3%) only on tongue. A total of 62 of 79 wolverines (78.5%) had higher larval burden in tongue than in diaphragm, whereas 17 wolverines (21.5%) had higher larval burden in diaphragm. The predilection site (higher larval burden) of Trichinella spp. larvae did not vary significantly between juvenile and adult wolverines ( P  = 0.2), between male and female wolverines ( P  = 0.9), and among wolverines classified as having low and high larval intensities overall ( P  = 0.2). Trichinella T6 was the predominant genotype (63 of 79; 80%), followed by T. nativa (T2) (6 of 79; 8%). Mixed infections of T2 and T6 were observed in 9 of 79 (12%) wolverines. Larval intensity of Trichinella T6 was higher in tongues than diaphragms. No statement can be made for T2 due to insufficient T2 positive samples. In conclusion, tongues are a better site for sampling than diaphragms in future surveys of Trichinella larval intensity in wolverines; however, either tissue is suitable for prevalence studies. [ABSTRACT FROM AUTHOR]

Purpose. The effect of mandatory provider-selected order indications (PSOIs) on appropriateness of antimicrobial ordering in a tertiary pediatric hospital was evaluated. Methods. Mandatory PSOIs for 14 antimicrobials were implemented in September 2013. Data on initial and final orders in the first 24 hours after ordering were collected from the electronic medical record. Orders from pre-PSOI and post-PSOI implementation were randomly selected and compared with documentation at the time of order to elicit the documentation-determined clinical indication (DDCI). Appropriateness of the order for the DDCI was evaluated and compared between groups using 2-sample t tests, chi-square tests, and logistic regression. Results. Among the total 1,304 orders included in the review, 275 (21.1%) were inappropriate based on DDCI. The indications associated with the greatest number of inappropriate orders in both groups were suspected sepsis/bacteremia, meningitis/central nervous system infection, and pneumonia. A total of 128 (18.3%) of 700 initial orders were inappropriate compared with the DDCI in the pre-PSOI period, and 82 (17.8%) of 461 initial orders were inappropriate in the post-PSOI period (p = 0.83). A total of 78 (11.1%) of 700 final orders were inappropriate in the pre-PSOI period, and 29 (6.3%) of 461 final orders were inappropriate in the post-intervention period (p = 0.01). Overall, 84 (12%) of 700 inappropriate orders reached the patient in the pre-PSOI period versus 43 (9.3%) of 461 inappropriate orders in the post-PSOI period (p = 0.15). Conclusion. PSOIs were effective in reducing inappropriate antimicrobial orders in the first 24 hours after ordering if the correct indication was selected. [ABSTRACT FROM AUTHOR]

The electromagnetic environment inside a shielding enclosure is affected by the absorption characteristics of the contents, which should, therefore, be represented in shielding measurements and simulations. At frequencies up to a few gigahertz, lossy dielectric materials have previously been used as surrogates for printed circuit boards in enclosure shielding assessment, both experimentally and in simulations. However, no systematic methodology for the design of these surrogates and their calibration against real hardware at high frequencies has been elucidated. In this paper, we show how both lossy dielectric material and microstrip transmission–line-based “representative contents” can be designed and calibrated against real printed circuit boards over the frequency range 2–20 GHz using power balance concepts. The calibration is made by matching the average absorption cross section of the surrogate to an average value for a class of real contents measured in a reverberation chamber. The surrogates are designed using efficient power balance models for layered media and field-excited microstrip lines and verified using full-wave simulation. The fabricated surrogates are validated by shielding measurements. The methodology presented could form an important part of future standards for enclosure qualification measurements that more accurately represent the internal environment of real equipment. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To assess trends in the duration of intravenous (IV) antibiotics for urinary tract infections (UTIs) in infants ≤60 days old between 2005 and 2015 and determine if the duration of IV antibiotic treatment is associated with readmission. METHODS: Retrospective analysis of infants ≤60 days old diagnosed with a UTI who were admitted to a children's hospital and received IV antibiotics. Infants were excluded if they had a previous surgery or comorbidities, bacteremia, or admission to the ICU. Data were analyzed from the Pediatric Health Information System database from 2005 through 2015. The primary outcome was readmission within 30 days for a UTI. RESULTS: The proportion of infants ≤60 days old receiving 4 or more days of IV antibiotics (long IV treatment) decreased from 50% in 2005 to 19% in 2015. The proportion of infants ≤60 days old receiving long IV treatment at 46 children's hospitals varied between 3% and 59% and did not correlate with readmission (correlation coefficient 0.13; P = .37). In multivariable analysis, readmission for a UTI was associated with younger age and female sex but not duration of IV antibiotic therapy (adjusted odds ratio for long IV treatment: 0.93 [95% confidence interval 0.52-1.67]). CONCLUSIONS: The proportion of infants ≤60 days old receiving long IV treatment decreased substantially from 2005 to 2015 without an increase in hospital readmissions. These findings support the safety of short-course IV antibiotic therapy for appropriately selected neonates. [ABSTRACT FROM AUTHOR]

