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9 - Post-Market Surveillance of Software Medical Devices
- from Part III - The Shape of the Elephant for Digital Home Diagnostics
- Edited by I. Glenn Cohen, Harvard Law School, Massachusetts, Daniel B. Kramer, Harvard Medical School, Massachusetts, Julia Adler-Milstein, University of California, San Francisco, Carmel Shachar, Harvard Law School, Massachusetts
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- Digital Health Care outside of Traditional Clinical Settings
- Published online:
- 25 April 2024
- Print publication:
- 02 May 2024, pp 123-138
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Summary
Medical devices increasingly include software components, which facilitate remote patient monitoring. The introduction of software into previously analog medical devices, as well as innovation in software-driven devices, may introduce new safety concerns – all the more so when such devices are used in patients’ homes, well outside of traditional health care delivery settings. We review four key mechanisms for the post-market surveillance of medical devices in the United States: (1) Post-market trials and registries; (2) manufacturing plant inspections; (3) adverse event reporting; and (4) recalls. We use comprehensive regulatory data documenting adverse events and recalls to describe trends in the post-market safety of medical devices, based on the presence or absence of software. Overall, devices with software are associated with more reported adverse events (i.e. individual injuries and deaths) and more high-severity recalls, compared to devices without software. However, in subgroup analyses of individual medical specialties, we consistently observe differences in recall probability but do not consistently detect differences in adverse events. These results suggest that adverse events are a noisy signal of post-market safety and not necessarily a reliable predictor of subsequent recalls. As patients and health care providers weigh the benefits of new remote monitoring technologies against potential safety issues, they should not assume that safety concerns will be readily identifiable through existing post-market surveillance mechanisms. Both health care providers and developers of remote patient monitoring technologies should therefore consider how they might proactively ensure that newly introduced remote patient monitoring technologies work safely and as intended.
Developmental trajectories of adolescent internalizing symptoms and parental responses to distress
- Jason D. Jones, R. Chris Fraley, Jessica A. Stern, Carl W. Lejuez, Jude Cassidy
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- Journal:
- Development and Psychopathology , First View
- Published online by Cambridge University Press:
- 23 February 2024, pp. 1-12
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Parents’ responses to their children’s negative emotions are a central aspect of emotion socialization that have well-established associations with the development of psychopathology. Yet research is lacking on potential bidirectional associations between parental responses and youth symptoms that may unfold over time. Further, additional research is needed on sociocultural factors that may be related to the trajectories of these constructs. In this study, we examined associations between trajectories of parental responses to negative emotions and adolescent internalizing symptoms and the potential role of youth sex and racial identity. Adolescents and caregivers (N = 256) completed six assessments that spanned adolescent ages 13–18 years. Multivariate growth models revealed that adolescents with higher internalizing symptoms at baseline experienced increasingly non-supportive parental responses over time (punitive and distress responses). By contrast, parental responses did not predict initial levels of or changes in internalizing symptoms. Parents of Black youth reported higher minimization and emotion-focused responses and lower distress responses compared to parents of White youth. We found minimal evidence for sex differences in parental responses. Internalizing symptoms in early adolescence had enduring effects on parental responses to distress, suggesting that adolescents may play an active role in shaping their emotion socialization developmental context.
4 Evaluating Plasma GFAP for the Detection of Alzheimer’s Disease Dementia
- Madeline Ally, Henrik Zetterberg, Kaj Blennow, Nicholas J. Ashton, Thomas K. Karikari, Hugo Aparicio, Michael A. Sugarman, Brandon Frank, Yorghos Tripodis, Ann C. McKee, Thor D. Stein, Brett Martin, Joseph N. Palmisano, Eric G. Steinberg, Irene Simkina, Lindsay Farrer, Gyungah Jun, Katherine W. Turk, Andrew E. Budson, Maureen K. O’Connor, Rhoda Au, Wei Qiao Qiu, Lee E. Goldstein, Ronald Killiany, Neil W. Kowall, Robert A. Stern, Jesse Mez, Michael L. Alosco
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 408-409
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Objective:
Blood-based biomarkers represent a scalable and accessible approach for the detection and monitoring of Alzheimer’s disease (AD). Plasma phosphorylated tau (p-tau) and neurofilament light (NfL) are validated biomarkers for the detection of tau and neurodegenerative brain changes in AD, respectively. There is now emphasis to expand beyond these markers to detect and provide insight into the pathophysiological processes of AD. To this end, a reactive astrocytic marker, namely plasma glial fibrillary acidic protein (GFAP), has been of interest. Yet, little is known about the relationship between plasma GFAP and AD. Here, we examined the association between plasma GFAP, diagnostic status, and neuropsychological test performance. Diagnostic accuracy of plasma GFAP was compared with plasma measures of p-tau181 and NfL.
Participants and Methods:This sample included 567 participants from the Boston University (BU) Alzheimer’s Disease Research Center (ADRC) Longitudinal Clinical Core Registry, including individuals with normal cognition (n=234), mild cognitive impairment (MCI) (n=180), and AD dementia (n=153). The sample included all participants who had a blood draw. Participants completed a comprehensive neuropsychological battery (sample sizes across tests varied due to missingness). Diagnoses were adjudicated during multidisciplinary diagnostic consensus conferences. Plasma samples were analyzed using the Simoa platform. Binary logistic regression analyses tested the association between GFAP levels and diagnostic status (i.e., cognitively impaired due to AD versus unimpaired), controlling for age, sex, race, education, and APOE e4 status. Area under the curve (AUC) statistics from receiver operating characteristics (ROC) using predicted probabilities from binary logistic regression examined the ability of plasma GFAP to discriminate diagnostic groups compared with plasma p-tau181 and NfL. Linear regression models tested the association between plasma GFAP and neuropsychological test performance, accounting for the above covariates.
