Robotic Assisted Percutaneous Coronary Intervention: Initial Australian Experience.

BACKGROUND & AIM: Robotic-assisted percutaneous coronary intervention (R-PCI) has been increasingly performed overseas. Initial observations have demonstrated its clinical efficacy and safety with additional potential benefits of more accurate lesion assessment and stent deployment, with reduced radiation exposure to operators and patients. However, data from randomised controlled trials or clinical experience from Australia are lacking. METHODS: This was a single-centre experience of all patients undergoing R-PCI as part of the run-in phase for an upcoming randomised clinical trial (ACTRN12623000480684). All R-PCI procedures were performed using the CorPath GRX robot (Corindus Vascular Robotics, Waltham, Massachusetts, USA). Key inclusion criteria included patients with obstructive coronary disease requiring percutaneous coronary intervention. Major exclusion criteria included ST-elevation myocardial infarction, cardiogenic shock or lesions deemed unsuitable for R-PCI by the operator. Clinical success was defined as residual stenosis <30% without in-hospital major adverse cardiovascular events (MACE). Technical success was defined as the completion of the R-PCI procedure without unplanned manual conversion. Procedural characteristics were compared between early (cases 1-3) and later (cases 4-21) cases. RESULTS: Twenty-one (21) patients with a total of 24 lesions were analysed. The mean age of patients was 66.5 years, and 66% of cases were male. Radial access was used in 18 cases (86%). Most lesions were American Heart Association/American College of Cardiology class B2/C (66%). Clinical success was achieved in 100% with manual conversion required in four cases (19%). No procedural complications or in-hospital MACE occurred. Compared to the early cases, later cases had a statistically significantly shorter fluoroscopy time (44.0mins vs 25.2mins, p<0.007), dose area product (967.3 dGy.cm2 vs 361.0dGy.cm2, p=0.01) and air kerma (2484.3mGy vs 797.4mGy, p=0.009) with no difference in contrast usage (136.7mL vs 131.4mL, p=0.88). CONCLUSIONS: We present the first clinical experience of R-PCI in Australia using the Corindus CorPath GRX robot. We achieved clinical success in all patients and technical success in the majority of cases with no procedural complications or in-hospital MACE. With increasing operator and staff experience, cases required shorter fluoroscopy time and less radiation exposure but similar contrast usage.

Historical evaluation of the in vivo adventitious virus test and its potential for replacement with next generation sequencing (NGS).

The Consortium on Adventitious Agent Contamination in Biomanufacturing (CAACB) collected historical data from 20 biopharmaceutical industry members on their experience with the in vivo adventitious virus test, the in vitro virus test, and the use of next generation sequencing (NGS) for viral safety. Over the past 20 years, only three positive in vivo adventitious virus test results were reported, and all were also detected in another concurrent assay. In more than three cases, data collected as a part of this study also found that the in vivo adventitious virus test had given a negative result for a sample that was later found to contain virus. Additionally, the in vivo adventitious virus test had experienced at least 21 false positives and had to be repeated an additional 21 times all while using more than 84,000 animals. These data support the consideration and need for alternative broad spectrum viral detection tests that are faster, more sensitive, more accurate, more specific, and more humane. NGS is one technology that may meet this need. Eighty one percent of survey respondents are either already actively using or exploring the use of NGS for viral safety. The risks and challenges of replacing in vivo adventitious virus testing with NGS are discussed. It is proposed to update the overall virus safety program for new biopharmaceutical products by replacing in vivo adventitious virus testing approaches with modern methodologies, such as NGS, that maintain or even improve the final safety of the product.

Improving Pediatric Readiness in General Emergency Departments: A Prospective Interventional Study.

