Exome sequencing (ES) has become an important tool in pediatric genomic medicine, improving identification of disease-associated variation due to assay breadth. Depth is also afforded by ES, enabling detection of lower-frequency mosaic variation compared to Sanger sequencing in the studied tissue, thus enhancing diagnostic yield. Within a pediatric tertiary-care hospital, we report two years of clinical ES data from probands evaluated for genetic disease to assess diagnostic yield, characteristics of causal variants, and prevalence of mosaicism among disease-causing variants. Exome-derived, phenotype-driven variant data from 357 probands was analyzed concurrent with parental ES data, when available. Blood was the source of nucleic acid. Sequence read alignments were manually reviewed for all assessed variants. Sanger sequencing was used for suspected de novo or mosaic variation. Clinical provider notes were reviewed to determine concordance between laboratory-reported data and the ordering provider's interpretation of variant-associated disease causality. Laboratory-derived diagnostic yield and provider-substantiated diagnoses had 91.4% concordance. The cohort returned 117 provider-substantiated diagnoses among 115 probands for a diagnostic yield of 32.2%. De novo variants represented 64.9% of disease-associated variation within trio analyses. Among the 115 probands, five harbored disease-associated somatic mosaic variation. Two additional probands were observed to inherit a disease-associated variant from an unaffected mosaic parent. Among inheritance patterns, de novo variation was the most frequent disease etiology. Somatic mosaicism is increasingly recognized as a significant contributor to genetic disease, particularly with increased sequence depth attainable from ES. This report highlights the potential and importance of detecting mosaicism in ES.

These data highlight the importance of MAX mutations in EC and point to increased vascularity as one mechanism contributing to clinical aggressiveness of EC.

Background Family members influence maternal, child, and adolescent nutrition and are increasingly engaged in nutrition interventions and research. However, gaps in the literature related to programmatic experiences and lessons learned from engaging these key influencers in nutrition activities remain. Objectives This research aimed to document global health professionals' experiences engaging family members in nutrition activities, and their perceived barriers, facilitators, and recommendations for nutrition activities that engage family members. Methods Global health and nutrition professionals were invited to complete an online survey about their experiences engaging family members in nutrition activities. The survey included 42 multiple-choice questions tabulated by frequency and 4 open-response questions, which were analyzed thematically. Results More than 180 respondents (n = 183) in 49 countries with experience engaging fathers, grandmothers, and other family members in nutrition activities participated in the survey. Participants highlighted the importance of conducting formative research with all members of the family system and using participatory processes in intervention design and implementation. Respondents reported engaging family members increases support for recommended behaviors, improves program sustainability, and facilitates family and community ownership. Some respondents also shared experiences with positive and negative unintended consequences when engaging family members; for example, one-fifth of participants reported that mothers were uncomfortable with involving men in discussions. Common challenges centered on limited resources for program delivery, not involving all influential family members, and traditional gender norms. Recommendations included incorporating family members in the project design phase and ensuring sufficient project resources to engage family members throughout the project lifecycle. Conclusions Surveying global health professionals provides an opportunity to learn from their experiences and fill gaps in the peer-reviewed literature to strengthen intervention design and implementation. Community ownership and sustainability emerged as key benefits of family engagement not previously reported in the literature, but responses also highlighted potential negative unintended consequences.

This paper introduces an integrative (or braided) approach to Indigenous youth mental health, designed in response to a synthesis of knowledge from three systematic literature reviews and four informant consultations with mental health providers in various disciplines. The braided approach includes core principles of Indigenous Healing models (IH), Child and Youth Care (CYC) approaches, and Dialectical Behaviour Therapy (DBT) practices. The purpose of this approach is to best serve the mental and spiritual health needs of Indigenous youth across Canada during the COVID-19 pandemic. Findings of this research project informed the design and implementation of an online Indigenous youth mental health program, which is discussed in relation to the research.

