Establishing the Top 10 Research Priorities for Adolescent and Young Adult (AYA) Cancer in Canada: A Protocol for a James Lind Alliance Priority Setting Partnership.

Adolescents and young adults (AYAs; 15-39 years) diagnosed with cancer have unique medical and psychosocial needs. These needs could be better addressed through research that is focused on the topics that matter most to them. However, there is currently no patient-oriented research agenda for AYA cancer in Canada. This manuscript describes the early development and project protocol for a priority-setting partnership (PSP) for establishing the top 10 research priorities for AYA cancer in Canada. This project follows the PSP methodology outlined by the James Lind Alliance (JLA) to engage patients, caregivers, and clinicians in research prioritization. The steps of a JLA PSP include establishing a steering group and project partners, gathering uncertainties, data processing and verifying uncertainties, interim priority setting, and a final priority setting workshop. The AYA cancer PSP will result in a top 10 list of research priorities identified by Canadian AYA patients, caregivers, and clinicians that will be published and shared broadly with the research community. The first steering group meeting was held in April 2023, and the project is ongoing. The establishment of a patient-oriented research agenda for AYA cancer will catalyze a long-term and impactful research focus and ultimately improve outcomes for AYA patients with cancer in Canada.

Making sense of the cancer journey: Pediatric cancer survivors' and their parents' autobiographical memories.

PURPOSE: Youth diagnosed with acute lymphoblastic leukemia (ALL) and their caregiver's experience a myriad of challenges in all domains of health that extend beyond treatment. Yet, little is known about how the cancer experience, and recollections associated with the experience, impact survivorship. We explored pediatric ALL survivors' and their caregivers' autobiographical memories of the cancer experience from diagnosis onwards. METHODS: Survivors of ALL, and one of their caregivers, were recruited through a local clinic. Survivors and their caregivers completed a demographic survey and semi-structured, private, one-on-one interviews. Demographic information were analyzed using descriptive statistics. Interviews were transcribed verbatim and analyzed using reflexive thematic analysis at the level of the individual and dyad. RESULTS: Insights from survivors (N = 19; Mage = 15.3 years) and their caregivers (n = 19; Mage = 45.4 years) were captured. Analyses generated two themes contingent on role (i.e., survivor or caregiver): (1) It is hard to recall my cancer experience and (2) We did as much as we could to manage our child's cancer experience and two unified themes (present in both survivors and their caregivers): (3) It took a village to get through the cancer experience and (4) The cancer diagnosis and experience has had a lasting impact. CONCLUSIONS: Findings highlight the varied and long-lasting ways cancer impacts survivors of pediatric ALL and their caregivers. Survivors had difficultly remembering their experience or felt that information was withheld and were acutely aware of their caregiver's distress. Caregivers were cautious and intentionally limited the information they shared. IMPLICATIONS FOR CANCER SURVIVORS: Survivors desired to be included within, or told about, decisions related to their healthcare and were acutely aware of their caregiver's distress. Efforts should be made to communicate with survivors (from diagnosis onward) openly and to consider strategies to minimize the short- and long-term impacts of pediatric ALL among survivors and their caregivers.

Exploring pain among young people who have completed treatment for acute lymphoblastic leukemia: experiences of youth and caregivers.

PURPOSE: Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed among individuals <14 years of age. The disease and its treatments are associated with negative side effects, including pain, which is both prevalent and distressing. Little is known about pain experiences in this population, which has slowed efforts to identify strategies to mitigate and cope with this adverse effect. This study sought to explore youth's and their caregiver's experiences with, and perspectives of, pain in the context of pediatric cancer treatment. METHODS: Youth and one of their caregivers were recruited through (omitted for peer review). Following completion of a demographic survey, youth and one of their caregivers were interviewed separately using a semi-structured, one-on-one interview guide. Demographic information was analyzed with descriptive statistics, and interviews were transcribed verbatim and analyzed using reflexive thematic analysis. RESULTS: Youth (n = 19; Mage = 15.3 years) and caregiver (n = 19; Mage = 45.4 years) perspectives informed 4 themes: (1) my pain experience is nuanced, multidimensional, and is changing over time; (2) the cancer experience has changed the way I experience and respond to pain; (3) I used strategies to manage pain, and not all of them worked; and (4) my pain experience was influenced by people around me. CONCLUSIONS: Findings extend prior work, suggesting that pain is common, distressing, multidimensional, and influenced by social context. Results highlight the number of ways in which youth and their caregivers attempt to manage their pain and factors influencing pain experiences. Greater efforts are needed to address pain during cancer treatment and survivorship.

Health related quality of life in children with sickle cell disease: A systematic review and meta-analysis.

