Quality Improvement to Engage General Pediatrics in Reducing Inaccurate Penicillin Allergy Labels.

OBJECTIVE: To remove inaccurate penicillin allergy labels in the general pediatric clinic setting. METHODS: From October 2017 through December 2021, this collaborative, quality improvement project used education, feedback, electronic health record alerts, and the introduction of oral amoxicillin challenges in a general pediatric clinic setting with the primary aim of decreasing the proportion of penicillin allergy labeled patients. Control charts were used to track the relationship between interventions and improvements in referral rates to allergy clinic, removal of the allergy label at clinic visits and the overall proportion of clinic patients labeled as PCN allergic. RESULTS: Referral rates to allergy clinic for penicillin allergy labeled patients increased from a baseline mean of 1.9% to 20.4%. The proportion of PCN allergy labeled patients who had the label removed during a pediatric clinic visit increased from a baseline of 1.1% to 6.6%. The overall proportion of penicillin allergy labeled clinic patients decreased from a baseline of 3.4% to 2.2%. CONCLUSION: With adequate education and collaboration with allergists, general pediatric practitioners can play a significant role in removing inaccurate penicillin allergy labels. Pediatricians can remove some of the burden placed on allergists by evaluating low risk patients in the primary care setting while referring higher risk patients to the specialist.

Anti-tumor effects of RTX-240: an engineered red blood cell expressing 4-1BB ligand and interleukin-15.

Recombinant agonists that activate co-stimulatory and cytokine receptors have shown limited clinical anticancer utility, potentially due to narrow therapeutic windows, the need for coordinated activation of co-stimulatory and cytokine pathways and the failure of agonistic antibodies to recapitulate signaling by endogenous ligands. RTX-240 is a genetically engineered red blood cell expressing 4-1BBL and IL-15/IL-15Rα fusion (IL-15TP). RTX-240 is designed to potently and simultaneously stimulate the 4-1BB and IL-15 pathways, thereby activating and expanding T cells and NK cells, while potentially offering an improved safety profile through restricted biodistribution. We assessed the ability of RTX-240 to expand and activate T cells and NK cells and evaluated the in vivo efficacy, pharmacodynamics and tolerability using murine models. Treatment of PBMCs with RTX-240 induced T cell and NK cell activation and proliferation. In vivo studies using mRBC-240, a mouse surrogate for RTX-240, revealed biodistribution predominantly to the red pulp of the spleen, leading to CD8 + T cell and NK cell expansion. mRBC-240 was efficacious in a B16-F10 melanoma model and led to increased NK cell infiltration into the lungs. mRBC-240 significantly inhibited CT26 tumor growth, in association with an increase in tumor-infiltrating proliferating and cytotoxic CD8 + T cells. mRBC-240 was tolerated and showed no evidence of hepatic injury at the highest feasible dose, compared with a 4-1BB agonistic antibody. RTX-240 promotes T cell and NK cell activity in preclinical models and shows efficacy and an improved safety profile. Based on these data, RTX-240 is now being evaluated in a clinical trial.

Engineered red blood cells as an off-the-shelf allogeneic anti-tumor therapeutic.

Checkpoint inhibitors and T-cell therapies have highlighted the critical role of T cells in anti-cancer immunity. However, limitations associated with these treatments drive the need for alternative approaches. Here, we engineer red blood cells into artificial antigen-presenting cells (aAPCs) presenting a peptide bound to the major histocompatibility complex I, the costimulatory ligand 4-1BBL, and interleukin (IL)-12. This leads to robust, antigen-specific T-cell expansion, memory formation, additional immune activation, tumor control, and antigen spreading in tumor models in vivo. The presence of 4-1BBL and IL-12 induces minimal toxicities due to restriction to the vasculature and spleen. The allogeneic aAPC, RTX-321, comprised of human leukocyte antigen-A*02:01 presenting the human papilloma virus (HPV) peptide HPV16 E711-19, 4-1BBL, and IL-12 on the surface, activates HPV-specific T cells and promotes effector function in vitro. Thus, RTX-321 is a potential 'off-the-shelf' in vivo cellular immunotherapy for treating HPV + cancers, including cervical and head/neck cancers.

