Prevalence of Errors in Anaphylaxis in Kids (PEAK): A Multicenter Simulation-Based Study

Background Multi-institutional, international practice variation of pediatric anaphylaxis management by health care providers has not been reported. Objective To characterize variability in epinephrine administration for pediatric anaphylaxis across institutions, including frequency and types of medication errors. Methods A prospective, observational, study using a standardized in situ simulated anaphylaxis scenario was performed across 28 health care institutions in 6 countries. The on-duty health care team was called for a child (patient simulator) in anaphylaxis. Real medications and supplies were obtained from their actual locations. Demographic data about team members, institutional protocols for anaphylaxis, timing of epinephrine delivery, medication errors, and systems safety issues discovered during the simulation were collected. Results Thirty-seven in situ simulations were performed. Anaphylaxis guidelines existed in 41% (15 of 37) of institutions. Teams used a cognitive aid for medication dosing 41% (15 of 37) of the time and 32% (12 of 37) for preparation. Epinephrine autoinjectors were not available in 54% (20 of 37) of institutions and were used in only 14% (5 of 37) of simulations. Median time to epinephrine administration was 95 seconds (interquartile range, 77-252) for epinephrine autoinjector and 263 seconds (interquartile range, 146-407.5) for manually prepared epinephrine (P = .12). At least 1 medication error occurred in 68% (25 of 37) of simulations. Nursing experience with epinephrine administration for anaphylaxis was associated with fewer preparation (P = .04) and administration (P = .01) errors. Latent safety threats were reported by 30% (11 of 37) of institutions, and more than half of these (6 of 11) involved a cognitive aid. Conclusions A multicenter, international study of simulated pediatric anaphylaxis reveals (1) variation in management between institutions in the use of protocols, cognitive aids, and medication formularies, (2) frequent errors involving epinephrine, and (3) latent safety threats related to cognitive aids among multiple sites

Emergency Department Presentations of Diabetic Ketoacidosis in a Large Cohort of Children

Background. Diabetic ketoacidosis (DKA) is a potentially life-threatening complication of childhood diabetes. However, the influence of demographic factors on presentation are not well-defined. Methods. We included children from 12 centers who were \u3c18 years with DKA (glucose \u3e 300 mg/dL, serum pH \u3c 7.25, or serum bicarbonate \u3c15 mEq/L) enrolled in the Pediatric Emergency Care Applied Research Network (PECARN) Fluid Therapies Under Investigation in DKA (FLUID) Trial. Data were also collected for children who presented to the centers during the enrollment period but were not enrolled due to disease or treatment-related reasons. We compared demographic, clinical, and biochemical findings among children with newly and previously diagnosed diabetes and children in different age groups. Results. Of the 1,679 DKA episodes in 1,553 children, 799 (47.5%) episodes occurred in children with newly diagnosed diabetes and 396 (23.6%) were severe (pH \u3c 7.1). Newly diagnosed children \u3c6 years of age were not more likely to have severe DKA in terms of pH, but had more severe hypocarbia and higher blood urea nitrogen levels, factors previously associated with the risk of cerebral injury. Lower socioeconomic status (SES) (based on family income and maternal education level) were associated with more severe DKA in new onset children, and recurrent DKA in the previously diagnosed children. Conclusions. Greater efforts are needed to identify the children with diabetes early and to prevent recurrent DKA, particularly among children in low-SES groups. Young children with DKA may need more intensive monitoring due to higher risk of cerebral injury

Frequency of the ATM IVS10-6T→G variant in Australian multiple-case breast cancer families

BACKGROUND: Germline mutations in the genes BRCA1 and BRCA2 account for only a proportion of hereditary breast cancer, suggesting that additional genes contribute to hereditary breast cancer. Recently a heterozygous variant in the ataxia–telangiectasia mutated (ATM) gene, IVS10-6T→G, was reported by an Australian multiple-case breast cancer family cohort study (the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer) to confer a substantial breast cancer risk. Although this variant can result in a truncated ATM product, its clinical significance as a high-penetrance breast cancer allele or its role as a low-penetrance risk-modifier is controversial. METHODS: We determined the frequency of ATM IVS10-6T→G variants in a cohort of individuals affected by breast and/or ovarian cancer who underwent BRCA1 and BRCA2 genetic testing at four major Australian familial cancer clinics. RESULTS: Seven of 495 patients (1.4%) were heterozygous for the IVS10-6T→G variant; the carrier rate in unselected Australian women with no family history of breast cancer is reported to be 6 of 725 (0.83%) (P = 0.4). Two of the seven probands also harboured a pathogenic BRCA1 mutation and one patient had a BRCA1 unclassified variant of uncertain significance. CONCLUSION: These findings indicate that the ATM IVS10-6T→G variant does not seem to occur at a significantly higher frequency in affected individuals from high-risk families than in the general population. A role for this variant as a low-penetrance allele or as a modifying gene in association with other genes (such as BRCA1) remains possible. Routine testing for ATM IVS10-6T→G is not warranted in mutation screening of affected individuals from high-risk families