An alternative to conventional models that treat decisions as open-loop independent choices is presented. The alterative model is based on observations of work situations such as healthcare, where decisionmaking is more typically a closed-loop, dynamic, problem-solving process. The article suggests five important distinctions between the processes assumed by conventional models and the reality of decisionmaking in practice. It is suggested that the logic of abduction in the form of an adaptive, muddling through process is more consistent with the realities of practice in domains such as healthcare. The practical implication is that the design goal should not be to improve consistency with normative models of rationality, but to tune the representations guiding the muddling process to increase functional perspicacity. [ABSTRACT FROM AUTHOR]

Background. Acute pediatric musculoskeletal infections are common, leading to significant use of resources and antimicrobial exposure. In order to decrease variability and improve the quality of care, Children's Hospital Colorado implemented a clinical care guideline (CCG) for these infections. The purpose of this study is to evaluate clinical and resource outcomes PRE and POST this CCG. Methods. Retrospective chart review evaluated patients admitted to a large pediatric quaternary referral center (CHCO) diagnosed with acute osteomyelitis, septic arthritis, pyomyositis, and/or musculoskeletal abscess prior to and after guideline implementation. Primary outcomes included length of stay and overall antibiotic use, with additional secondary clinical, process, and therapeutic outcomes examined. Results. 82 patients were identified in both the pre-CCG and post-CCG cohorts. There was a reduction in the median of all primary outcomes, including length of stay (0.6 median days decrease, P = .04), length of IV antibiotic therapy (4.9 median days decrease, P < .0001), and days of IV antibiotic therapy (6.4 median days decrease, P = .0004). Our median length of stay post-CCG was 4.9 days, the shortest reported length of stay for pediatric acute musculoskeletal infections to date. Additionally, there was a 24.5 hour reduction in median length of fever (P = .02), faster CRP normalization (P < .0001), 50% decrease in the number of related readmissions (P = .02), 34% decrease in central venous catheters placed (P < .0001), decreased time to first culture (P = .02), and 79% pathogen identification post-CCG (P = .056).Conclusions. Implementation of a CCG for acute musculoskeletal infections improves patient, process and resource outcomes. [ABSTRACT FROM AUTHOR]