Results:The mean (SD) age of the sample was 74.34 (7.54), 319 (56.3%) were female, 75 (13.2%) were Black, and 223 (39.3%) were APOE e4 carriers. Higher GFAP concentrations were associated with increased odds for having cognitive impairment (GFAP z-score transformed: OR=2.233, 95% CI [1.609, 3.099], p<0.001; non-z-transformed: OR=1.004, 95% CI [1.002, 1.006], p<0.001). ROC analyses, comprising of GFAP and the above covariates, showed plasma GFAP discriminated the cognitively impaired from unimpaired (AUC=0.75) and was similar, but slightly superior, to plasma p-tau181 (AUC=0.74) and plasma NfL (AUC=0.74). A joint panel of the plasma markers had greatest discrimination accuracy (AUC=0.76). Linear regression analyses showed that higher GFAP levels were associated with worse performance on neuropsychological tests assessing global cognition, attention, executive functioning, episodic memory, and language abilities (ps<0.001) as well as higher CDR Sum of Boxes (p<0.001).
Conclusions:Higher plasma GFAP levels differentiated participants with cognitive impairment from those with normal cognition and were associated with worse performance on all neuropsychological tests assessed. GFAP had similar accuracy in detecting those with cognitive impairment compared with p-tau181 and NfL, however, a panel of all three biomarkers was optimal. These results support the utility of plasma GFAP in AD detection and suggest the pathological processes it represents might play an integral role in the pathogenesis of AD.
6 Association Between American Football Play and Parkinson's Disease: Analysis of the Fox Insight Data Set
- Hannah Bruce, Yorghos Tripodis, Michael McClean, Monica Korell, Caroline M Tanner, Brittany Contreras, Joshua Gottesman, Leslie Kirsch, Yasir Karim, Brett Martin, Joseph Palmisano, Thor D Stein, Jesse Mez, Robert A Stern, Charles H Adler, Chris Nowinski, Ann C McKee, Michael L Alosco
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 415-416
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Objective:
Parkinsonism and Parkinson's disease (PD) have been described as consequences of repetitive head impacts (RHI) from boxing, since 1928. Autopsy studies have shown that RHI from other contact sports can also increase risk for neurodegenerative diseases, including chronic traumatic encephalopathy (CTE) and Lewy bodies. In vivo research on the relationship between American football play and PD is scarce, with small samples, and equivocal findings. This study leveraged the Fox Insight study to evaluate the association between American football and parkinsonism and/or PD Diagnosis and related clinical outcomes.
Participants and Methods:Fox Insight is an online study of people with and without PD who are 18+ years (>50,000 enrolled). Participants complete online questionnaires on motor function, cognitive function, and general health behaviors. Participants self-reported whether they "currently have a diagnosis of Parkinson's disease, or parkinsonism, by a physician or other health care professional." In November 2020, the Boston University Head Impact Exposure Assessment was launched in Fox Insight for large-scale data collection on exposure to RHI from contact sports and other sources. Data used in this abstract were obtained from the Fox Insight database https://foxinsight-info.michaeljfox.org/insight/explore/insight.jsp on 01/06/2022. The sample includes 2018 men who endorsed playing an organized sport. Because only 1.6% of football players were women, analyses are limited to men. Responses to questions regarding history of participation in organized football were examined. Other contact and/or non-contact sports served as the referent group. Outcomes included PD status (absence/presence of parkinsonism or PD) and Penn Parkinson's Daily Activities Questionnaire-15 (PDAQ-15) for assessment of cognitive symptoms. Binary logistic regression tested associations between history and years of football play with PD status, controlling for age, education, current heart disease or diabetes, and family history of PD. Linear regressions, controlling for these variables, were used for the PDAQ-15.
Results:Of the 2018 men (mean age=67.67, SD=9.84; 10, 0.5% Black), 788 (39%) played football (mean years of play=4.29, SD=2.88), including 122 (16.3%) who played youth football, 494 (66.0%) played high school, 128 (17.1%) played college football, and 5 (0.7%) played at the semi-professional or professional level. 1738 (86.1%) reported being diagnosed with parkinsonism/PD, and 707 of these were football players (40.7%). History of playing any level of football was associated with increased odds of having a reported parkinsonism or PD diagnosis (OR=1.52, 95% CI=1.14-2.03, p=0.004). The OR remained similar among those age <69 (sample median age) (OR=1.45, 95% CI=0.97-2.17, p=0.07) and 69+ (OR=1.45, 95% CI=0.95-2.22, p=0.09). Among the football players, there was not a significant association between years of play and PD status (OR=1.09, 95% CI=1.00-1.20, p=0.063). History of football play was not associated with PDAQ-15 scores (n=1980) (beta=-0.78, 95% CI=-1.59-0.03, p=0.059) among the entire sample.
Conclusions:Among 2018 men from a data set enriched for PD, playing organized football was associated with increased odds of having a reported parkinsonism/PD diagnosis. Next steps include examination of the contribution of traumatic brain injury and other sources of RHI (e.g., soccer, military service).
64 Neuroimaging Evidence of Neurodegenerative Disease in Former Professional American Football Players Who “Fail” Validity Testing: A Case Series
- Ranjani Shankar, Julia Culhane, Leonardo Iaccarino, Chris Nowinski, Nidhi Mundada, Karen Smith, Jeremy Tanner, Charles Windon, Yorghos Tripodis, Gustavo Mercier, Thor D Stein, Anne C McKee, Robert A Stern, Neil Kowall, Bruce L Miller, Jesse Mez, Ron Killiany, Gil D Rabinovici, Michael L Alosco, Breton M Asken
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 574-575
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Objective:
Former professional American football players have a high relative risk for neurodegenerative diseases like chronic traumatic encephalopathy (CTE). Interpreting low cognitive test scores in this population occasionally is complicated by performance on validity testing. Neuroimaging biomarkers may help inform whether a neurodegenerative disease is present in these situations. We report three cases of retired professional American football players who completed comprehensive neuropsychological testing, but “failed” performance validity tests, and underwent multimodal neuroimaging (structural MRI, Aß-PET, and tau-PET).
