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.

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.

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.

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.

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.

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.).

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.

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.

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.

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.

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.

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.

Predictive energy equations are inaccurate for determining energy expenditure in adult burn injury: a retrospective observational study.

BACKGROUND: Severe burn injuries are associated with hypermetabolism. This study aimed to compare the measured energy expenditure (mEE) with predicted energy requirements (pERs), and to correlate energy expenditure (EE) with clinical parameters in adults with severe burn injury. METHODS: Data were retrospectively analysed on 29 burn patients (median (interquartile range) age: 46 (28-61) years, % total body surface area burn: 37% (18-46%)) admitted to an intensive care unit. Indirect calorimetry was performed on 1-4 occasions per patient to measure EE. mEE was compared with pER calculated using four prediction equations. Bland-Altman and correlation analyses were performed. RESULTS: Mean ± SD mEE was 9752 ± 2089 kJ/day (143 ± 32% of predicted basal metabolic rate). Bland-Altman analysis demonstrated clinically important overestimation for three of the four prediction equations and wide 95% limits of agreement for all equations. Overestimation of EE was more marked early post-burn. mEE correlated with day post-burn (r = 0.42, P = 0.004) and number of operations prior to first EE measurement (r = 0.34, P = 0.016), but not with % total body surface area (r = 0.02, P = 0.9). CONCLUSIONS: Patients with severe burn injury exhibit hypermetabolism. The observed poor agreement between pER and mEE at an individual level indicates the value of indirect calorimetry in determining EE in burn injury.

Biopharmaceutical Industry Approaches to Facility Segregation for Viral Safety: An Effort from the Consortium on Adventitious Agent Contamination in Biomanufacturing.

Appropriate segregation within manufacturing facilities is required by regulators and utilized by manufacturers to ensure that the final product has not been contaminated with (a) adventitious viruses, (b) another pre-/postviral clearance fraction of the same product, or (c) another product processed in the same facility. However, there is no consensus on what constitutes appropriate facility segregation to minimize these risks. In part, this is due to the fact that a wide variety of manufacturing facilities and operational practices exist, including single-product and multiproduct manufacturing, using traditional segregation strategies with separate rooms for specific operations that may use stainless steel or disposable equipment to more modern ballroom-style operations that use mostly disposable equipment (i.e., pre- and postviral clearance manufacturing operations are not physically segregated by walls). Further, consensus is lacking around basic definitions and approaches related to facility segregation. For example, given that several unit operations provide assurance of virus clearance during downstream processing, how does one define pre- and postviral clearance and at which point(s) should a viral segregation barrier be introduced? What is a "functionally closed" system? How can interventions be conducted so that the system remains functionally closed? How can functionally closed systems be used to adequately isolate a product stream and ensure its safety? To address these issues, the member companies of the Consortium on Adventitious Agent Contamination in Biomanufacturing (CAACB) have conducted a facility segregation project with the following goals: define "pre- and postviral clearance zones" and "pre- and postviral clearance materials"; define "functionally closed" manufacturing systems; and identify an array of facility segregation approaches that are used for the safe and effective production of recombinant biologics as well as plasma products. This article reflects the current thinking from this collaborative endeavor.LAY ABSTRACT: Operations in biopharmaceutical manufacturing are segregated to ensure that the final product has not been contaminated with adventitious viruses, another fraction of the same product, or with another product from within the same facility. Yet there is no consensus understanding of what appropriate facility segregation looks like. There are a wide variety of manufacturing facilities and operational practices. There are existing facilities with separate rooms and more modern approaches that use disposable equipment in an open ballroom without walls. There is also no agreement on basic definitions and approaches related to facility segregation approaches. For example, many would like to claim that their manufacturing process is functionally closed, yet exactly how a functionally closed system may be defined is not clear. To address this, the member companies of the Consortium on Adventitious Agent Contamination in Biomanufacturing (CAACB) have conducted a project with the goal of defining important manufacturing terms relevant to designing an appropriately segregated facility and identifying different facility segregation approaches that are used for the safe and effective production of recombinant biologics as well as plasma products.

Feasibility study on medical isotope production using a compact neutron generator.