Altered translation of GATA1 in Diamond-Blackfan anemia

Ribosomal protein haploinsufficiency occurs in diverse human diseases including Diamond-Blackfan anemia (DBA)[superscript 1, 2], congenital asplenia[superscript 3] and T cell leukemia[superscript 4]. Yet, how mutations in genes encoding ubiquitously expressed proteins such as these result in cell-type– and tissue-specific defects remains unknown[superscript 5]. Here, we identify mutations in GATA1, encoding the critical hematopoietic transcription factor GATA-binding protein-1, that reduce levels of full-length GATA1 protein and cause DBA in rare instances. We show that ribosomal protein haploinsufficiency, the more common cause of DBA, can lead to decreased GATA1 mRNA translation, possibly resulting from a higher threshold for initiation of translation of this mRNA in comparison with other mRNAs. In primary hematopoietic cells from patients with mutations in RPS19, encoding ribosomal protein S19, the amplitude of a transcriptional signature of GATA1 target genes was globally and specifically reduced, indicating that the activity, but not the mRNA level, of GATA1 is decreased in patients with DBA associated with mutations affecting ribosomal proteins. Moreover, the defective hematopoiesis observed in patients with DBA associated with ribosomal protein haploinsufficiency could be partially overcome by increasing GATA1 protein levels. Our results provide a paradigm by which selective defects in translation due to mutations affecting ubiquitous ribosomal proteins can result in human disease.National Institutes of Health (U.S.) (Grant P01 HL32262)National Institutes of Health (U.S.) (Grant U54 HG003067-09

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Clinical Performance of the Novel GenMark Dx ePlex® Blood Culture ID Gram-Positive Panel

BACKGROUND: Rapid identification from positive blood cultures is standard of care (SOC) in many clinical microbiology laboratories. The GenMark Dx ePlex® Blood Culture ID Gram Positive (BCID-GP) Panel is a multiplex nucleic acid amplification assay based on competitive DNA hybridization and electrochemical detection using eSensor® technology. This multicenter study compared the Investigational Use Only (IUO) BCID-GP Panel to comparator methods for identification of 20 gram-positive bacteria, four antimicrobial resistance genes, and both Pan MATERIALS AND METHODS: Ten microbiology laboratories throughout the USA collected residual, de-identified positive blood culture samples for analysis. Five laboratories tested both clinical and contrived samples with the BCID-GP Panel. Comparator identification methods included each laboratory\u27s SOC, which included MALDI-TOF MS and automated identification systems, and targeted PCR/qPCR with bidirectional sequencing. RESULTS: A total of 2,342 evaluable samples (1,777 clinical, 565 contrived) were tested with the BCID-GP Panel. The overall sample accuracy for on-panel organisms was 89% before discordant resolution. For pathogenic gram-positive targets ( CONCLUSION: The ePlex BCID-GP Panel compares favorably to SOC and targeted molecular methods for the identification of twenty gram-positive pathogens and four antimicrobial resistance genes in positive blood culture bottles. This panel detects a broad range of pathogens and mixed infections with yeast and gram-negative organisms from the same positive blood culture bottle

What Do Pediatric Subinterns Say About Their Learning and Assessment? A Qualitative Analysis of Individual Learning Plans.

OBJECTIVE: To perform a qualitative content analysis of learning and assessment strategies that pediatric sub-interns describe in Individualized Learning Plans (ILPs) and to explore barriers and facilitators to their learning. METHODS: We analyzed ILPs from medical students enrolled in pediatric sub-internships at 10 U.S. medical schools that utilized a standardized curriculum and were recruited to reflect diversity in geographic location, funding, and enrollment. Students used an ILP to record three or more selected learning objectives, rationale for selection, and reflection on learning and assessment strategies. Investigators used the constant comparative method to perform a content analysis of the ILPs, grouping codes into themes, and verifying relationships between codes within themes. RESULTS: 204 ILPs that included student reflections on 850 learning objectives were analyzed. Content was analyzed in five categories: rationale for selecting objectives, learning strategies, assessment strategies, challenges to learning, and facilitators of learning. Students showed strong commitment to individualized, self-directed learning, developed a wide range of creative learning strategies, and relied heavily on self-reflection to assess their progress. The learning environment both helped and hindered students\u27 ability to make and assess progress on their selected learning objectives. CONCLUSIONS: Through ILP-guided reflection and a formal curriculum, students can choose well-justified learning objectives and demonstrate resourcefulness and independence in developing self-directed learning and assessments strategies. The strategies that students identified in this study provide a menu of learning and assessment options for sub-interns. Identified challenges and facilitators of learning provide guidance for educators who seek to enhance the clinical learning environment