OBJECTIVE: To describe the impact of a national interventional collaborative on pediatric readiness within general emergency departments (EDs). STUDY DESIGN: A prospective, multicenter, interventional study measured pediatric readiness in general EDs before and after participation in a pediatric readiness improvement intervention. Pediatric readiness was assessed using the weighted pediatric readiness score (WPRS) on a 100-point scale. The study protocol extended over 6 months and involved 3 phases: (1) a baseline on-site assessment of pediatric readiness and simulated quality of care; (2) pediatric readiness interventions; and (3) a follow-up on-site assessment of WPRS. The intervention phase included a benchmarking performance report, resources toolkits, and ongoing interactions between general EDs and academic medical centers. RESULTS: Thirty-six general EDs were enrolled, and 34 (94%) completed the study. Four EDs (11%) were located in Canada, and the rest were in the US. The mean improvement in WPRS was 16.3 (P < .001) from a baseline of 62.4 (SEM = 2.2) to 78.7 (SEM = 2.1), with significant improvement in the domains of administration/coordination of care; policies, protocol, and procedures; and quality improvement. Six EDs (17%) were fully adherent to the protocol timeline. CONCLUSIONS: Implementing a collaborative intervention model including simulation and quality improvement initiatives is associated with improvement in WPRS when disseminated to a diverse group of general EDs partnering with their regional pediatric academic medical centers. This work provides evidence that innovative collaboration facilitated by academic medical centers can serve as an effective strategy to improve pediatric readiness and processes of care.

3D Echo in Routine Clinical Practice - State of the Art in 2019.

Three-dimensional (3D) echo has been around for almost five decades. Recent advances in ultrasound, electronic and computing technologies have moved 3D echo from the research environment to everyday clinical practice. Real time 3D echo and full volume acquisition are now possible with transthoracic as well as transoesophageal probes. The main advantages of 3D echo are the infinite cut planes possible, allowing direct, en face, and anatomical views of cardiac structures, avoiding foreshortening and circumventing the geometric assumptions of the cardiac chambers inherent in any 2D echo techniques. Three-dimensional echo is still dependent on image quality, subjected to ultrasound artifacts and faces the compromise between spatial and temporal resolution. In routine clinical practice in 2019, we recommend a focussed 3D examination after a full 2D echo study. The area where 3D echo has been consistently shown to have superior accuracy and reproducibility over 2D echo is in the assessment of left ventricular (LV) volumes and ejection fraction. We recommend obtaining a full volume 3D echo data set from the apical window, from which LV volumes and LV global longitudinal strain can be measured. Further 3D examination can be performed depending on the pathologies identified on 2D examination. Three-dimensional echo is superior to 2D echo in the assessment of mitral valve pathologies and atrial septal defects. Furthermore, real time 3D transoesophageal echo is a very useful technique in guiding structural cardiac intervention, both before, during and after the procedure. While 3D echo is not the holy grail of echocardiography, it does represent a useful technique in selected areas of cardiac imaging.

Emergency department ondansetron use in children with type 1 diabetes mellitus and vomiting.

OBJECTIVE: To assess the hypothesis that ondansetron administration to children with type 1 diabetes mellitus (T1DM) presenting for emergency department (ED) care with intercurrent illness and vomiting improves clinical outcomes by reducing hospitalization rates (primary), length of ED stay, intravenous fluid (IVF) administration, and revisits (secondary outcomes). STUDY DESIGN: We conducted a single-center, 10-year retrospective cohort study of 345 ED encounters of children aged 6 months-8 years with T1DM and vomiting. We compared outcomes among children receiving and not receiving ondansetron. To avoid selection bias related to ondansetron administration, we also investigated outcomes by conducting comparisons by ondansetron usage periods (ie, low [2002-2004] vs high [2009-2011]). RESULTS: Ondansetron usage increased from 0% to 67% of ED encounters between 2002 and 2011. Admission rates were similar among those administered [54% (58/107)] and not administered ondansetron [55% (131/238)]. Length of stay was longer in children receiving ondansetron (409 vs 315 minutes; P = .03). IVF administration (77% vs 77%) and revisits (5.6% vs 5.9%) were similar. Ondansetron administration was not associated with reduced admission in logistic regression modeling. Admission rate (62%; 56/91 vs 49%; 57/111) (-13%, 95% CI -23%, 3%), length of stay (395 vs 327 minutes [IQR 164 501]; P < .001), and IVF administration decreased (84% [77/91] to 70% [78/111]; P = .02] when comparing low and high ondansetron usage periods. CONCLUSIONS: Ondansetron administration was not independently associated with lower admission rates. Over time, along with increasing ondansetron use, there have been reductions in admissions, length of stay, and IVF administration in children with T1DM.

