Providing culturally responsive care in a pediatric setting: are our trainees ready?

BACKGROUND: Extensive data consistently demonstrates inequities in access and delivery of healthcare for patients from historically marginalized populations, resulting in poorer health outcomes. To address this systemic oppression in healthcare, it is necessary to embed principles of equity, diversity, and inclusion (EDI) at an early stage within medical education. This study aimed to assess pediatric trainees' perceived interest in EDI curricula as well as their confidence in applying this knowledge to provide culturally responsive care. METHODS: An anonymous online survey was distributed to pediatric trainees at the University of Toronto. Closed-ended questions used a Likert scale to assess respondents' confidence and interest in providing culturally responsive care to patients. Open-ended questions explored trainees' perceptions of effective EDI learning modalities. A mixed methods approach was utilized, where quantitative data was summarized using descriptive statistics and descriptive content analysis was used to highlight themes within qualitative data. RESULTS: 116 pediatric trainees completed the survey, of which 72/116 (62%) were subspecialty residents/fellows and 44/116 (38%) were core residents. 97% of all responses agreed or strongly agreed that it was important to learn about providing culturally responsive care to patients from historically marginalized communities; however, many trainees lacked confidence in their knowledge of providing culturally responsive care (42%) and applying their knowledge in clinical practice (47%). Respondents identified direct clinical exposure through rotations, immersive experiences, and continuity clinics as effective EDI teaching modalities. Identified barriers included time constraints in the clinical environment, burnout, and lack of exposure to diverse patient populations. CONCLUSION: Most pediatric trainees want to provide culturally responsive care to patients from historically marginalized communities, but do not feel confident in their knowledge to do so. Trainees value learning about EDI through direct clinical exposure and immersive experiences, rather than didactic lectures or modules. These study findings will be utilized to develop and implement an enhanced EDI education curriculum for pediatric trainees at the University of Toronto and other postgraduate residency programs.

Trajectory of Left Ventricular Remodeling in Children With Valvar Aortic Stenosis Following Balloon Aortic Valvuloplasty.

BACKGROUND: Aortic valve stenosis is the most common type of congenital left ventricular (LV) outflow tract obstruction. Balloon aortic valvuloplasty (BAV) has become the first-line treatment pathway in many centers. Our aim was to assess the trajectory of LV remodeling following BAV in children and its relationship to residual aortic stenosis (AS) and insufficiency (AI). METHODS: Children <18 years of age who underwent BAV for isolated aortic stenosis from 2004 to 2012 were eligible for inclusion. Those with AI before BAV, other complex congenital heart lesions, or <2 accessible follow-up echocardiograms were excluded. Baseline and serial echocardiographic data pertaining to aortic valve and LV size and function were retrospectively collected through December 2017 or the first reintervention. Longitudinal data was assessed using per-patient time profiles with superimposed trend lines using locally estimated scatterplot smoothing. Associations with reintervention or death were also evaluated. RESULTS: Among the 98 enrolled children, the median (interquartile range) age at BAV was 2.8 months (0.2-75). The median (interquartile range) follow-up was 6.8 years (1.9-9.0). Children with predominantly residual AI (n=11) demonstrated progressive increases in their LV end-diastolic dimension Z score within the first 3 years after the BAV, followed by a plateau (P<0.001). Their mean LV circumferential and longitudinal strain values remained within the normal range but lower than in the non-AI group (P<0.001 and P=0.001, respectively). Children with predominantly residual aortic stenosis (n=44) had no changes in LV dimensions but had a rapid early increase in mean LV circumferential and longitudinal strain. The cumulative proportion (95% CI) of reintervention at 5 years following BAV was 33.7% (23.6%-42.4%). CONCLUSIONS: Our study demonstrates that LV remodeling occurs mainly during the first 3 years in children with predominantly residual AI after BAV, with no subsequent significant functional changes over the medium term. These data improve our understanding of expected patient trajectories and thus may inform decisions on the timing of reintervention.

A genome-wide CRISPR/Cas9 screen in acute myeloid leukemia cells identifies regulators of TAK-243 sensitivity.

TAK-243 is a first-in-class inhibitor of ubiquitin-like modifier activating enzyme 1 that catalyzes ubiquitin activation, the first step in the ubiquitylation cascade. Based on its preclinical efficacy and tolerability, TAK-243 has been advanced to phase I clinical trials in advanced malignancies. Nonetheless, the determinants of TAK-243 sensitivity remain largely unknown. Here, we conducted a genome-wide CRISPR/Cas9 knockout screen in acute myeloid leukemia (AML) cells in the presence of TAK-243 to identify genes essential for TAK-243 action. We identified BEN domain-containing protein 3 (BEND3), a transcriptional repressor and a regulator of chromatin organization, as the top gene whose knockout confers resistance to TAK-243 in vitro and in vivo. Knockout of BEND3 dampened TAK-243 effects on ubiquitylation, proteotoxic stress, and DNA damage response. BEND3 knockout upregulated the ATP-binding cassette efflux transporter breast cancer resistance protein (BCRP; ABCG2) and reduced the intracellular levelsof TAK-243. TAK-243 sensitivity correlated with BCRP expression in cancer cell lines of different origins. Moreover, chemical inhibition and genetic knockdown of BCRP sensitized intrinsically resistant high-BCRP cells to TAK-243. Thus, our data demonstrate that BEND3 regulates the expression of BCRP for which TAK-243 is a substrate. Moreover, BCRP expression could serve as a predictor of TAK-243 sensitivity.

Mitochondrial carrier homolog 2 is necessary for AML survival.

Through a clustered regularly insterspaced short palindromic repeats (CRISPR) screen to identify mitochondrial genes necessary for the growth of acute myeloid leukemia (AML) cells, we identified the mitochondrial outer membrane protein mitochondrial carrier homolog 2 (MTCH2). In AML, knockdown of MTCH2 decreased growth, reduced engraftment potential of stem cells, and induced differentiation. Inhibiting MTCH2 in AML cells increased nuclear pyruvate and pyruvate dehydrogenase (PDH), which induced histone acetylation and subsequently promoted the differentiation of AML cells. Thus, we have defined a new mechanism by which mitochondria and metabolism regulate AML stem cells and gene expression.