Impactful co-design: Adult decision-makers' perspectives on actualising children's ideas for health-promoting neighbourhoods in Aotearoa New Zealand.

Our study sought to understand adult decision-makers' views on what was important for actualising children's ideas using co-design, towards creating health-promoting local environments. Ten adult decision-makers, experienced in co-design with children aged 5-13 years in Aotearoa New Zealand, participated in individual interviews. We generated three themes (Empowering children within co-design; Being intentional about children's influence; Curating who is involved) using reflexive thematic analysis. Our themes informed a novel framework of 'impactful co-design' accompanied by a practical checklist for adult decision-makers (practitioners, policy-makers, and researchers). Study findings affirm co-designing local neighbourhoods as an inherently social and technical endeavour, advocate for greater consideration of inclusivity and cultural context, and highlight the need for co-design with children to include safety, empowerment, and evaluation. We position impactful co-design as one useful process to enact children's meaningful participation.

Recruitment and Retention of Hematopoietic Cell Transplantation and Cellular Therapy Physicians: A Report from the ASTCT Talent Acquisition Task Force.

A shortage of transplant and cellular therapy (TCT) physicians is expected given the expansion of TCT indications and the scope of practice of TCT programs in recent years. American Society of Transplantation and Cellular Therapy (ASTCT) conducted a survey of early career transplant physicians and trainees to assess the factors that prompted them to pursue to career in TCT. This was a cross-sectional survey conducted via emails sent to the ASTCT membership. Fifty-nine respondents completed the survey. The vast majority of respondents decided to pursue a career in TCT during their hematology/oncology fellowship (41%), followed by during residency (25%) or medical school (18%), and a majority of them had some exposure to TCT in their clinical training already. The most common reason for choosing to specialize in TCT was interest in the clinical practice of TCT (81%) closely followed by the scientific allure of the field (75%). Most respondents were extremely committed to remaining in this field of practice. We found that those in the field report high levels of satisfaction despite factors that would otherwise predispose them to burnout. A systematic and sustained effort to promote trainee engagement that could result in improved recruitment and retention in the field of TCT is needed. Professional societies in partnership with educational institutions could conduct outreach and help attract trainees from diverse backgrounds.

Altered microbial bile acid metabolism exacerbates T cell-driven inflammation during graft-versus-host disease.

Microbial transformation of bile acids affects intestinal immune homoeostasis but its impact on inflammatory pathologies remains largely unknown. Using a mouse model of graft-versus-host disease (GVHD), we found that T cell-driven inflammation decreased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and reduced the levels of unconjugated and microbe-derived bile acids. Several microbe-derived bile acids attenuated farnesoid X receptor (FXR) activation, suggesting that loss of these metabolites during inflammation may increase FXR activity and exacerbate the course of disease. Indeed, mortality increased with pharmacological activation of FXR and decreased with its genetic ablation in donor T cells during mouse GVHD. Furthermore, patients with GVHD after allogeneic hematopoietic cell transplantation showed similar loss of BSH and the associated reduction in unconjugated and microbe-derived bile acids. In addition, the FXR antagonist ursodeoxycholic acid reduced the proliferation of human T cells and was associated with a lower risk of GVHD-related mortality in patients. We propose that dysbiosis and loss of microbe-derived bile acids during inflammation may be an important mechanism to amplify T cell-mediated diseases.

CAR19 monitoring by peripheral blood immunophenotyping reveals histology-specific expansion and toxicity.

Chimeric antigen receptor (CAR) T cells directed against CD19 (CAR19) are a revolutionary treatment for B-cell lymphomas. CAR19 cell expansion is necessary for CAR19 function but is also associated with toxicity. To define the impact of CAR19 expansion on patient outcomes, we prospectively followed a cohort of 236 patients treated with CAR19 (brexucabtagene autoleucel or axicabtagene ciloleucel) for mantle cell (MCL), follicular (FL), and large B-cell lymphoma (LBCL) over the course of five years and obtained CAR19 expansion data using peripheral blood immunophenotyping for 188 of these patients. CAR19 expansion was higher in patients with MCL compared to other lymphoma histologic subtypes. Notably, patients with MCL had increased toxicity and required four-fold higher cumulative steroid doses than patients with LBCL. CAR19 expansion was associated with the development of cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), and the requirement for granulocyte colony stimulating factor (GCSF) after day 14 post-infusion. Younger patients and those with elevated lactate dehydrogenase (LDH) had significantly higher CAR19 expansion. In general, no association between CAR19 expansion and LBCL treatment response was observed. However, when controlling for tumor burden, we found that lower CAR19 expansion in conjunction with low LDH was associated with improved outcomes in LBCL. In sum, this study finds CAR19 expansion principally associates with CAR-related toxicity. Additionally, CAR19 expansion as measured by peripheral blood immunophenotyping may be dispensable to favorable outcomes in LBCL.

Impacts of sociodemographic factors, identities and neighbourhood safety on the relationship between urban green space and adolescent mental well-being: Findings from Tamaki Makaurau Auckland, Aotearoa New Zealand.