Background. Rapid diagnostic technologies for infectious diseases have the potential to improve clinical outcomes, but guideline-recommended antimicrobial stewardship (AS) strategies are not currently optimized for rapid intervention. We evaluated the clinical impact and provider acceptability of implementing real-time AS decision support for children with positive blood culture results according to the FilmArray blood culture identification panel (BCID [BioFire Diagnostics]) at Children's Hospital Colorado. Methods. A pre-post quasi-experimental design was used to compare the outcomes of 100 postintervention children with positive blood culture results matched with 200 preintervention control children. Causative organisms in the preintervention group were identified using conventional microbiologic techniques and communicated to providers by a microbiology technologist. Postintervention organisms were identified by the BCID and communicated by an AS provider in real time with interpretation and antimicrobial recommendations. The primary outcome was time to optimal antimicrobial therapy (time from blood culture collection to start of predetermined pathogen-specific regimen or antimicrobial discontinuation for contaminants) compared by a log-rank test and Kaplan-Meier analysis. Provider acceptability of the intervention was assessed via E-mailed surveys. Results. The median time to optimal therapy decreased from 60.2 hours before intervention to 26.7 hours after intervention (P = .001). Among children with blood cultures that contained true pathogens, the time to effective antimicrobial therapy decreased from 6.9 to 3.4 hours (P = .03). Unnecessary antibiotic initiation for children with a culture that contained organisms considered to be contaminants decreased from 76% to 26% (P < .001). Providers reported a change in management as a result of BCID results in 73% of the cases and a mean overall satisfaction rating of 4.8 on a 5-point Likert scale. Conclusions. Real-time AS decision support for rapid diagnostics is associated with improved antimicrobial use and high satisfaction ratings by providers. [ABSTRACT FROM AUTHOR]

Aim The objective of this paper is to identify attribute patterns of influential individuals in intensive care units using unsupervised cluster analysis. Background Despite the acknowledgement that culture of an organisation is critical to improving patient safety, specific methods to shift culture have not been explicitly identified. Methods A social network analysis survey was conducted and an unsupervised cluster analysis was used. Results A total of 100 surveys were gathered. Unsupervised cluster analysis was used to group individuals with similar dimensions highlighting three general genres of influencers: well-rounded, knowledge and relational. Conclusions Culture is created locally by individual influencers. Cluster analysis is an effective way to identify common characteristics among members of an intensive care unit team that are noted as highly influential by their peers. To change culture, identifying and then integrating the influencers in intervention development and dissemination may create more sustainable and effective culture change. Additional studies are ongoing to test the effectiveness of utilising these influencers to disseminate patient safety interventions. Implications for nursing management This study offers an approach that can be helpful in both identifying and understanding influential team members and may be an important aspect of developing methods to change organisational culture. [ABSTRACT FROM AUTHOR]

Implementation of a unique in-person pediatric antimicrobial stewardship program was associated with a significant increase in infectious disease consultations at a quaternary care children's hospital. This study demonstrates that antimicrobial stewardship programs support, and do not compete with, infectious disease programs. [ABSTRACT FROM AUTHOR]

Choanal swabs were collected three times at 2 wk intervals from 17 asymptomatic captive chelonians, eight Forsten's tortoises ( Indotestudo forstenii) and nine Sulawesi forest turtles ( Leucocephalon yuwonoi), to document individual Mycoplasma spp. shedding patterns. Four of the Forsten's tortoises and six of the Sulawesi forest turtles tested positive repeatedly for Mycoplasma spp. DNA using a PCR assay. Clarithromycin, a macrolide antibiotic, was administered orally to all animals at 20 mg/kg every 2 to 3 days for a total of 90 days. While no adverse effects were noted, this extended 3 month long course of clarithromycin failed to suppress Mycoplasma spp. shedding in all but one of the 10 Mycoplasma spp. PCR-positive animals. [ABSTRACT FROM AUTHOR]