Participants and Methods:Three cases were identified from the Focused Neuroimaging for the Neurodegenerative Disease Chronic Traumatic Encephalopathy (FIND-CTE) study, an ongoing multimodal imaging study of retired National Football League players with complaints of progressive cognitive decline conducted at Boston University and the UCSF Memory and Aging Center. Participants were relatively young (age range 55-65), had 16 or more years of education, and two identified as Black/African American. Raw neuropsychological test scores were converted to demographically-adjusted z-scores. Testing included standalone (Test of Memory Malingering; TOMM) and embedded (reliable digit span, RDS) performance validity measures. Validity cutoffs were TOMM Trial 2 < 45 and RDS < 7. Structural MRIs were interpreted by trained neurologists. Aß-PET with Florbetapir was used to quantify cortical Aß deposition as global Centiloids (0 = mean cortical signal for a young, cognitively normal, Aß negative individual in their 20s, 100 = mean cortical signal for a patient with mild-to-moderate Alzheimer’s disease dementia). Tau-PET was performed with MK-6240 and first quantified as standardized uptake value ratio (SUVR) map. The SUVR map was then converted to a w-score map representing signal intensity relative to a sample of demographically-matched healthy controls.
Results:All performed in the average range on a word reading-based estimate of premorbid intellect. Contribution of Alzheimer’s disease pathology was ruled out in each case based on Centiloids quantifications < 0. All cases scored below cutoff on TOMM Trial 2 (Case #1=43, Case #2=42, Case #3=19) and Case #3 also scored well below RDS cutoff (2). Each case had multiple cognitive scores below expectations (z < -2.0) most consistently in memory, executive function, processing speed domains. For Case #1, MRI revealed mild atrophy in dorsal fronto-parietal and medial temporal lobe (MTL) regions and mild periventricular white matter disease. Tau-PET showed MTL tau burden modestly elevated relative to controls (regional w-score=0.59, 72nd%ile). For Case #2, MRI revealed cortical atrophy, mild hippocampal atrophy, and a microhemorrhage, with no evidence of meaningful tau-PET signal. For Case #3, MRI showed cortical atrophy and severe white matter disease, and tau-PET revealed significantly elevated MTL tau burden relative to controls (w-score=1.90, 97th%ile) as well as focal high signal in the dorsal frontal lobe (overall frontal region w-score=0.64, 74th%ile).
Conclusions:Low scores on performance validity tests complicate the interpretation of the severity of cognitive deficits, but do not negate the presence of true cognitive impairment or an underlying neurodegenerative disease. In the rapidly developing era of biomarkers, neuroimaging tools can supplement neuropsychological testing to help inform whether cognitive or behavioral changes are related to a neurodegenerative disease.
4 Risk Factor and Biomarker Correlates of FLAIR White Matter Hyperintensities in Former American Football Players
- Monica T Ly, Fatima Tuz-Zahra, Yorghos Tripodis, Charles H Adler, Laura J Balcer, Charles Bernick, Elaine Peskind, Megan L Mariani, Rhoda Au, Sarah J Banks, William B Barr, Jennifer V Wethe, Mark W Bondi, Lisa Delano-Wood, Robert C Cantu, Michael J Coleman, David W Dodick, Michael D McClean, Jesse Mez, Joseph N Palmisano, Brett Martin, Kaitlin Hartlage, Alexander P Lin, Inga K Koerte, Jeffrey L Cummings, Eric M Reiman, Martha E Shenton, Robert A Stern, Sylvain Bouix, Michael L Alosco
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 608-610
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Objective:
White matter hyperintensity (WMH) burden is greater, has a frontal-temporal distribution, and is associated with proxies of exposure to repetitive head impacts (RHI) in former American football players. These findings suggest that in the context of RHI, WMH might have unique etiologies that extend beyond those of vascular risk factors and normal aging processes. The objective of this study was to evaluate the correlates of WMH in former elite American football players. We examined markers of amyloid, tau, neurodegeneration, inflammation, axonal injury, and vascular health and their relationships to WMH. A group of age-matched asymptomatic men without a history of RHI was included to determine the specificity of the relationships observed in the former football players.
Participants and Methods:240 male participants aged 45-74 (60 unexposed asymptomatic men, 60 male former college football players, 120 male former professional football players) underwent semi-structured clinical interviews, magnetic resonance imaging (structural T1, T2 FLAIR, and diffusion tensor imaging), and lumbar puncture to collect cerebrospinal fluid (CSF) biomarkers as part of the DIAGNOSE CTE Research Project. Total WMH lesion volumes (TLV) were estimated using the Lesion Prediction Algorithm from the Lesion Segmentation Toolbox. Structural equation modeling, using Full-Information Maximum Likelihood (FIML) to account for missing values, examined the associations between log-TLV and the following variables: total cortical thickness, whole-brain average fractional anisotropy (FA), CSF amyloid ß42, CSF p-tau181, CSF sTREM2 (a marker of microglial activation), CSF neurofilament light (NfL), and the modified Framingham stroke risk profile (rFSRP). Covariates included age, race, education, APOE z4 carrier status, and evaluation site. Bootstrapped 95% confidence intervals assessed statistical significance. Models were performed separately for football players (college and professional players pooled; n=180) and the unexposed men (n=60). Due to differences in sample size, estimates were compared and were considered different if the percent change in the estimates exceeded 10%.