Rate-limiting step analysis of the microbial desulfurization of dibenzothiophene in a model oil system.

A mechanistic analysis of the various mass transport and kinetic steps in the microbial desulfurization of dibenzothiophene (DBT) by Rhodococcus erythropolis IGTS8 in a model biphasic (oil-water), small-scale system was performed. The biocatalyst was distributed into three populations, free cells in the aqueous phase, cell aggregates and oil-adhered cells, and the fraction of cells in each population was measured. The power input per volume (P/V) and the impeller tip speed (vtip ) were identified as key operating parameters in determining whether the system is mass transport controlled or kinetically controlled. Oil-water DBT mass transport was found to not be limiting under the conditions tested. Experimental results at both the 100 mL and 4 L (bioreactor) scales suggest that agitation leading to P/V greater than 10,000 W/ m(3) and/or vtip greater than 0.67 m/s is sufficient to overcome the major mass transport limitation in the system, which was the diffusion of DBT within the biocatalyst aggregates.

Stabilizing the heterologously expressed uric acid-xanthine transporter UapA from the lower eukaryote Aspergillus nidulans.

Despite detailed genetic and mutagenic analysis and a recent high-resolution structure of a bacterial member of the nucleobase-ascorbate transporter (NAT) family, understanding of the mechanism of action of eukaryotic NATs is limited. Preliminary studies successfully expressed and purified wild-type UapA to high homogeneity; however, the protein was extremely unstable, degrading almost completely after 48 h at 4°C. In an attempt to increase UapA stability we generated a number of single point mutants (E356D, E356Q, N409A, N409D, Q408E and G411V) previously shown to have reduced or no transport activity, but correct targeting to the membrane. The mutant UapA constructs expressed well as GFP fusions in Saccharomyces cerevisiae and exhibited similar fluorescent size exclusion chromatography (FSEC) profiles to the wild-type protein, following solubilization in 1% DDM, LDAO or OM + 1 mM xanthine. In order to assess the relative stabilities of the mutants, solubilized fractions prepared in 1% DDM + 1 mM xanthine were heated at 45°C for 10 min prior to FSEC. The Q408E and G411V mutants gave markedly better profiles than either wild-type or the other mutants. Further FSEC analysis following solubilization of the mutants in 1% NG ± xanthine confirmed that G411V is more stable than the other mutants, but showed that Q408E is unstable under these conditions. G411V and an N-terminally truncated construct G411VΔ1-11 were submitted to large-scale expression and purification. Long-term stability analysis revealed that G411VΔ1-11 was the most stable construct and the most suited to downstream structural studies.

S-nitrosoglutathione reductase deficiency increases mutagenesis from alkylation in mouse liver.

In human hepatocellular carcinoma (HCC) and many other cancers, somatic point mutations are highly prevalent, yet the mechanisms critical in their generation remain poorly understood. S-nitrosoglutathione reductase (GSNOR), a key regulator of protein S-nitrosylation, is frequently deficient in human HCC. Targeted deletion of the GSNOR gene in mice can reduce the activity of the DNA repair protein O (6)-alkylguanine-DNA alkyltransferase (AGT) and promote both carcinogen-induced and spontaneous HCC. In this study, we report that following exposure to the environmental carcinogen diethylnitrosamine, the mutation frequency of a transgenic reporter in the liver of GSNOR-deficient mice (GSNOR(-/-)) is significantly higher than that in wild-type control. In wild-type mice, diethylnitrosamine treatment does not significantly increase the frequency of the transition from G:C to A:T, a mutation deriving from diethylnitrosamine-induced O (6)-ethylguanines that are normally repaired by AGT. In contrast, the frequency of this transition from diethylnitrosamine is increased ~20 times in GSNOR(-/-) mice. GSNOR deficiency also significantly increases the frequency of the transversion from A:T to T:A, a mutation not affected by AGT. GSNOR deficiency in our experiments does not significantly affect either the frequencies of the other diethylnitrosamine-induced point mutations or hepatocyte proliferation. Thus, GSNOR deficiency, through both AGT-dependent and AGT-independent pathways, significantly raises the rates of specific types of DNA mutations. Our results demonstrate a critical role for GSNOR in maintaining genomic integrity in mice and support the hypothesis that GSNOR deficiency is an important cause of the widespread mutations in human HCC.