This review had three aims: 1) describe the measures used to assess health-related quality of life (HRQL) in pediatric patients diagnosed with sickle cell disease (SCD); 2) document the biopsychosocial factors related to HRQL in pediatric patients diagnosed with SCD; and 3) complete a meta-analysis comparing HRQL in pediatric patients diagnosed with SCD to healthy controls. Included studies were published in English, quantitatively assessed HRQL as a primary aim, in both SCD and controls, and included participants between 0 and 21 years of age. The final review included 66 articles, with a total of 8642 participants with SCD, 4 months-21 years of age, and 62,458 controls, 5-27 years of age. HRQL was predominately measured using the Pediatric Quality of Life Inventory Generic Core and Sickle Cell Disease Module. Meta-analyses revealed children with SCD had significantly worse HRQL compared to healthy controls (standardized mean difference = -0.93, 95% CI = -1.25, -0.61, p < 0.00001). Worse HRQL was associated with more severe SCD, female sex, and pain. The findings indicate that children with SCD are at risk for worse HRQL compared to their healthy peers and their HRQL may be impacted by several biopsychosocial factors. Future research is needed to examine how sociocultural factors uniquely impact this population and their overall quality of life.

Computational Saturation Mutagenesis to Investigate the Effects of Neurexin-1 Mutations on AlphaFold Structure.

Neurexin-1 (NRXN1) is a membrane protein essential in synapse formation and cell signaling as a cell-adhesion molecule and cell-surface receptor. NRXN1 and its binding partner neuroligin have been associated with deficits in cognition. Recent genetics research has linked NRXN1 missense mutations to increased risk for brain disorders, including schizophrenia (SCZ) and autism spectrum disorder (ASD). Investigation of the structure-function relationship in NRXN1 has proven difficult due to a lack of the experimental full-length membrane protein structure. AlphaFold, a deep learning-based predictor, succeeds in high-quality protein structure prediction and offers a solution for membrane protein model construction. In the study, we applied a computational saturation mutagenesis method to analyze the systemic effects of missense mutations on protein functions in a human NRXN1 structure predicted from AlphaFold and an experimental Bos taurus structure. The folding energy changes were calculated to estimate the effects of the 29,540 mutations of AlphaFold model on protein stability. The comparative study on the experimental and computationally predicted structures shows that these energy changes are highly correlated, demonstrating the reliability of the AlphaFold structure for the downstream bioinformatics analysis. The energy calculation revealed that some target mutations associated with SCZ and ASD could make the protein unstable. The study can provide helpful information for characterizing the disease-causing mutations and elucidating the molecular mechanisms by which the variations cause SCZ and ASD. This methodology could provide the bioinformatics protocol to investigate the effects of target mutations on multiple AlphaFold structures.

Uranium Bioaccumulation Dynamics in the Mayfly Neocloeon triangulifer and Application to Site-Specific Prediction.

Little is known about the underlying mechanisms governing the bioaccumulation of uranium (U) in aquatic insects. We experimentally parameterized conditional rate constants for aqueous U uptake, dietary U uptake, and U elimination for the aquatic baetid mayfly Neocloeon triangulifer. Results showed that this species accumulates U from both the surrounding water and diet, with waterborne uptake prevailing. Elevated dietary U concentrations decreased feeding rates, presumably by altering food palatability or impairing the mayfly's digestive processes, or both. Nearly 90% of the accumulated U was eliminated within 24 h after the waterborne exposure ceased, reflecting the desorption of weakly bound U from the insect's integument. To examine whether the experimentally derived rate constants for N. triangulifer could be generalized to baetid mayflies, mayfly U concentrations were predicted using the water chemistry and U measured in periphyton from springs in Grand Canyon (United States) and were compared to U concentrations in spring-dwelling mayflies. Predicted and observed mayfly U concentrations were in good agreement. Under the modeled site-specific conditions, waterborne U uptake accounted for 52-93% of the bioaccumulated U. U accumulation was limited in these wild populations due to a combination of factors including low concentrations of bioavailable dissolved U species, slow U uptake rates from food, and fast U elimination.

Severing Ties: Different Responses of Larval and Adult Aquatic Insects to Atrazine and Selenium.

Aquatic insects link aquatic and terrestrial ecosystems through their metamorphosis and subsequent transition from water to land. Chemical stressors in freshwater, such as agricultural contaminants, can potentially disrupt insect life cycles and reduce the number of insects emerging as terrestrial adults, thereby damaging or severing this linkage. Atrazine and selenium, though frequently detected in waterways and often co-occurring, have not been previously studied together in controlled experiments. We conducted a six-week mesocosm experiment to measure the responses of larval and emerging aquatic insects to treatments of atrazine (15 µg/L), selenium (10 µg/L), and a direct combination of the two. Peak adult insect abundance was reduced in all treatments by 35% to 45% relative to the control. Further, cumulative adult emergence in the combined treatment was 33% lower than in the control. However, no reductions in primary production were observed with treatments, and consistent reductions in benthic insect abundance relative to the control were not observed until the end of the experiment, when overall abundance was low. Results suggest that adult insects are more sensitive than larval insects to atrazine and selenium and that the impacts of these contaminants are stronger on the terrestrial than the aquatic ecosystem.