Results:In the former football players (mean age=57.2, 34% Black, 29% APOE e4 carrier), reduced cortical thickness (B=-0.25, 95% CI [0.45, -0.08]), lower average FA (B=-0.27, 95% CI [-0.41, -.12]), higher p-tau181 (B=0.17, 95% CI [0.02, 0.43]), and higher rFSRP score (B=0.27, 95% CI [0.08, 0.42]) were associated with greater log-TLV. Compared to the unexposed men, substantial differences in estimates were observed for rFSRP (Bcontrol=0.02, Bfootball=0.27, 994% difference), average FA (Bcontrol=-0.03, Bfootball=-0.27, 802% difference), and p-tau181 (Bcontrol=-0.31, Bfootball=0.17, -155% difference). In the former football players, rFSRP showed a stronger positive association and average FA showed a stronger negative association with WMH compared to unexposed men. The effect of WMH on cortical thickness was similar between the two groups (Bcontrol=-0.27, Bfootball=-0.25, 7% difference).
Conclusions:These results suggest that the risk factor and biological correlates of WMH differ between former American football players and asymptomatic individuals unexposed to RHI. In addition to vascular risk factors, white matter integrity on DTI showed a stronger relationship with WMH burden in the former football players. FLAIR WMH serves as a promising measure to further investigate the late multifactorial pathologies of RHI.
5 Antemortem Plasma GFAP Predicts Alzheimer’s Disease Neuropathological Changes
- Madeline Ally, Henrik Zetterberg, Kaj Blennow, Nicholas J. Ashton, Thomas K. Karikari, Hugo Aparicio, Michael A. Sugarman, Brandon Frank, Yorghos Tripodis, Brett Martin, Joseph N. Palmisano, Eric G. Steinberg, Irene Simkina, Lindsay Farrer, Gyungah Jun, Katherine W. Turk, Andrew E. Budson, Maureen K. O’Connor, Rhoda Au, Wei Qiao Qiu, Lee E. Goldstein, Ronald Killiany, Neil W. Kowall, Robert A. Stern, Jesse Mez, Bertran R. Huber, Ann C. McKee, Thor D. Stein, Michael L. Alosco
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 409-410
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Objective:
Blood-based biomarkers offer a more feasible alternative to Alzheimer’s disease (AD) detection, management, and study of disease mechanisms than current in vivo measures. Given their novelty, these plasma biomarkers must be assessed against postmortem neuropathological outcomes for validation. Research has shown utility in plasma markers of the proposed AT(N) framework, however recent studies have stressed the importance of expanding this framework to include other pathways. There is promising data supporting the usefulness of plasma glial fibrillary acidic protein (GFAP) in AD, but GFAP-to-autopsy studies are limited. Here, we tested the association between plasma GFAP and AD-related neuropathological outcomes in participants from the Boston University (BU) Alzheimer’s Disease Research Center (ADRC).
Participants and Methods:This sample included 45 participants from the BU ADRC who had a plasma sample within 5 years of death and donated their brain for neuropathological examination. Most recent plasma samples were analyzed using the Simoa platform. Neuropathological examinations followed the National Alzheimer’s Coordinating Center procedures and diagnostic criteria. The NIA-Reagan Institute criteria were used for the neuropathological diagnosis of AD. Measures of GFAP were log-transformed. Binary logistic regression analyses tested the association between GFAP and autopsy-confirmed AD status, as well as with semi-quantitative ratings of regional atrophy (none/mild versus moderate/severe) using binary logistic regression. Ordinal logistic regression analyses tested the association between plasma GFAP and Braak stage and CERAD neuritic plaque score. Area under the curve (AUC) statistics from receiver operating characteristics (ROC) using predicted probabilities from binary logistic regression examined the ability of plasma GFAP to discriminate autopsy-confirmed AD status. All analyses controlled for sex, age at death, years between last blood draw and death, and APOE e4 status.
Results:Of the 45 brain donors, 29 (64.4%) had autopsy-confirmed AD. The mean (SD) age of the sample at the time of blood draw was 80.76 (8.58) and there were 2.80 (1.16) years between the last blood draw and death. The sample included 20 (44.4%) females, 41 (91.1%) were White, and 20 (44.4%) were APOE e4 carriers. Higher GFAP concentrations were associated with increased odds for having autopsy-confirmed AD (OR=14.12, 95% CI [2.00, 99.88], p=0.008). ROC analysis showed plasma GFAP accurately discriminated those with and without autopsy-confirmed AD on its own (AUC=0.75) and strengthened as the above covariates were added to the model (AUC=0.81). Increases in GFAP levels corresponded to increases in Braak stage (OR=2.39, 95% CI [0.71-4.07], p=0.005), but not CERAD ratings (OR=1.24, 95% CI [0.004, 2.49], p=0.051). Higher GFAP levels were associated with greater temporal lobe atrophy (OR=10.27, 95% CI [1.53,69.15], p=0.017), but this was not observed with any other regions.
Conclusions:The current results show that antemortem plasma GFAP is associated with non-specific AD neuropathological changes at autopsy. Plasma GFAP could be a useful and practical biomarker for assisting in the detection of AD-related changes, as well as for study of disease mechanisms.
Dynamic HTA for digital health solutions: opportunities and challenges for patient-centered evaluation
- Jan B. Brönneke, Annika Herr, Simon Reif, Ariel D. Stern
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- Journal:
- International Journal of Technology Assessment in Health Care / Volume 39 / Issue 1 / 2023
- Published online by Cambridge University Press:
- 17 November 2023, e72
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Objectives
Germany’s 2019 Digital Healthcare Act (Digitale-Versorgung-Gesetz, or DVG) created a number of opportunities for the digital transformation of the healthcare delivery system. Key among these was the creation of a reimbursement pathway for patient-centered digital health applications (digitale Gesundheitsanwendungen, or DiGA). Worldwide, this is the first structured pathway for “prescribable” health applications at scale. As of October 10, 2023, 49 DiGA were listed in the official directory maintained by Germany’s Federal Institute for Drugs and Medical Devices (BfArM); these are prescribable by physicians and psychotherapists and reimbursed by the German statutory health insurance system for all its 73 million beneficiaries. Looking ahead, a major challenge facing DiGA manufacturers will be the generation of the evidence required for ongoing price negotiations and reimbursement. Current health technology assessment (HTA) methods will need to be adapted for DiGA.