Purpose/Objectives: Accelerated partial breast irradiation (APBI) has been shown to have both acceptable oncologic and cosmetic outcomes for early stage breast cancer following breast-conserving surgery (BCS). Given the demonstrated financial toxicity (FT) of conventional radiation treatments on breast cancer patients, we wanted to quantitatively assess the FT on patients treated with APBI in our phase I five fraction stereotactic APBI (S-PBI) trial, which could be generalized across APBI treatment regimens. Methods: A phase I dose escalation trial of S-PBI for early stage breast cancer following BCS was conducted. Women age > 18 years with in-situ or stage I-II (AJCC 7) invasive breast cancer < 3 cm following BCS with > 2 mm margins were treated with S-PBI in 5 fractions to a total dose of 30 to 40 Gy over 2.5 Gy increments (Clinical trials.gov ID NCT01162200). One month following completion of treatment, patients were asked to complete our novel “Patient Perspective Cost and Convenience of Care Questionnaire” developed at our institution. Results: Of 75 patients enrolled and treated, questionnaire data was available for 66 patients. Our trial encompassed a wide spectrum of annual household incomes, with 25.5% of patients (n=14/55) reporting income of less than $30k and 45.5% (n=25/55) reporting incomes of more than $80k. Educational status was also well represented with 53.1% completing at least some college (n= 34/64), 25% holding post graduate or professional degrees (n=16/64), and 21.9% patients reporting a high school equivalent or less (n=14/64). Overall 48.4% of patients (n=30/62) said that oncologic treatment did not present a financial burden; however, 29.0% (n=20/62) patients reported a somewhat to significant financial burden. Neither household income nor patient education status predicted perceived FT. Of the 6 patients (9.7%) who reported significant FT, 5 reported travelling at least 25 miles one way for treatment with 2 of these patient travelling over 175 miles. Half of the patients reported having private insurance for medication (49.2%, n=32/65), 33.8% had governmental coverage (n=22/65), 6.1% had both private and government coverage, 7.7% had no coverage (n=5/65), and 3.0% were unsure of their coverage (n=2/65). Only 1 of the 6 patients with significant FT had no coverage. Over half of the patients (54.2%, n=34/62) reported a co-pay during their treatment with a median out of pocket cost of $300 for treatment (range $10-10000, n=16). Over half of the patients were working full or part time during treatment (54.2%, n=32/59). All 26 patients that were working full time had to take time off work for treatment (median of 5 days, range 0.25 days – 10 days). Over a third of these patients (34.6%, n=9) had to use vacation time or unpaid time off. There was an additional patient who reported months off without pay. Additionally, 24.2% of patients (n=15/62) reported they had family or friends take time off work due to the patient’s treatment. Finally, patients were surveyed on the treatment related disruption to their daily activities and enjoyment of life rated on a scale 0-10, with 0 being no disruption, median values were 3 and 1, respectively. Patients also reported a median score of 10 (scale 0-10, 10 being most satisfied) on satisfaction with treatment time. Conclusions: In this cohort of patients, interestingly FT was significant primarily in the 10% of patients who traveled a significant distance for these treatments. However, despite this, and the fact that patients were undergoing cytotoxic cancer therapy, impressively, all patients were uniformly satisfied with treatment time (median score of 10), and most did not express significant disruption to their life. We plan to explore the impact of further reducing treatment fractions (with our single fraction S-PBI studies) on FT and quality of life in future studies. Citation Format: Ambrosia Simmons, David Sher, Dong W. Nathan Kim, Marilyn Leitch, Rachel Wooldridge, Sally Goudreau, Stephen Seiler, Sarah Neufeld, Maggie Stein, Kevin Albuquerque, Ann Spangler, John Heinzerling, Dan Gardwoood, Stella Stevenson, Chul Ahn, Chuxiong Ding, Robert Timmerman, Asal Rahimi. Financial Toxicity Outcomes on a Phase I 5-fraction Partial Breast Irradiation Protocol for Early Stage Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-55.