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Purpose Limiting family presence runs counter to the family-centred values of Canadian pediatric intensive care units (PICUs). This study explores how implementing and enforcing COVID-19-related restricted family presence (RFP) policies impacted PICU clinicians nationally. Methods We conducted a cross-sectional, online, self-administered survey of Canadian PICU clinicians to assess experience and opinions of restrictions, moral distress (Moral Distress Thermometer, range 0–10), and mental health impacts (Impact of Event Scale [IES], range 0–75 and attributable stress [five-point Likert scale]). For analysis, we used descriptive statistics, multivariate regression modelling, and a general inductive approach for free text. Results Representing 17/19 Canadian PICUs, 368 of 388 respondents (94%) experienced RFP policies and were predominantly female (333/368, 91%), English speaking (338/368, 92%), and nurses (240/368, 65%). The mean (standard deviation [SD]) reported moral distress score was 4.5 (2.4) and was associated with perceived differential impact on families. The mean (SD) total IES score was 29.7 (10.5), suggesting moderate traumatic stress with 56% (176/317) reporting increased/significantly increased stress from restrictions related to separating families, denying access, and concern for family impacts. Incongruence between RFP policies/practices and PICU values was perceived by 66% of respondents (217/330). Most respondents (235/330, 71%) felt their opinions were not valued when implementing policies. Though respondents perceived that restrictions were implemented for the benefit of clinicians (252/332, 76%) and to protect families (236/315, 75%), 57% (188/332) disagreed that their RFP experience was mainly positive. Conclusion Pediatric intensive care unit-based RFP rules, largely designed and implemented without bedside clinician input, caused increased psychological burden for clinicians, characterized as moderate moral distress and trauma triggered by perceived impacts on families.

Purpose We performed this study to explore family member experiences with restrictions to family presence during their child’s PICU admission, leveraging the unique context of the COVID-19 pandemic to aid in future ethical and informed decision-making. Methods Qualitative interpretive descriptive study with family members of Canadian PICU patients admitted from March 2020 to April 2021 who experienced restricted family presence (RFP) policies. Respondents were purposively sampled for demographic-based maximum variation.We generated themes through inductive thematic analysis of open-ended interviews. Results Fourteen parental figures from five regions across Canada participated. We identified four themes associated with the lived experience and impact of the restrictions on family members of critically ill children: (1) challenges to fulfilling the parent role, (2) isolation from primary supports during a time of crisis, (3) navigating increased logistical difficulties, and (4) seeking compassionate approaches within the healthcare system. Conclusion : RFP policies created a range of barriers for family members of critically ill children. Healthcare organizations and teams may play a role in removing barriers through consistent and empathetic application of rules with consideration for the duality of the parent role in PICUs, providing important post-pandemic policy and practice implications. What is known: • Parental presence with critically ill children may improve health outcomes for patients and their families. • Restrictions to family presence in PICUs continue to occur internationally and, during COVID-19, resulted in parental isolation, anxiety, and increased stress.  What is new: • By isolating family members and removing supports, COVID-19-related restrictions in Canadian PICUs challenged family members’ ability to fulfil their parent roles while meeting their own needs.  • Families need empathetic, advocacy-based approaches from clinicians and healthcare systems to maintain trust and therapeutic relationships in a family-centered organization.

Inbreeding is a potent evolutionary force shaping the distribution of genetic variation within and among populations of plants and animals. Yet, our understanding of the forces shaping the expression and evolution of nonrandom mating in general, and inbreeding in particular, remains remarkably incomplete. Most research on plant mating systems focuses on self-fertilization and its consequences for automatic selection, inbreeding depression, purging, and reproductive assurance, whereas studies of animal mating systems have often assumed that inbreeding is rare, and that natural selection favors traits that promote outbreeding. Given that many sessile and sedentary marine invertebrates and marine macroalgae share key life history features with seed plants (e.g., low mobility, modular construction, and the release of gametes into the environment), their mating systems may be similar. Here, we show that published estimates of inbreeding coefficients (F IS) for sessile and sedentary marine organisms are similar and at least as high as noted in terrestrial seed plants. We also found that variation in FIS within invertebrates is related to the potential to selffertiliz, disperse, and choose mates. The similarity of F IS for these organismal groups suggests that inbreeding could play a larger role in the evolution of sessile and sedentary marine organisms than is currently recognized. Specifically, associations between traits of marine invertebrates and F IS suggest that inbreeding could drive evolutionary transitions between hermaphroditism and separate sexes, direct development and multiphasic life cycles, and external and internal fertilization.