MethodsWe describe the core issues that distinguish HTA in this setting: (i) explicit allowance for more flexible research designs, (ii) the nature of initial evidence generation, which can be delivered (in its final form) up to one year after becoming reimbursable, and (iii) the dynamic nature of both product development and product evaluation. We present the digital health applications in the German DiGA scheme as a case study and highlight the role of RWE in the successful evaluation of DiGA on an ongoing basis.
ResultsWhen a DiGA is likely to be updated and assessed regularly, full-scale RCTs are infeasible; we therefore make the case for using real-world data and real-world evidence (RWE) for dynamic HTAs.
ConclusionsContinous evaluation using RWD is a regulatory innovation that can help improve the quality of DiGAs on the market.
The GLEAMing of the first supermassive black holes: II. A new sample of high-redshift radio galaxy candidates
- J. W. Broderick, G. Drouart, N. Seymour, T. J. Galvin, N. Wright, A. Carnero Rosell, R. Chhetri, H. Dannerbauer, S. P. Driver, J. S. Morgan, V. A. Moss, S. Prabu, J. M. Afonso, C. De Breuck, B. H. C. Emonts, T. M. O. Franzen, C. M. Gutiérrez, P. J. Hancock, G. H. Heald, N. Hurley-Walker, R. J. Ivison, M. D. Lehnert, G. Noirot, M. Read, S. S. Shabala, D. Stern, W. J. Sutherland, E. Sutorius, R. J. Turner, J. Vernet
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- Publications of the Astronomical Society of Australia / Volume 39 / 2022
- Published online by Cambridge University Press:
- 28 November 2022, e061
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While unobscured and radio-quiet active galactic nuclei are regularly being found at redshifts $z > 6$ , their obscured and radio-loud counterparts remain elusive. We build upon our successful pilot study, presenting a new sample of low-frequency-selected candidate high-redshift radio galaxies (HzRGs) over a sky area 20 times larger. We have refined our selection technique, in which we select sources with curved radio spectra between 72–231 MHz from the GaLactic and Extragalactic All-sky Murchison Widefield Array (GLEAM) survey. In combination with the requirements that our GLEAM-selected HzRG candidates have compact radio morphologies and be undetected in near-infrared $K_{\rm s}$ -band imaging from the Visible and Infrared Survey Telescope for Astronomy Kilo-degree Infrared Galaxy (VIKING) survey, we find 51 new candidate HzRGs over a sky area of approximately $1200\ \mathrm{deg}^2$ . Our sample also includes two sources from the pilot study: the second-most distant radio galaxy currently known, at $z=5.55$ , with another source potentially at $z \sim 8$ . We present our refined selection technique and analyse the properties of the sample. We model the broadband radio spectra between 74 MHz and 9 GHz by supplementing the GLEAM data with both publicly available data and new observations from the Australia Telescope Compact Array at 5.5 and 9 GHz. In addition, deep $K_{\rm s}$ -band imaging from the High-Acuity Widefield K-band Imager (HAWK-I) on the Very Large Telescope and from the Southern Herschel Astrophysical Terahertz Large Area Survey Regions $K_{\rm s}$ -band Survey (SHARKS) is presented for five sources. We discuss the prospects of finding very distant radio galaxies in our sample, potentially within the epoch of reionisation at $z \gtrsim 6.5$ .
Identifying barriers to compliance with a universal inpatient protocol for Staphylococcus aureus nasal decolonization with povidone-iodine
- Rebecca A. Stern, Bryan D. Harris, Mary DeVault, Thomas R. Talbot
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- Infection Control & Hospital Epidemiology / Volume 44 / Issue 7 / July 2023
- Published online by Cambridge University Press:
- 26 September 2022, pp. 1167-1170
- Print publication:
- July 2023
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Academic hospital nurses were surveyed to assess adherence barriers to a universal povidone-iodine nasal decolonization protocol to prevent Staphylococcus aureus infection. Low training rates, inadequate supplies, documentation and tracking challenges, patient refusal, and burnout contributed to suboptimal adherence. Prioritizing education is essential but alone is insufficient for successful protocol adoption.
Aneurysms of the fetal arterial duct are usually benign
- Katherine Dalldorf, Kenan W. D. Stern, David Ezon
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- Cardiology in the Young / Volume 33 / Issue 6 / June 2023
- Published online by Cambridge University Press:
- 22 June 2022, pp. 933-938
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Introduction:
Fetal arterial duct aneurysm, saccular, or fusiform enlargement of the arterial duct affect > 8% of pregnancies. It is uncommonly associated with serious sequelae postnatally, including thromboembolic events such as stroke and left pulmonary artery obstruction, rupture with demise, and vocal cord compression. Risk factors include maternal diabetes, late maternal age, maternal blood type A, large size for gestational age, and connective tissue disorders. The clinical importance remains unknown, making it difficult to determine how to monitor this finding postnatally.
Methods:This is a retrospective echocardiogram study assessing the outcomes of fetally diagnosed arterial duct aneurysm. Images and records were reviewed to confirm the diagnosis and assess risk factors and outcomes. Descriptive statistics were performed.