Background. Appendicitis is a common surgical emergency in pediatric patients, and broad-spectrum antibiotic therapy is warranted in their care. A simplified once-daily regimen of ceftriaxone and metronidazole (CTX plus MTZ) is cost effective in perforated patients. The goal of this evaluation is to compare a historic regimen of cefoxitin (CFX) in nonperforated cases and ertapenem (ERT) in perforated and abscessed cases with CTX plus MTZ for all cases in terms of efficacy and cost. Methods. A retrospective review compared outcomes of nonperforated, perforated, and abscessed cases who received the historic regimen or CTX plus MTZ. Length of stay, time to afebrile, time to full feeds, postoperative abscess, and wound infection rates, inpatient readmissions, and antibiotic costs were evaluated. Results. There were a total of 841 cases reviewed (494 nonperforated, 247 perforated, and 100 abscessed). Overall, the CTX plus MTZ group had a shorter time to afebrile (P < .001). Treatment groups did not differ in length of stay. Postoperative abscess rates were similar between groups (4.1% vs 3.3%, not significant). Other postoperative complications were similar between groups. Total antibiotic cost savings were over $110 000 during the study period (from November 2010 to June 2013). Conclusions. Both CFX and/or ERT and CTX plus MTZ result in low abscess and complication rates, suggesting both are effective strategies. Treatment with CTX plus MTZ results in a shorter time to afebrile, while also providing significant antibiotic cost savings. Ceftriaxone plus MTZ is a streamlined, cost-effective regimen in the treatment of nonperforated, perforated, and abscessed appendicitis. [ABSTRACT FROM AUTHOR]

Context: Colorectal cancer (CRC) is a leading cause of cancer in the US but is preventable by screening. Screening rates remain low despite addressing established barriers. "Sludge," as popularized by Cass Sunstein, JD, describes "excessive or unjustified frictions, such as paperwork burdens, that cost time or money... that may be frustrating, stigmatizing, or humiliating; and that might end up depriving people of access to important goods, opportunities, and services." Studies of CRC screening mention administrative barriers, but it is unclear how often such sludge impedes CRC screening. Objective: Identify, describe, and quantify sludge in the delivery of CRC screening. Study Design: Observational, mixed methods. Analysis: Descriptive analysis of administrative and claims datasets, content analysis of qualitative interviews. Setting: Regional health system in Southeastern US. Population studied: 1) Claims and administrative data from 2021 about CRC screening. 2) Clinicians and administrators in the CRC screening process. Instruments: "Sludge Audit" to document the extent of sludge from datasets and interviews. Outcome measures: Descriptive measures of screening rates in eligible populations, low value screening rate, rates of certain "sludge" categories (time, communication, paperwork, technology, processes), and qualitative themes derived from interview data. Results: The screening rate in 2021 was 60.4%, but 52% of positive stool-based tests were not followed by colonoscopy. 32% of the screenings were considered low value (outside age range, duplicate tests, or non-indicated repeat testing). Administrative data revealed: a wait time of 221 days on average from referral to test, 787 patients with more than 3 missed calls to schedule appointment, 3900 prior authorizations needed to perform screening, 14 to 30 electronic health record "clicks" required to order screening, 1950 duplicate referrals, and a 27% no-show rate for colonoscopies. Qualitative analysis revealed: problems with communication with patients, excessive wait times, difficulty accessing screening results once performed, and inconsistent insurance and pre-procedural requirements. Conclusions: Multiple areas of sludge in the CRC screening process appear to significantly impede screening rates. Further investigation is planned to elicit more systematic information from stakeholders, including patients, and to evaluate the impact on vulnerable populations. [ABSTRACT FROM AUTHOR]

For nearly a century, aluminum salts have been the most widely used vaccine adjuvant formulation, and have thus established a history of safety and efficacy. Nevertheless, for extremely challenging disease targets such as tuberculosis or HIV, the adjuvant activity of aluminum salts may not be potent enough to achieve protective efficacy. Adsorption of TLR ligands to aluminum salts facilitates enhanced adjuvant activity, such as in the human papilloma virus vaccine Cervarix®. However, some TLR ligands such as TLR7/8 agonist imidazoquinolines do not efficiently adsorb to aluminum salts. The present report describes a formulation approach to solving this challenge by developing a lipid-based nanosuspension of a synthetic TLR7/8 ligand (3M-052) that facilitates adsorption to aluminum oxyhydroxide via the structural properties of the helper lipid employed. In immunized mice, the aluminum oxyhydroxide-adsorbed formulation of 3M-052 enhanced antibody and TH1-type cellular immune responses to vaccine antigens for tuberculosis and HIV. [ABSTRACT FROM AUTHOR]