The COVID-19 pandemic has presented a unique opportunity to explore how health systems adapt under rapid and constant change and develop a better understanding of health system transformation. Learning health systems (LHS) have been proposed as an ideal structure to inform a data-driven response to a public health emergency like COVID-19. The aim of this study was to use a LHS framework to identify assets and gaps in health system pandemic planning and response during the initial stages of the COVID-19 pandemic at a single Canadian Health Centre. This paper reports the data triangulation stage of a concurrent triangulation mixed methods study which aims to map study findings onto the LHS framework. We used a triangulation matrix to map quantitative (textual and administrative sources) and qualitative (semi-structured interviews) data onto the seven characteristics of a LHS and identify assets and gaps related to health-system receptors and research-system supports. We identified several health system assets within the LHS characteristics, including appropriate decision supports and aligned governance. Gaps were identified in the LHS characteristics of engaged patients and timely production and use of research evidence. The LHS provided a useful framework to examine COVID-19 pandemic response measures. We highlighted opportunities to strengthen the LHS infrastructure for rapid integration of evidence and patient experience data into future practice and policy changes.

Existing barriers to care were exacerbated by the development and implementation of necessary public health restrictions during the COVID-19 pandemic. Children with complex care needs and their families represent a small portion of the paediatric population, and yet they require disproportionately high access to services. Little is known about the impact of COVID-19 public health measures on this population. This study will generate evidence to uncover the wider impact of COVID-19 measures on the lives of children with complex care needs and their families in relation to policy and service changes. This multi-site sequential mixed methods study will take place across the Canadian Maritime provinces and use an integrated knowledge translation approach. There are two phases to this study: 1) map COVID-19 public health restrictions and service changes impacting children with complex care needs by conducting an environmental scan of public health restrictions and service changes between March 2020 and March 2022 and interviewing key informants involved in the development or implementation of restrictions and service changes, and 2) explore how children with complex care needs and their families experienced public health restrictions and service changes to understand how their health and well-being were impacted.

EBV causes infectious mononucleosis and is associated with certain malignancies. EBV nuclear antigen 1 (EBNA1) mediates EBV genome replication, partition, and transcription, and is essential for persistence of the viral genome in host cells. Here we demonstrate that Hsp90 inhibitors decrease EBNA1 expression and translation, and that this effect requires the Gly-Ala repeat domain of EBNA1. Hsp90 inhibitors induce the death of established, EBV-transformed lymphoblastoid cell lines at doses nontoxic to normal cells, and this effect is substantially reversed when lymphoblastoid cell lines are stably infected with a retrovirus expressing a functional EBNA1 mutant lacking the Gly-Ala repeats. Hsp90 inhibitors prevent EBV transformation of primary B cells, and strongly inhibit the growth of EBV-induced lymphoproliferative disease in SCID mice. These results suggest that Hsp90 inhibitors may be particularly effective for treating EBV-induced diseases requiring the continued presence of the viral genome.

IntroductionChildren with medical complexity and their families are an important population of interest within the Canadian healthcare system. Despite representing less than 1% of the paediatric population, children with medical complexity require extensive care and account for one third of paediatric healthcare expenditures. Opportunities to conduct research to assess disparities in care and appropriate allocation of health resources relies on the ability to accurately identify this heterogeneous group of children. This study aims to better understand the population of children with medical complexity in the Canadian Maritimes, including Nova Scotia (NS), New Brunswick (NB) and Prince Edward Island (PEI). This will be achieved through three objectives: (1) Evaluate the performance of three algorithms to identify children with medical complexity in the Canadian Maritimes in administrative data; then using the ‘best fit’ algorithm (2) Estimate the prevalence of children with medical complexity in the Canadian Maritimes from 2003 to 2017 and (3) Describe patterns of healthcare utilisation for this cohort of children across the Canadian Maritimes.Methods and analysisThe research will be conducted in three phases. In Phase 1, an expert panel will codevelop a gold-standard definition of paediatric medical complexity relevant to the Canadian Maritime population. A two-gate validation process will then be conducted using NS data and the gold-standard definition to determine the ‘best fit’ algorithm. During phase 2 the ‘best fit’ algorithm will be applied to estimate the prevalence of children with medical complexity in NS, NB and PEI. Finally, in phase 3 will describe patterns of healthcare utilisation across the Canadian Maritimes.Ethics and disseminationEthics approval for this protocol was granted by the institutional research ethics board at the IWK Health Centre (REB # 1026245). A waiver of consent was approved. This study will use an integrated knowledge translation approach, where end users are involved in each stage of the project, which could increase uptake of the research into policy and practice. The findings of this research study will be submitted for publication and dissemination through conference presentations and with our end users.