Experience with a "Feed and Swaddle" program in infants up to six months of age.

BACKGROUND: Feed and swaddle is a technique in which an infant is fed and allowed to fall asleep to facilitate diagnostic imaging. This study reviews our experience and diagnostic success in premature and term infants up to 6 months old undergoing brain magnetic resonance imaging (MRI) using a feed and swaddle technique and with comparable patients imaged under anesthesia. METHODS: We reviewed the charts of all infants ≤6 months who underwent brain MRI at our institution between 1 January 2013 and 31 March 2016. We recorded and analyzed demographic information, scan indication, scan length, prematurity status, anesthetic technique if used, complications, and diagnostic success or failure. RESULTS: One hundred and sixty-four term infants underwent brain MRI using a feed and swaddle technique. The success rate in term infants <90 days was 91.1% (113/124) versus 95.0% (38/40) in infants ≥90 days and ≤181 days old. Fifty-three premature infants underwent feed and swaddle for brain MRI with a diagnostic success rate of 92.5% (49/53). No complications were noted in any feed and swaddle patients. Those who received anesthesia had a diagnostic success rate of 100% (70/70) but experienced complications including hypoxemia, 14.3% (10/70); hypothermia, 18.9% (10/53); bradycardia, 10.1% (7/69); and hypotension, 4.2% (3/70). CONCLUSION: Given the high rate of success and absence of complications with feed and swaddle in children ≤6 months for brain MRI and the presence of anesthesia-related complications, most infants should undergo a trial of feed and swaddle prior to undergoing brain MRI with anesthesia.

Assessment of Common Criteria for Awake Extubation in Infants and Young Children.

BACKGROUND: Practice patterns surrounding awake extubation of pediatric surgical patients remain largely undocumented. This study assessed the value of commonly used predictors of fitness for extubation to determine which were most salient in predicting successful extubation following emergence from general anesthesia with a volatile anesthetic in young children. METHODS: This prospective, observational study was performed in 600 children from 0 to 7 yr of age. The presence or absence of nine commonly used extubation criteria in children were recorded at the time of extubation including: facial grimace, eye opening, low end-tidal anesthetic concentration, spontaneous tidal volume greater than 5 ml/kg, conjugate gaze, purposeful movement, movement other than coughing, laryngeal stimulation test, and oxygen saturation. Extubations were graded as Successful, Intervention Required, or Major Intervention Required using a standard set of criteria. The Intervention Required and Major Intervention Required outcomes were combined as a single outcome for analysis of predictors of success. RESULTS: Successful extubation occurred in 92.7% (556 of 600) of cases. Facial grimace odds ratio, 1.93 (95% CI, 1.03 to 3.60; P = 0.039), purposeful movement odds ratio, 2.42 (95% CI, 1.14 to 5.12; P = 0.022), conjugate gaze odds ratio, 2.10 (95% CI, 1.14 to 4.01; P = 0.031), eye opening odds ratio, 4.44 (95% CI, 1.06 to 18.64; P= 0.042), and tidal volume greater than 5 ml/kg odds ratio, 2.66 (95% CI, 1.21 to 5.86; P = 0.015) were univariately associated with the Successful group. A stepwise increase in any one, in any order, of these five predictors being present, from one out of five and up to five out of five yielded an increasing positive predictive value for successful extubation of 88.3% (95% CI, 82.4 to 94.3), 88.4% (95% CI, 83.5 to 93.3), 96.3% (95% CI, 93.4 to 99.2), 97.4% (95% CI, 94.4 to 100), and 100% (95% CI, 90 to 100). CONCLUSIONS: Conjugate gaze, facial grimace, eye opening, purposeful movement, and tidal volume greater than 5 ml/kg were each individually associated with extubation success in pediatric surgical patients after volatile anesthetic. Further, the use of a multifactorial approach using these predictors, may lead to a more rational and robust approach to successful awake extubation.