Implementation of a North American pediatric emergency medicine simulation curriculum using the virtual resuscitation room.

Background: Simulation provides consistent opportunities for residents to practice high-stakes, low-frequency events such as pediatric resuscitations. To increase standardization across North American residency programs, the Emergency Medicine Resident Simulation Curriculum for Pediatrics (EM ReSCu Peds) was developed. However, access to high-quality simulation/pediatric expertise is not uniform. As the concurrent COVID-19 pandemic necessitated new virtual simulation methods, we adapted the Virtual Resus Room (VRR) to teach EM ReSCu Peds. VRR is an award-winning, low-resource, open-access distance telesimulation platform we hypothesize will be effective and scalable for teaching this curriculum. Methods: EM residents completed six VRR EM ReSCu Peds simulation cases and received immediate facilitator-led teledebriefing. Learners completed retrospective pre-post surveys after each case. Learners and facilitators completed end-of-day surveys. Primary outcomes were learning effectiveness measured by a composite of the Simulation Effectiveness in Teaching Modified (SET-M) tool and self-reported changes in learner comfort with case objectives. Secondary outcome was VRR scalability to teach EM ReSCu Peds using a composite outcome of net promoter scores (NPS), resource utilization, open-text feedback, and technical issues. Results: Learners reported significantly increased comfort with 95% (54/57) of EM ReSCu Peds-defined case objectives (91% cognitive, 9% psychomotor), with moderate (Cohen's d 0.71, 95% CI 0.67-0.76) overall effect size. SET-M responses indicated simulation effectiveness, particularly with debriefing. Ninety EM residents from three North American residency programs were taught by 59 pediatric faculty from six programs over 4 days-more than possible if simulations were conducted in person. Learners (39) and faculty (68) NPS were above software industry benchmarks (13). Minor, quickly resolved, technical issues were reported by 18% and 29% of learners and facilitators, respectively. Conclusions: Learners and facilitators report that the VRR is an effective and scalable platform to teach EM ReSCu Peds. This low-cost, accessible distance simulation intervention could increase equitable, global access to high-quality pediatric emergency education.

MIT CAACB Risk Assessment Case Study: Assessing Virus Cross-Contamination Risk between Two Simultaneous Processes in an Open Biomanufacturing Facility.

Some members of MIT's Consortium on Adventitious Agent Contamination in Biomanufacturing (CAACB) previously published content on the "Quality Risk Management in the Context of Viral Contamination", which described tools, procedures, and methodologies for assessing and managing the risk of a potential virus contamination in cell culture processes. To address the growing industry interest in moving manufacturing toward open ballrooms with functionally closed systems and to demonstrate how the ideas of risk management can be leveraged to perform a risk assessment, CAACB conducted a case study exercise of these new manufacturing modalities. In the case study exercise, a cross-functional team composed of personnel from many of CAACB's industry membership collaboratively assessed the risks of viral cross-contamination between a human and non-human host cell system in an open manufacturing facility. This open manufacturing facility had no walls to provide architectural separation of two processes occurring simultaneously, specifically a recombinant protein perfusion cell culture process using the human cell line, HEK-293 (Process 1) and a downstream postviral filtration unit operation (Process 2) of a recombinant protein produced in CHO cells. This viral risk assessment focused on cross-contamination of the Process 2 filtration unit operation after the Process 1 perfusion bioreactor was contaminated with a virus that went undetected. The workflow for quality risk management that is recommended by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) was followed, which included identifying and mapping the manufacturing process, defining the risk question, risk evaluation, and risk control. The case study includes a completed Failure Mode and Effects Analysis (FMEA) to provide descriptions of the specific risks and corresponding recommended risk reduction actions.

Factors Associated With Improved Pediatric Resuscitative Care in General Emergency Departments.