Purpose Pediatric intensive care units (PICUs) worldwide restricted family presence in response to the COVID-19 pandemic. We aimed to explore the experiences and impact of restricted family presence policies on Canadian PICU clinicians. Methods We conducted a qualitative study that followed an interpretive phenomenological design. Participants were PICU clinicians providing direct patient care in Canada during periods of COVID-19-related restricted family presence. We purposively sampled for maximum variation among survey participants who consented to be contacted for further research on the same topic. In-depth interviews were conducted remotely via telephone or video-call, audio-recorded, and transcribed. Interviews were inductively coded and underwent thematic analysis. Proposed themes were member-checked by interviewees. Results Sixteen PICU clinicians completed interviews. Interviewees practiced across Canada, represented a range of disciplines (eight nurses, two physicians, two respiratory therapists, two child life specialists, two social workers) and years in profession (0–34 years). We identified four themes representing the most meaningful aspects of restricted family presence for participants: 1) balancing infection control and family presence; 2) feeling disempowered by hospital and policy-making hierarchies; 3) empathizing with family trauma; and 4) navigating threats to the therapeutic relationship. Conclusion Pediatric intensive care unit clinicians were impacted by restricted family presence policies during the COVID-19 pandemic. These policies contributed to feelings of disempowerment and challenged clinicians’ perceived ability to provide the best family-centred care possible. Frontline expertise should be incorporated into the design and implementation of policies to best support family-centred care in any context and minimize risks of moral distress for PICU clinicians.

As a group of Health System Impact (HSI) postdoctoral fellows, Sim and colleagues offer their reflections on ‘driving change’ within the health system and present a framework for understanding the HSI fellow as an embedded researcher. Our commentary offers a different perspective of the fellow’s role by highlighting the integrated knowledge translation (IKT) approach we consider to be foundational to the fellowship experience. Further, we provide several recommendations to enhance Sim and colleagues’ framework to ensure we capture the full value of the fellowship program to the HSI fellow, health system organization, and academic institution.

Clofarabine, a deoxyadenosine analog, was an active anticancer drug in our in vitro high-throughput screening against mouse ependymoma neurospheres. To characterize the clofarabine disposition in mice for further preclinical efficacy studies, we evaluated the plasma and central nervous system disposition in a mouse model of ependymoma. A plasma pharmacokinetic study of clofarabine (45 mg/kg, IP) was performed in CD1 nude mice bearing ependymoma to obtain initial plasma pharmacokinetic parameters. These estimates were used to derive D-optimal plasma sampling time points for cerebral microdialysis studies. A simulation of clofarabine pharmacokinetics in mice and pediatric patients suggested that a dosage of 30 mg/kg IP in mice would give exposures comparable to that in children at a dosage of 148 mg/m 2 . Cerebral microdialysis was performed to study the tumor extracellular fluid (ECF) disposition of clofarabine (30 mg/kg, IP) in the ependymoma cortical allografts. Plasma and tumor ECF concentration–time data were analyzed using a nonlinear mixed effects modeling approach. The median unbound fraction of clofarabine in mouse plasma was 0.79. The unbound tumor to plasma partition coefficient ( K pt,uu : ratio of tumor to plasma AUC u,0–inf ) of clofarabine was 0.12 ± 0.05. The model-predicted mean tumor ECF clofarabine concentrations were below the in vitro 1-h IC 50 (407 ng/mL) for ependymoma neurospheres. Thus, our results show the clofarabine exposure reached in the tumor ECF was below that associated with an antitumor effect in our in vitro washout study. Therefore, clofarabine was de-prioritized as an agent to treat ependymoma, and further preclinical studies were not pursued.