Management of headwaters based on macroinvertebrate assemblages and environmental attributes.

The ecosystem function of headwaters is important and increasingly well-recognized, but institutional structures to administer their protection and management are lacking or poorly developed. Although the reasons for this mismatch are various, one of practical concern is the potential administrative burden imposed by the sizable number of headwaters. Two essential components of an administrative framework for managing waters is classification by type so that proper expectations can be set, and development of indicators that measure whether those expectations are being met. Ordinations of macroinvertebrate assemblages sampled from 1016 sites in 934 headwater streams draining <13 km2 across Ohio, USA, revealed a highly distinct subset of sites characterized by a combination of taxa having an affinity for cold water and sensitivity to environmental disturbance. Bayesian Network (BN) modeling revealed that several environmental variables, notably water temperature, percent forest cover, and drainage area predict membership in this subset. More generally across all streams, macroinvertebrate assemblages signaled ecological status along a stressor gradient defined by habitat quality and intensity of land uses. Collectively, these results suggest a hierarchical administrative framework wherein stream habitat quality, as measured by summary habitat index scores, can screen and assign protections to waters generally expected to support assemblages consistent with good ecological status. Forest cover and water temperature can serve as an additional screen to assign higher levels of protection consistent with higher ecological status. In cases where levels of protection based on screening are questioned or likely to be contentious, assessment of the macroinvertebrate assemblage can demonstrate the appropriate level.

Microbial stability of syringes of anesthetic drugs prepared in the operating room.

STUDY OBJECTIVE: To determine whether microbial contamination of anesthesia syringes prepared in the operating room (OR) become contaminated in a time-dependent fashion. DESIGN: Observational. SETTING: Operating suite in a major university hospital. PATIENTS: None (in vitro study). 400 syringes were studied for microbial contamination. INTERVENTIONS: Syringes prepared in the OR by anesthesia personnel were sampled at 1, 2, 3, or 4 h in a sterile fashion and sent to the microbiology laboratory for quantitative culture of any bacteria. MEASUREMENTS: Colony forming units (CFU) per mL of drug were calculated and any identified positive cultures were identified by Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry. Logistic regression was used to test the effect of time since preparation on prevalence of positive culture, as was the effect of number of accesses of the syringe and identity of the drug. MAIN RESULTS: Overall, 9/400 (2.25%) syringes were positive for bacteria. The median (interquartile range [IQR]) concentration of bacteria among positive cultures was 100 (100,100) CFU. All cultured species were generally nonpathogenic common contaminants. There was no effect of time since preparation, number of accesses of the syringe at the time of sampling, or drug identity (propofol vs. other). CONCLUSIONS: Contamination of anesthesia syringes is uncommon and occurs at a low overall concentration of bacteria. Contamination does not appear to be time related, and thus calls into question the reasonableness of USP Chapter 797's one-hour requirement.

Quantifying Variability in Four US Streams Using a Long-Term Data Set: Patterns in Water Quality Endpoints.

Temporal and spatial patterns of variability in aquatic ecosystems can be complex and difficult to quantify or predict. However, understanding this variability is critical to making a wide range of water quality assessment and management decisions effectively. Here we report on the nature and magnitude of spatial and temporal variation observed in conductivity, total phosphorus, and total nitrogen during a 15-year study of four U.S. stream systems receiving pulp and paper mill effluent discharges. Sampling locations included mainstem sites upstream and downstream of effluent discharge, as well as tributary sites. In all four stream systems, variability in conductivity as measured by the coefficient of variation was typically in the range of 10-50%, and was as low or lower than the variability in nutrient endpoints. The effect of effluent discharge was relatively minor overall, except in some site-specific instances. Some relatively large differences between tributary and mainstem variability were also observed. Flow variation tended to have a more consistent and larger effect on conductivity variation compared to the nutrient endpoints. After removing flow effects, significant relatively complex trends over time were observed at several sites. Changes in variability during the study also were observed. This paper highlights the importance of long-term studies to accurately characterize water quality variability used in water quality management decision-making.