OBJECTIVES: To describe the quality of pediatric resuscitative care in general emergency departments (GEDs) and to determine hospital-level factors associated with higher quality. METHODS: Prospective observational study of resuscitative care provided to 3 in situ simulated patients (infant seizure, infant sepsis, and child cardiac arrest) by interprofessional GED teams. A composite quality score (CQS) was measured and the association of this score with modifiable and nonmodifiable hospital-level factors was explored. RESULTS: A median CQS of 62.8 of 100 (interquartile range 50.5-71.1) was noted for 287 resuscitation teams from 175 emergency departments. In the unadjusted analyses, a higher score was associated with the modifiable factor of an affiliation with a pediatric academic medical center (PAMC) and the nonmodifiable factors of higher pediatric volume and location in the Northeast and Midwest. In the adjusted analyses, a higher CQS was associated with modifiable factors of an affiliation with a PAMC and the designation of both a nurse and physician pediatric emergency care coordinator, and nonmodifiable factors of higher pediatric volume and location in the Northeast and Midwest. A weak correlation was noted between quality and pediatric readiness scores. CONCLUSIONS: A low quality of pediatric resuscitative care, measured using simulation, was noted across a cohort of GEDs. Hospital factors associated with higher quality included: an affiliation with a PAMC, designation of a pediatric emergency care coordinator, higher pediatric volume, and geographic location. A weak correlation was noted between quality and pediatric readiness scores.

Regional mechanical properties of human pulmonary root used for the Ross operation.

BACKGROUND AND AIM OF THE STUDY: Significant dilation of the pulmonary autograft after the Ross operation is problematic and requires reoperation. Autograft remodeling occurs in response to the immediate rise in pressure and consequent wall stress. The stress-strain response of the pulmonary root plays an important role in understanding the structural and functional changes of the autograft following the Ross procedure. At present, limited data are available on the mechanical properties of fresh human pulmonary roots; hence, the study aim was to determine the regional mechanical properties of human pulmonary roots. METHODS: Eighteen fresh healthy specimens of human pulmonary root were obtained from the California Transplant Donor Network (Oakland, CA, USA). Five regions of the pulmonary root--anterior and posterior pulmonary artery (PA), and each of the three sinuses--were subjected to displacement-controlled equibiaxial stretch testing within 24 h of cross-clamp time. Comparisons between the different regions of the pulmonary root were made based on tissue stiffness at physiologic stress. Histologic analyses were also performed of the fibrous structures of the PA and sinuses. RESULTS: Human PA and sinuses demonstrated a nonlinear response to loading, with no directional dependency to biaxial loading. The anterior PA was significantly more compliant than the posterior PA and the three sinuses in both circumferential and longitudinal directions (p < 0.04). However, there was no significant difference between the stiffness of the posterior PA and that of the three sinuses (p > 0.43), or among the three sinuses (p > 0.30) in the two directions. A tight, more dense weave of elastin was found in the anterior PA than in either the posterior PA or the sinuses. CONCLUSION: Significant inherent differences in compliance were demonstrated among different regions of the human pulmonary root. These regional differences may impact upon pulmonary autograft remodeling following the Ross operation, and also influence late autograft dilation.

Paediatrics: how to manage acute asthma exacerbations.

BACKGROUND: Asthma is the most common chronic disease of childhood and a major source of childhood health burden worldwide. These burdens are particularly marked when children experience characteristic 'symptom flare-ups' or acute asthma exacerbations (AAEs). AAE are associated with significant health and economic impacts, including acute Emergency Department visits, occasional hospitalizations, and rarely, death. To treat children with AAE, several medications have been studied and used. METHODS: We conducted a narrative review of the literature with the primary objective of understanding the evidence of their efficacy. We present this efficacy evidence in the context of a general stepwise management pathway for paediatric AAEs. This framework is developed from the combined recommendations of eight established (inter)national paediatric guidelines. DISCUSSION: Management of paediatric AAE centres around four major care goals: (1) immediate and objective assessment of AAE severity; (2) prompt and effective medical interventions to decrease respiratory distress and improve oxygenation; (3) appropriate disposition of patient; and (4) safe discharge plans. Several medications are currently recommended with varying efficacies, including heliox, systemic corticosteroids, first-line bronchodilators (salbutamol/albuterol), adjunctive bronchodilators (ipratropium bromide, magnesium sulfate) and second-line bronchodilators (aminophylline, i.v. salbutamol, i.v. terbutaline, epinephrine, ketamine). Care of children with AAE is further enhanced using clinical severity scoring, pathway-driven care and after-event discharge planning. CONCLUSIONS: AAEs in children are primarily managed by medications supported by a growing body of literature. Continued efforts to study the efficacy of second-line bronchodilators, integrate AAE management with long-term asthma control and provide fair/equitable care are required.