Results:Fifty-three affected fetuses were identified. The median gestational age at diagnosis was 34.9 weeks (IQR 32.6, 36.6). The median maternal age was 31 years (IQR 27.3–34.1). Eight (15%) had maternal diabetes. The most common blood type was type O. The median maximal dimension of the aneurysm was 7.6 mm (IQR 6.1, 8.7). The aortic end was the maximal dimension in 67.9%. Median postnatal follow-up period was 76 days (IQR 7.5, 368). No patients sustained postnatal demise related to the duct, rupture of the ductal aneurysm, cerebral infarction, or other sequelae. No newborn had associated connective tissue disorders. No patients underwent ductal intervention.
Conclusion:In our experience, no adverse outcomes related to the ductal aneurysm were identified. This should be considered when counselling families about the need for postnatal follow-up.
HST WFC3/Grism observations of the candidate ultra-high-redshift radio galaxy GLEAM J0917–0012
- N. Seymour, G. Drouart, G. Noirot, J. W. Broderick, R. J. Turner, S. S. Shabala, D. K. Stern, S. Bellstedt, S. Driver, L. Davies, C. A. De Breuck, J. A. Afonso, J. D. R. Vernet, T. J. Galvin
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- Publications of the Astronomical Society of Australia / Volume 39 / 2022
- Published online by Cambridge University Press:
- 12 April 2022, e016
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We present Hubble Space Telescope Wide Field Camera 3 photometric and grism observations of the candidate ultra-high-redshift ( $z>7$ ) radio galaxy, GLEAM J0917–0012. This radio source was selected due to the curvature in its 70–230 MHz, low-frequency Murchison Widefield Array radio spectrum and its faintness in K-band. Follow-up spectroscopic observations of this source with the Jansky Very Large Array and Atacama Large Millimetre Array were inconclusive as to its redshift. Our F105W and F0986M imaging observations detect the host of GLEAM J0917–0012 and a companion galaxy, $\sim$ one arcsec away. The G102 grism observations reveal a single weak line in each of the spectra of the host and the companion. To help identify these lines we utilised several photometric redshift techniques including template fitting to the grism spectra, fitting the ultraviolet (UV)-to-radio photometry with galaxy templates plus a synchrotron model, fitting of the UV-to-near-infrared photometry with EAZY, and fitting the radio data alone with RAiSERed. For the host of GLEAM J0917–0012 we find a line at $1.12\,\mu$ m and the UV-to-radio spectral energy distribution (SED) fitting favours solutions at $z\sim 2$ or $z\sim 8$ . While this fitting shows a weak preference for the lower redshift solution, the models from the higher redshift solution are more consistent with the strength of the spectral line. The redshift constraint by RAiSERed of $>6.5$ also supports the interpretation that this line could be Lyman $-\alpha$ at $z=8.21$ ; however EAZY favours the $z\sim 2$ solution. We discuss the implications of both solutions. For the companion galaxy we find a line at $0.98\,\mu$ m and the SED fitting favours solutions at $z<3$ implying that the line could be the [OII] $\lambda3727$ doublet at $z=1.63$ (although the EAZY solution is $z\sim 2.6\pm 0.5$ ). Further observations are still required to unambiguously determine the redshift of this intriguing candidate ultra-high-redshift radio galaxy.
Self-Assembling Toroidal Cell Constructs for Tissue Engineering Applications
- Austin Worden, Mark J. Uline, Tarek Shazly, Matt Stern, Jay D. Potts
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- Journal:
- Microscopy and Microanalysis / Volume 28 / Issue 2 / April 2022
- Published online by Cambridge University Press:
- 02 March 2022, pp. 543-552
- Print publication:
- April 2022
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Developing tissues have intricate, three-dimensional (3D) organizations of cells and extracellular matrix (ECM) that provide the framework necessary to meet morphogenic and necessary demands. Migrating cells, in vivo, are exposed to numerous conflicting signals: chemokines, ECM, growth factors, and physical forces. While most of these have been studied individually in vivo or in vitro, our understanding of how cells integrate these various signals is lacking. We previously developed a novel self-organizing cellularized collagen hydrogel model that is adaptable, tunable, reproducible, and capable of mimicking the multitude of stimuli that cells experience. Our model produced self-assembled toroids of cells that were formed by 24 h. Data we present here show toroids initially form as early as 3 h after seeding. Additionally, toroids formed when cells were seeded on various collagen subtypes and were sensitive to the composition of the hydrogel. Moreover, we found differences in remodeling in toroid gels compared to gels with cells embedded in them using both a collagen binding peptide and rheology. Using scanning electron microscopy, we observed toroids forming a crater-like structure compared to whole gel contractions in mixed in gels. Finally, when multiple cells were mixed prior to seeding, heterogeneous toroids formed with some containing clusters of cells.
The nature and likely redshift of GLEAM J0917–0012
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- Guillaume Drouart, Nick Seymour, Jess W. Broderick, José Afonso, Rajan Chhetri, Carlos De Breuck, Bjorn Emonts, Tim J. Galvin, Matthew D. Lehnert, John Morgan, Daniel Stern, Joël Vernet, Nigel Wright
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- Journal:
- Publications of the Astronomical Society of Australia / Volume 38 / 2021
- Published online by Cambridge University Press:
- 21 September 2021, e049
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We previously reported a putative detection of a radio galaxy at $z=10.15$ , selected from the GaLactic and Extragalactic All-sky Murchison Widefield Array (GLEAM) survey. The redshift of this source, GLEAM J0917–0012, was based on three weakly detected molecular emission lines observed with the Atacama Large Millimetre Array (ALMA). In order to confirm this result, we conducted deep spectroscopic follow-up observations with ALMA and the Karl Jansky Very Large Array (VLA). The ALMA observations targeted the same CO lines previously reported in Band 3 (84–115 GHz) and the VLA targeted the CO(4-3) and [CI(1-0)] lines for an independent confirmation in Q-band (41 and 44 GHz). Neither observation detected any emission lines, removing support for our original interpretation. Adding publicly available optical data from the Hyper Suprime-Cam survey, Widefield Infrared Survey Explorer (WISE), and Herschel Space Observatory in the infrared, as well as $<$ 10 GHz polarisation and 162 MHz inter-planetary scintillation observations, we model the physical and observational characteristics of GLEAM J0917–0012 as a function of redshift. Comparing these predictions and observational relations to the data, we are able to constrain its nature and distance. We argue that if GLEAM J0917–0012 is at $z<3,$ then it has an extremely unusual nature, and that the more likely solution is that the source lies above $z=7$ .