Compact neutron generators can provide high flux of neutrons with energies ranging from thermal (0.025 eV) to 14 MeV. Recent measurements demonstrated high neutron yields from the D-7Li fusion reaction at an interaction energy of 500 keV. Using the D-7Li reaction and applying new advancements in high flux neutron generator technology along with the commercial availability of high voltage DC power supplies enables the production of useful quantities of radioisotopes for medical applications. Using the known neutron reaction cross-sections, it has been estimated that hundreds-to-thousands MBq (or tens-to-hundreds mCi) of 99Mo, 225Ac, 64Cu and 67Cu can be obtained from a compact high flux neutron generator.

A systematic review of adverse drug events associated with administration of common asthma medications in children.

OBJECTIVE: To systematically review the literature and determine frequencies of adverse drug events (ADE) associated with pediatric asthma medications. METHODS: Following PRISMA guidelines, we systematically searched six bibliographic databases between January 1991 and January 2017. Study eligibility, data extraction and quality assessment were independently completed and verified by two reviewers. We included randomized control trials (RCT), case-control, cohort, or quasi-experimental studies where the primary objective was identifying ADE in children 1 month- 18 years old exposed to commercial asthma medications. The primary outcome was ADE frequency. FINDINGS: Our search identified 14,540 citations. 46 studies were included: 24 RCT, 15 cohort, 4 RCT pooled analyses, 1 case-control, 1 open-label trial and 1 quasi-experimental study. Studies examined the following drug classes: inhaled corticosteroids (ICS) (n = 24), short-acting beta-agonists (n = 10), long-acting beta-agonists (LABA) (n = 3), ICS + LABA (n = 3), Leukotriene Receptor Antagonists (n = 3) and others (n = 3). 29 studies occurred in North America, and 29 were industry funded. We report a detailed index of 406 ADE descriptions and frequencies organized by drug class. The majority of data focuses on ICS, with 174 ADE affecting 13 organ systems including adrenal and growth suppression. We observed serious ADE, although they were rare, with frequency ranging between 0.9-6% per drug. There were no confirmed deaths, except for 13 potential deaths in a LABA study including combined adult and pediatric participants. We identified substantial methodological concerns, particularly with identifying ADE and determining severity. No studies utilized available standardized causality, severity or preventability assessments. CONCLUSION: The majority of studies focus on ICS, with adrenal and growth suppression described. Serious ADE are relatively uncommon, with no confirmed pediatric deaths. We identify substantial methodological concerns, highlighting need for standardization with future research examining pediatric asthma medication safety.

Structure of eukaryotic purine/H(+) symporter UapA suggests a role for homodimerization in transport activity.

The uric acid/xanthine H(+) symporter, UapA, is a high-affinity purine transporter from the filamentous fungus Aspergillus nidulans. Here we present the crystal structure of a genetically stabilized version of UapA (UapA-G411VΔ1-11) in complex with xanthine. UapA is formed from two domains, a core domain and a gate domain, similar to the previously solved uracil transporter UraA, which belongs to the same family. The structure shows UapA in an inward-facing conformation with xanthine bound to residues in the core domain. Unlike UraA, which was observed to be a monomer, UapA forms a dimer in the crystals with dimer interactions formed exclusively through the gate domain. Analysis of dominant negative mutants is consistent with dimerization playing a key role in transport. We postulate that UapA uses an elevator transport mechanism likely to be shared with other structurally homologous transporters including anion exchangers and prestin.

Oligomerization of the UapA Purine Transporter Is Critical for ER-Exit, Plasma Membrane Localization and Turnover.

Central to the process of transmembrane cargo trafficking is the successful folding and exit from the ER (endoplasmic reticulum) through packaging in COPII vesicles. Here, we use the UapA purine transporter of Aspergillus nidulans to investigate the role of cargo oligomerization in membrane trafficking. We show that UapA oligomerizes (at least dimerizes) and that oligomerization persists upon UapA endocytosis and vacuolar sorting. Using a validated bimolecular fluorescence complementation assay, we provide evidence that a UapA oligomerization is associated with ER-exit and turnover, as ER-retained mutants due to either modification of a Tyr-based N-terminal motif or partial misfolding physically associate but do not associate properly. Co-expression of ER-retained mutants with wild-type UapA leads to in trans plasma membrane localization of the former, confirming that oligomerization initiates in the ER. Genetic suppression of an N-terminal mutation in the Tyr motif and mutational analysis suggest that transmembrane α-helix 7 affects the oligomerization interface. Our results reveal that transporter oligomerization is essential for membrane trafficking and turnover and is a common theme in fungi and mammalian cells.