An Unexpected Cause of Heart Failure in a Young Woman With Treated Lymphoma.

Arteriovenous fistula is a rare complication of lumbar surgery that may cause high-output cardiac failure. We describe the case of a patient with treated lymphoma and recent spinal surgery who presented with heart failure. Logical deduction from clinical and imaging findings helped us arrive at this unusual diagnosis. (Level of Difficulty: Intermediate.).

Increased Rates of Peanut and Tree Nut Aspiration as a Possible Consequence of Allergy Prevention by Early Introduction.

BACKGROUND: Pediatric airway foreign bodies (FBs) are a surgical emergency, and peanuts and tree nuts (PN/TNs) can pose a significant aspiration risk in young children. In 2015, the Learning Early About Peanut allergy (LEAP) trial established that early introduction of peanuts in high-risk infants reduced the risk of developing a peanut allergy. Infant feeding guidelines were subsequently modified to actively encourage the introduction of allergenic foods for all infants. The impact of this shift in feeding advice on the incidence of PN/TN inhalation has not been previously studied. OBJECTIVE: To determine the incidence of PN/TN inhalation presentations to a quaternary pediatric hospital between 2008 and 2018. METHODS: A retrospective cohort study of children who were diagnosed with an airway FB by rigid bronchoscopy. RESULTS: There were 200 cases of FB inhalation (35% PN/TN, 34% other foods, and 31% inorganic material). There was a rise in the total incidence of FB inhalation over the study period (incidence ratio rate [IRR], 1.09; P < .001). The rise was due to PN/TN (IRR, 1.16; P < .002) and other food inhalation (IRR, 1.12; P = .01), with no significant increase in inorganic FB aspiration (IRR, 1; P = .94). Between pre-LEAP (2008-2014) and post-LEAP (2015-2018) periods, there was a trebling, doubling, and no increase in the rate of PN/TN, other food, and inorganic FB inhalation, respectively. CONCLUSIONS: Since the publication of the LEAP study, there has been a rise in PN/TN and other hard solid food inhalation at our institution. This study highlights the urgent need to engage the public to promote safe introduction of hard foods in young children.

Expression and purification of a functional uric acid-xanthine transporter (UapA).

The Nucleobase-Ascorbate Transporters (NATs) family includes carriers with fundamental functions in uptake of key cellular metabolites, such as uric acid or vitamin C. The best studied example of a NAT transporter is the uric acid-xanthine permease (UapA) from the model ascomycete Aspergillus nidulans. Detailed genetic and biochemical analyses have revealed much about the mechanism of action of this protein; however, the difficulties associated with handling eukaryotic membrane proteins have limited efforts to elucidate the precise structure-function relationships of UapA by structural analysis. In this manuscript, we describe the heterologous overexpression of functional UapA as a fusion with GFP in different strains of Saccharomyces cerevisiae. The UapA-GFP construct expressed to 2.3 mg/L in a pep4Delta deletion strain lacking a key vacuolar endopeptidase and 3.8 mg/L in an npi1-1 mutant strain with defective Rsp5 ubiquitin ligase activity. Epifluorescence microscopy revealed that the UapA-GFP was predominately localized to the plasma membrane in both strains, although a higher intensity of fluorescence was observed for the npi1-1 mutant strain plasma membrane. In agreement with these observations, the npi1-1 mutant strain demonstrated a approximately 5-fold increase in uptake of [(3)H]-xanthine compared to the pep4Delta deletion strain. Despite yielding the best results for functional expression, in-gel fluorescence of the UapA-GFP expressed in the npi1-1 mutant strain revealed that the protein was subject to significant proteolytic degradation. Large scale expression of the protein using the pep4Delta deletion strain followed by purification produced mg quantities of pure, monodispersed protein suitable for further structural and functional studies. In addition, this work has generated a yeast cell based system for performing reverse genetics and other targeted approaches, in order to further understand the mechanism of action of this important model protein.

Non-inferiority trials in cardiology: what clinicians need to know.