Quantifying Variability in Four U.S. Streams Using a Long-Term Dataset: Patterns in Biotic Endpoints.

Effective water resources assessment and management requires quantitative information on the variability of ambient and biological conditions in aquatic communities. Although it is understood that natural systems are variable, robust estimates of long-term variation in community-based structure and function metrics are rare in U.S. waters. We used a multi-year, seasonally sampled dataset from multiple sites (n = 5-6) in four streams (Codorus Creek, PA; Leaf River, MS; McKenzie and Willamette Rivers, OR) to examine spatial and temporal variation in periphyton chlorophyll a, and fish and macroinvertebrate metrics commonly used in bioassessment programs. Within-site variation of macroinvertebrate metrics and benthic chlorophyll a concentration showed coefficient of variation ranging from 16 to 136%. Scale-specific variability patterns (stream-wide, season, site, and site-season patterns) in standardized biotic endpoints showed that within-site variability patterns extended across sites with variability greatest in chlorophyll a and lowest in Hilsenhoff's Biotic Index. Across streams, variance components models showed that variance attributed to the interaction of space and time and sample variance accounted for the majority of variation in macroinvertebrate metrics and chlorophyll a, while most variation in fish metrics was attributed to sample variance. Clear temporal patterns in measured endpoints were rare and not specific to any one stream or assemblage, while apparent shifts in metric variability related to point source discharges were seen only in McKenzie River macroinvertebrate metrics in the fall. Results from this study demonstrate the need to consider and understand spatial, seasonal, and longer term variability in the development of bioassessment programs and subsequent decisions.

Assessing the fit of biotic ligand model validation data in a risk management decision context.

Biotic ligand models (BLMs) have advanced the ability to predict the concentrations of metals in surface waters likely to harm aquatic organisms. BLMs have been developed for several metals including Cu, Zn, Cd, and Ag. Additionally, the US Environmental Protection Agency has published guidance on the use of a BLM to develop water quality criteria for Cu. To validate the predictive performance of many BLMs, model predictions based on test water quality have been compared with corresponding laboratory toxicity measurements. Validation results are typically described in the published literature in terms of the proportion of predicted effect concentrations that fall within a factor of 2 of measured values. In this article, an alternative is presented using a receiver operating characteristics approach and regression prediction limit analyses, quantifying the probabilities of true and false predictions of excess toxicity risk based on toxic unit calculations and a risk management threshold of 1. The approaches are applied to a published Zn BLM and 3 simulated data sets that reflect attributes of other published BLM validation data. The overall accuracy of the unified Zn BLM is estimated to be 80% to 90%, and analyses of simulated data suggest a similar level of accuracy for other published BLMs. Further application of these validation methods to other BLMs may provide more complete and transparent information on their possible predictive value when used in the management of risks due to aqueous metals.

Maximizing the accuracy of field-derived numeric nutrient criteria in water quality regulations.

High levels of the nutrients nitrogen and phosphorus can cause unhealthy biological or ecological conditions in surface waters and prevent the attainment of their designated uses. Regulatory agencies are developing numeric criteria for these nutrients in an effort to ensure that the surface waters in their jurisdictions remain healthy and productive, and that water quality standards are met. These criteria are often derived using field measurements that relate nutrient concentrations and other water quality conditions to expected biological responses such as undesirable growth or changes in aquatic plant and animal communities. Ideally, these numeric criteria can be used to accurately "diagnose" ecosystem health and guide management decisions. However, the degree to which numeric nutrient criteria are useful for decision making depends on how accurately they reflect the status or risk of nutrient-related biological impairments. Numeric criteria that have little predictive value are not likely to be useful for managing nutrient concerns. This paper presents information on the role of numeric nutrient criteria as biological health indicators, and the potential benefits of sufficiently accurate criteria for nutrient management. In addition, it describes approaches being proposed or adopted in states such as Florida and Maine to improve the accuracy of numeric criteria and criteria-based decisions. This includes a preference for developing site-specific criteria in cases where sufficient data are available, and the use of nutrient concentration and biological response criteria together in a framework to support designated use attainment decisions. Together with systematic planning during criteria development, the accuracy of field-derived numeric nutrient criteria can be assessed and maximized as a part of an overall effort to manage nutrient water quality concerns.