Simulation and flow physics of a shocked and reshocked high-energy-density mixing layer
- Jason D. Bender, Oleg Schilling, Kumar S. Raman, Robert A. Managan, Britton J. Olson, Sean R. Copeland, C. Leland Ellison, David J. Erskine, Channing M. Huntington, Brandon E. Morgan, Sabrina R. Nagel, Shon T. Prisbrey, Brian S. Pudliner, Philip A. Sterne, Christopher E. Wehrenberg, Ye Zhou
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- Journal:
- Journal of Fluid Mechanics / Volume 915 / 25 May 2021
- Published online by Cambridge University Press:
- 22 March 2021, A84
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This paper describes a computational investigation of multimode instability growth and multimaterial mixing induced by multiple shock waves in a high-energy-density (HED) environment, where pressures exceed 1 Mbar. The simulations are based on a series of experiments performed at the National Ignition Facility (NIF) and designed as an HED analogue of non-HED shock-tube studies of the Richtmyer–Meshkov instability and turbulent mixing. A three-dimensional computational modelling framework is presented. It treats many complications absent from canonical non-HED shock-tube flows, including distinct ion and free-electron internal energies, non-ideal equations of state, radiation transport and plasma-state mass diffusivities, viscosities and thermal conductivities. The simulations are tuned to the available NIF data, and traditional statistical quantities of turbulence are analysed. Integrated measures of turbulent kinetic energy and enstrophy both increase by over an order of magnitude due to reshock. Large contributions to enstrophy production during reshock are seen from both the baroclinic source and enstrophy–dilatation terms, highlighting the significance of fluid compressibility in the HED regime. Dimensional analysis reveals that Reynolds numbers and diffusive Péclet numbers in the HED flow are similar to those in a canonical non-HED analogue, but conductive Péclet numbers are much smaller in the HED flow due to efficient thermal conduction by free electrons. It is shown that the mechanism of electron thermal conduction significantly softens local spanwise gradients of both temperature and density, which causes a minor but non-negligible decrease in enstrophy production and small-scale mixing relative to a flow without this mechanism.
Sustaining University Operations During the COVID-19 Pandemic
- Benjamin J. Ryan, Michael P. Muehlenbein, Jon Allen, Joshua Been, Kenneth Boyd, Mark Brickhouse, Bryan W. Brooks, Matthew Burchett, C. Kevin Chambliss, Jason D. Cook, Adam Ecklund, Lori Fogleman, Peter Granick, Sharra Hynes, Tonya Hudson, Michelle Huse, Micah Lamb, Tiffany Lowe, Jim Marsh, Niesha Nixon, Dennis Nolan, George Nuñez, Walter “Sparky” Matthews, Sharon Stern, Meaghann Wheelis, Nancy Brickhouse
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- Journal:
- Disaster Medicine and Public Health Preparedness / Volume 16 / Issue 5 / October 2022
- Published online by Cambridge University Press:
- 08 March 2021, pp. 1901-1909
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Colleges and universities around the world engaged diverse strategies during the COVID-19 pandemic. Baylor University, a community of ˜22,700 individuals, was 1 of the institutions which resumed and sustained operations. The key strategy was establishment of multidisciplinary teams to develop mitigation strategies and priority areas for action. This population-based team approach along with implementation of a “Swiss Cheese” risk mitigation model allowed small clusters to be rapidly addressed through testing, surveillance, tracing, isolation, and quarantine. These efforts were supported by health protocols including face coverings, social distancing, and compliance monitoring. As a result, activities were sustained from August 1 to December 8, 2020. There were 62,970 COVID-19 tests conducted with 1435 people testing positive for a positivity rate of 2.28%. A total of 1670 COVID-19 cases were identified with 235 self-reports. The mean number of tests per week was 3500 with approximately 80 of these positive (11/d). More than 60 student tracers were trained with over 120 personnel available to contact trace, at a ratio of 1 per 400 university members. The successes and lessons learned provide a framework and pathway for similar institutions to mitigate the ongoing impacts of COVID-19 and sustain operations during a global pandemic.
RADIOCARBON RESERVOIR AGES IN THE HOLOCENE DEAD SEA
- Nurit Weber, Boaz Lazar, Ofra Stern, George Burr, Ittai Gavrieli, Mark Roberts, Mark D Kurz, Yoseph Yechieli, Mordechai Stein
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- Journal:
- Radiocarbon / Volume 62 / Issue 5 / October 2020
- Published online by Cambridge University Press:
- 24 April 2020, pp. 1453-1473
- Print publication:
- October 2020
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The sources and fate of radiocarbon (14C) in the Dead Sea hypersaline solution are evaluated with 14C measurements in organic debris and primary aragonite collected from exposures of the Holocene Ze’elim Formation. The reservoir age (RA) is defined as the difference between the radiocarbon age of the aragonite at time of its precipitation (representing lakeʼs dissolved inorganic carbon [DIC]) and the age of contemporaneous organic debris (representing atmospheric radiocarbon). Evaluation of the data for the past 6000 yr from Dead Sea sediments reveal that the lakeʼs RA decreased from 2890 yr at 6 cal kyr BP to 2300 yr at present. The RA lies at ~2400 yr during the past 3000 yr, when the lake was characterized by continuous deposition of primary aragonite, which implies a continuous supply of freshwater-bicarbonate into the lake. This process reflects the overall stability of the hydrological-climate conditions in the lakeʼs watershed during the late Holocene where bicarbonate originated from dissolution of the surface cover in the watershed that was transported to the Dead Sea by the freshwater runoff. An excellent correlation (R2=0.98) exists between aragonite ages and contemporaneous organic debris, allowing the estimation of ages of various primary deposits where organic debris are not available.