Clinical trials traditionally aim to show a new treatment is superior to placebo or standard treatment, that is, superiority trials. There is an increasing number of trials demonstrating a new treatment is non-inferior to standard treatment. The hypotheses, design and interpretation of non-inferiority trials are different to superiority trials. Non-inferiority trials are designed with the notion that the new treatment offers advantages over standard treatment in certain important aspects. The non-inferior margin is a predetermined margin of difference between the new and standard treatment that is considered acceptable or tolerable for the new treatment to be considered 'similar' or 'not worse'. Both relative difference and absolute difference methods can be used to define the non-inferior margin. Sequential testing for non-inferiority and superiority is often performed. Non-inferiority trials may be necessary in situations where it is no longer ethical to test any new treatment against placebo. There are inherent assumptions in non-inferiority trials which may not be correct and which are not being tested. Successive non-inferiority trials may introduce less and less effective treatments even though these treatments may have been shown to be non-inferior. Furthermore, poor quality trials favour non-inferior results. Intention-to-treat analysis, the preferred way to analyse randomised trials, may favour non-inferiority. Both intention-to-treat and per-protocol analyses should be recommended in non-inferiority trials. Clinicians should be aware of the pitfalls of non-inferiority trials and not accept non-inferiority on face value. The focus should not be on the p values but on the effect size and confidence limits.

Development of an in situ simulation-based continuing professional development curriculum in pediatric emergency medicine.

BACKGROUND: Continuing professional development (CPD) activities delivered by simulation to independently practicing physicians are becoming increasingly popular. At present, the educational potential of such simulations is limited by the inability to create effective curricula for the CPD audience. In contrast to medical trainees, CPD activities lack pre-defined learning expectations and, instead, emphasize self-directed learning, which may not encompass true learning needs. We hypothesize that we could generate an interprofessional CPD simulation curriculum for practicing pediatric emergency medicine (PEM) physicians in a single-center tertiary care hospital using a deliberative approach combined with Kern's six-step method of curriculum development. METHODS: From a comprehensive core list of 94 possible PEM clinical presentations and procedures, we generated an 18-scenario CPD simulation curriculum. We conducted a comprehensive perceived and unperceived needs assessment on topics to include, incorporating opinions of faculty PEM physicians, hospital leadership, interprofessional colleagues, and expert opinion on patient benefit, simulation feasibility, and value of simulating the case for learning. To systematically rank items while balancing the needs of all stakeholders, we used a prioritization matrix to generate objective "priority scores." These scores were used by CPD planners to deliberately determine the simulation curriculum contents. RESULTS: We describe a novel three-step CPD simulation curriculum design method involving (1) systematic and deliberate needs assessment, (2) systematic prioritization, and (3) curriculum synthesis. Of practicing PEM physicians, 17/20 responded to the perceived learning needs survey, while 6/6 leaders responded to the unperceived needs assessment. These ranked data were input to a five-variable prioritization matrix generating priority scores. Based on local needs, the highest 18 scoring clinical presentations and procedures were selected for final inclusion in a PEM CPD simulation curriculum. An interim survey of PEM physician (21/24 respondents) opinions was collected, with 90% finding educational value with the curriculum. The curriculum includes items not identified by self-directed learning that PEM physicians thought should be included. CONCLUSIONS: We highlight a novel methodology for PEM physicians that can be adapted by other specialities when designing their own CPD simulation curriculum. This methodology objectively considers and prioritizes the needs of practicing physicians and stakeholders involved in CPD.

Viral contamination in biologic manufacture and implications for emerging therapies.

Recombinant protein therapeutics, vaccines, and plasma products have a long record of safety. However, the use of cell culture to produce recombinant proteins is still susceptible to contamination with viruses. These contaminations cost millions of dollars to recover from, can lead to patients not receiving therapies, and are very rare, which makes learning from past events difficult. A consortium of biotech companies, together with the Massachusetts Institute of Technology, has convened to collect data on these events. This industry-wide study provides insights into the most common viral contaminants, the source of those contaminants, the cell lines affected, corrective actions, as well as the impact of such events. These results have implications for the safe and effective production of not just current products, but also emerging cell and gene therapies which have shown much therapeutic promise.