Assessing the predictive performance of risk-based water quality criteria using decision error estimates from receiver operating characteristics (ROC) analysis.

Field data relating aquatic ecosystem responses with water quality constituents that are potential ecosystem stressors are being used increasingly in the United States in the derivation of water quality criteria to protect aquatic life. In light of this trend, there is a need for transparent quantitative methods to assess the performance of models that predict ecological conditions using a stressor-response relationship, a response variable threshold, and a stressor variable criterion. Analysis of receiver operating characteristics (ROC analysis) has a considerable history of successful use in medical diagnostic, industrial, and other fields for similarly structured decision problems, but its use for informing water quality management decisions involving risk-based environmental criteria is less common. In this article, ROC analysis is used to evaluate predictions of ecological response variable status for 3 water quality stressor-response data sets. Information on error rates is emphasized due in part to their common use in environmental studies to describe uncertainty. One data set is comprised of simulated data, and 2 involve field measurements described previously in the literature. These data sets are also analyzed using linear regression and conditional probability analysis for comparison. Results indicate that of the methods studied, ROC analysis provides the most comprehensive characterization of prediction error rates including false positive, false negative, positive predictive, and negative predictive errors. This information may be used along with other data analysis procedures to set quality objectives for and assess the predictive performance of risk-based criteria to support water quality management decisions.

Structures of adnectin/protein complexes reveal an expanded binding footprint.

Adnectins are targeted biologics derived from the tenth type III domain of human fibronectin (¹°Fn3), a member of the immunoglobulin superfamily. Target-specific binders are selected from libraries generated by diversifying the three ¹°Fn3 loops that are analogous to the complementarity determining regions of antibodies. The crystal structures of two Adnectins were determined, each in complex with its therapeutic target, EGFR or IL-23. Both Adnectins bind different epitopes than those bound by known monoclonal antibodies. Molecular modeling suggests that some of these epitopes might not be accessible to antibodies because of the size and concave shape of the antibody combining site. In addition to interactions from the Adnectin diversified loops, residues from the N terminus and/or the ß strands interact with the target proteins in both complexes. Alanine-scanning mutagenesis confirmed the calculated binding energies of these ß strand interactions, indicating that these nonloop residues can expand the available binding footprint.

Estimating the designated use attainment decision error rates of US Environmental Protection Agency's proposed numeric total phosphorus criteria for Florida, USA, colored lakes.

The utility of numeric nutrient criteria established for certain surface waters is likely to be affected by the uncertainty that exists in the presence of a causal link between nutrient stressor variables and designated use-related biological responses in those waters. This uncertainty can be difficult to characterize, interpret, and communicate to a broad audience of environmental stakeholders. The US Environmental Protection Agency (USEPA) has developed a systematic planning process to support a variety of environmental decisions, but this process is not generally applied to the development of national or state-level numeric nutrient criteria. This article describes a method for implementing such an approach and uses it to evaluate the numeric total P criteria recently proposed by USEPA for colored lakes in Florida, USA. An empirical, log-linear relationship between geometric mean concentrations of total P (a potential stressor variable) and chlorophyll a (a nutrient-related response variable) in these lakes-that is assumed to be causal in nature-forms the basis for the analysis. The use of the geometric mean total P concentration of a lake to correctly indicate designated use status, defined in terms of a 20 µg/L geometric mean chlorophyll a threshold, is evaluated. Rates of decision errors analogous to the Type I and Type II error rates familiar in hypothesis testing, and a 3rd error rate, E(ni) , referred to as the nutrient criterion-based impairment error rate, are estimated. The results show that USEPA's proposed "baseline" and "modified" nutrient criteria approach, in which data on both total P and chlorophyll a may be considered in establishing numeric nutrient criteria for a given lake within a specified range, provides a means for balancing and minimizing designated use attainment decision errors.