A 9-year-old boy with acute psychosis and non-convulsive status epilepticus
- N. Fisch, H. Goldberg-Stern, S. Kivity, D. Inbar, A. Shuper
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- Journal:
- European Psychiatry / Volume 26 / Issue S2 / March 2011
- Published online by Cambridge University Press:
- 16 April 2020, p. 1716
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Pediatric patients with epilepsy have an increased risk of ictal, postictal or interictal psychotic symptoms. We describe a child with mild epilepsy who was hospitalized in our Pediatric ward with acute severe psychosis. His epilepsy was well controlled and he was known to have a 4 mm large frontal cystic lesion per brain MRI. He did not have overt seizures upon admission, but his EEG showed non-convulsive, high voltage spike/slow wave activity. Treatment with valproic acid led to concomitant resolution of the psychotic symptoms and EEG abnormalities. Several months later psychotic symptoms recurred, this time in a milder form, again associated with the same EEG pattern. Lamotrigine was added to the treatment regimen and both symptoms and electrographic changes resolved. No change was noted on repeat MRI.
This child presents an unusual relationship between acute psychosis and markedly abnormal EEG, both resolving with anti-epileptic medication, and a potential causative relationship to a frontal lesion. We discuss this unusual connection between the psychiatric (psychosis), epileptic (non-convulsive status epilepticus) and organic brain (frontal benign lesion) disorders in this child.
5 - Diamonds and the Mantle Geodynamics of Carbon
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- By Steven B. Shirey, Karen V. Smit, D. Graham Pearson, Michael J. Walter, Sonja Aulbach, Frank E. Brenker, Hélène Bureau, Antony D. Burnham, Pierre Cartigny, Thomas Chacko, Daniel J. Frost, Erik H. Hauri, Dorrit E. Jacob, Steven D. Jacobsen, Simon C. Kohn, Robert W. Luth, Sami Mikhail, Oded Navon, Fabrizio Nestola, Paolo Nimis, Mederic Palot, Evan M. Smith, Thomas Stachel, Vincenzo Stagno, Andrew Steele, Richard A. Stern, Emilie Thomassot, Andrew R. Thomson, Yaakov Weiss
- Edited by Beth N. Orcutt, Isabelle Daniel, Université Claude-Bernard Lyon I, Rajdeep Dasgupta, Rice University, Houston
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- Book:
- Deep Carbon
- Published online:
- 03 October 2019
- Print publication:
- 17 October 2019, pp 89-128
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Summary
The science of studying diamond inclusions for understanding Earth history has developed significantly over the past decades, with new instrumentation and techniques applied to diamond sample archives revealing the stories contained within diamond inclusions. This chapter reviews what diamonds can tell us about the deep carbon cycle over the course of Earth’s history. It reviews how the geochemistry of diamonds and their inclusions inform us about the deep carbon cycle, the origin of the diamonds in Earth’s mantle, and the evolution of diamonds through time.
LO45: Simulation-based research in emergency medicine in Canada: priorities and perspectives
- T. Chaplin, B. Thoma, A. Petrosoniak, K. Caners, T. McColl, C. Forristal, C. Dakin, J. Deshaies, E. Raymond-Dufresne, M. Fotheringham, D. Ha, N. Holm, J. Huffman, A. Lonergan, G. Mastoras, M. O'Brien, M. Paradis, N. Sowers, E. Stern, A. Hall
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- Journal:
- Canadian Journal of Emergency Medicine / Volume 21 / Issue S1 / May 2019
- Published online by Cambridge University Press:
- 02 May 2019, pp. S23-S24
- Print publication:
- May 2019
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Introduction: Simulation has assumed an integral role in the Canadian healthcare system with applications in quality improvement, systems development, and medical education. High quality simulation-based research (SBR) is required to ensure the effective and efficient use of this tool. This study sought to establish national SBR priorities and describe the barriers and facilitators of SBR in Emergency Medicine (EM) in Canada. Methods: Simulation leads (SLs) from all fourteen Canadian Departments or Divisions of EM associated with an adult FRCP-EM training program were invited to participate in three surveys and a final consensus meeting. The first survey documented active EM SBR projects. Rounds two and three established and ranked priorities for SBR and identified the perceived barriers and facilitators to SBR at each site. Surveys were completed by SLs at each participating institution, and priority research themes were reviewed by senior faculty for broad input and review. Results: Twenty SLs representing all 14 invited institutions participated in all three rounds of the study. 60 active SBR projects were identified, an average of 4.3 per institution (range 0-17). 49 priorities for SBR in Canada were defined and summarized into seven priority research themes. An additional theme was identified by the senior reviewing faculty. 41 barriers and 34 facilitators of SBR were identified and grouped by theme. Fourteen SLs representing 12 institutions attended the consensus meeting and vetted the final list of eight priority research themes for SBR in Canada: simulation in CBME, simulation for interdisciplinary and inter-professional learning, simulation for summative assessment, simulation for continuing professional development, national curricular development, best practices in simulation-based education, simulation-based education outcomes, and simulation as an investigative methodology. Conclusion: Conclusion: This study has summarized the current SBR activity in EM in Canada, as well as its perceived barriers and facilitators. We also provide a consensus on priority research themes in SBR in EM from the perspective of Canadian simulation leaders. This group of SLs has formed a national simulation-based research group which aims to address these identified priorities with multicenter collaborative studies.