Using Monte Carlo analysis to characterize the uncertainty in final acute values derived from aquatic toxicity data.

Many ambient water quality criteria established to protect aquatic life from acute toxicity are calculated using a procedure described in the US Environmental Protection Agency's "1985 Guidelines" (USEPA 1985). The procedure yields a final acute value (FAV) from acceptable median lethal or effective concentrations (LC50 or EC50, respectively) that is a single-point, deterministic estimate of the concentration of a chemical substance that will protect 95% of aquatic species from >50% mortality or other acute toxic effects. However, because of variation and uncertainty associated with toxicity test results, uncertainty in the estimated FAV exists that is not accounted for by the 1985 Guidelines procedure. Here, Monte Carlo analysis is used to characterize this uncertainty. The analysis uses Cu EC50 values adjusted for differences in test water chemistry obtained from USEPA's final freshwater Cu criteria guidance published in 2007. Additional Monte Carlo simulations illustrate Cu FAV distributions obtained using a subset of tested species and assuming fewer replicate tests. The deterministic procedure yields an FAV of 4.68 µg/L for the complete data set. By comparison, 3 replicate Monte Carlo simulations yielded mean FAVs of 4.66 µg/L. The 5th and 95th percentiles of the distribution of calculated FAVs were 4.14 µg/L and 5.20 µg/L, respectively. Reducing the number of tested genera from 27 to 8 (the minimum recommended by the 1985 Guidelines) and setting the number of tests per species equal to 3 yielded 5th and 95th percentiles of 1.22 µg/L and 6.18 µg/L, respectively, compared to a deterministic estimate of 2.80 µg/L. Results of this study indicate that Monte Carlo analysis can be used to improve the understanding and communication of uncertainty associated with water quality criteria derived from acute toxicity data using the 1985 Guidelines. This may benefit the development, revision, and application of these criteria in the future.

Office-based interventions for recognizing abnormal pediatric blood pressures.

Interventions to improve pediatric blood pressure (BP) screening have not been well studied. The authors measured staff acceptance of 2 simple in-office interventions and measured the effect on physician recognition of elevated BP measurements. Group 1 used simplified normative pediatric BP tables affixed to the growth chart, group 2 used a personal digital assistant program (PDA) to calculate BP percentiles as part of the vital signs, and group 3 served as the control. Group detection rates by compliant (C) and noncompliant (NC) with the intervention were: (1) (BP table) C = 18%, NC = 12%; (2) (PDA) C = 33%, NC = 26%; and (3) (control) 18%. There was no statistically significant intervention effect with documented compliance (P = .27) nor was there an effect in the noncompliant records (P = .12). Although the interventions were used inconsistently, their presence in the medical record did not improve performance. Future education and interventions are needed to reduce barriers to elevated pediatric BP recognition.

Learning management systems: technology to measure the medical knowledge competency of the ACGME.

AIMS: We report how the learning management system (LMS) Web Course Tools (WebCT) was used to design, implement and evaluate the web-based course "Principles of Ambulatory Paediatrics", taken by paediatric residents during an ambulatory block rotation. This report also illustrates how WebCT can be used to measure the medical knowledge competency required by the Accreditation Council for Graduate Medical Education (ACGME). METHODS: Eighty paediatric residents completed a 1-month outpatient rotation between July 1, 2001 and June 30, 2002. During this rotation residents were required to complete 4 modules in asthma, otitis media, gastroenteritis and fever, respectively. Each module was evaluated using a standard questionnaire. RESULTS: Completion rates for the required modules ranged from 64-72%. Residents in all 3 years of training showed improvement between the pre- and post-test scores for each module, except for postgraduate Year 2 residents in the asthma module. Most residents somewhat agreed, agreed or strongly agreed that the module components were useful and that the experience of completing the modules would improve their ability to take care of patients. CONCLUSIONS: The LMS WebCT is an innovative and adaptable approach for designing a web-based course for primary care education in paediatrics. The LMS addresses the educational needs of both a clinical division and a residency programme. The LMS also provides an information technology infrastructure to measure the medical knowledge competency required by the ACGME.