This study explored the relationship between green space accessibility (GSA) in residential area and adolescents' mental well-being, and whether the relationship was moderated by sociodemographic factors (sex, ethnicity, neighbourhood deprivation), identities (gender and sexuality minority, disability) and perceived neighbourhood safety simultaneously. Data from 3813 adolescents who lived in Tamaki Makaurau Auckland, Aotearoa New Zealand were obtained from the Youth19 Rangatahi Smart Survey. A Gaussian-based two-step floating catchment area method was employed to measure the spatial accessibility to green space at the neighbourhood level. The World Health Organization-5 Well-being Index was used to assess emotional well-being (EW), and the Reynolds Adolescent Depression Scale-short form was employed to measure depressive symptoms (DS). Through moderation analyses, results showed that perceived neighbourhood safety plays a vital role in the GSA - mental well-being association, with a negative trend in adolescents who reported being less safe in neighbourhoods. Adverse associations of GSA were found in gender and sexuality minority, disabled, Asian and Pacific adolescents, under the condition of not feeling safe in neighbourhoods all the time. The results showed marginalised adolescents tended to feel less safe in neighbourhoods, have lower EW and a higher level of DS. Additionally, the results from bivariate correlations showed there were inequalities in GSA for adolescents who lived in most deprived neighbourhoods and adolescents of Maori ethnicity. This study provides novel evidence of the importance of safe and inclusive green space for effectively promoting mental health and mitigating health inequalities of adolescents in urban areas.

Physical activity, screen time and dietary behaviours in New Zealand adolescents prior to and following the onset of the COVID-19 pandemic.

BACKGROUND: Insufficient physical activity, high screen time, and unhealthy dietary patterns among adolescents may have worsened during the pandemic, but data are lacking. This study compared physical activity, screen time and fruit and vegetable intake in adolescents from Dunedin, New Zealand, 5-6 years before (Study 1) and during (Study 2) the COVID-19 pandemic. METHODS: Adolescents completed an online survey as part of the Built Environment and Active Transport to School (BEATS) studies in 2014/2015 (Study 1; n = 1,266; age: 15.3 ± 1.4 years; 54.6% female) and 2021/2022 (Study 2; n = 819; age: 15.2 ± 1.4 years; 47.4% female). The proportion of adolescents meeting guidelines for physical activity (≥ 60 min/day of moderate-to-vigorous physical activity), outside school screen time (≤ 2 h/day) and fruit and vegetable intake (> 1 serving/day for both fruit and vegetables) was calculated. Data were analysed using multivariable linear and logistic regression modelling. RESULTS: Few adolescents met recommended health behaviour guidelines. Compared to Study 1, significantly greater proportions of adolescents at Study 2 met guidelines for physical activity (16.7% vs. 23.1%; p < 0.001) and outside school screen time (13.3% vs. 18.3%; p < 0.001) while fruit and vegetable intake was not different (29.6% vs. 27.0%; p = 0.322). Compared to Study 1, average outside school screen time at Study 2 was lower on both weekdays (5.0 ± 2.9 vs. 4.6 ± 2.9; p < 0.001) and weekend days (6.9 ± 3.5 vs. 6.1 ± 3.6 h/day; p < 0.001). Reported frequency of consuming sweets was higher and soft drinks lower at Study 2 versus Study 1. CONCLUSIONS: Despite observed higher levels of physical activity and lower levels of outside school screen time during the pandemic compared to the pre-pandemic levels, few adolescents met health behaviour guidelines at both time points. Therefore, comprehensive health promotion that aims to improve physical activity levels, screen time and dietary patterns for adolescents is still necessary to prevent chronic health conditions adulthood.

Clinical features of neurotoxicity after CD19 CAR T-cell therapy in mantle cell lymphoma.

ABSTRACT: CD19 chimeric antigen receptor (CAR) T-cell therapy has proven highly effective for treating relapsed/refractory mantle cell lymphoma (MCL). However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant concern. This study aimed to evaluate the clinical, radiological, and laboratory correlatives associated with ICANS development after CD19 CAR T-cell therapy in patients with MCL. All patients (N = 26) who received standard-of-care brexucabtagene autoleucel until July 2022 at our institution were evaluated. Laboratory and radiographic correlatives including brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) were evaluated to determine the clinical impact of ICANS. Seventeen (65%) patients experienced ICANS after treatment, with a median onset on day 6. Ten (38%) patients experienced severe (grade ≥3) ICANS. All patients with ICANS had antecedent cytokine release syndrome (CRS), but no correlation was observed between ICANS severity and CRS grade. Overall, 92% of EEGs revealed interictal changes; no patients experienced frank seizures because of ICANS. In total, 86% of patients with severe ICANS with postinfusion brain MRIs demonstrated acute neuroimaging findings not seen on pretreatment MRI. Severe ICANS was also associated with higher rates of cytopenia, coagulopathy, increased cumulative steroid exposure, and prolonged hospitalization. However, severe ICANS did not affect treatment outcomes of patients with MCL. Severe ICANS is frequently associated with a range of postinfusion brain MRI changes and abnormal EEG findings. Longer hospitalization was observed in patients with severe ICANS, especially those with abnormal acute MRI or EEG findings, but there was no discernible impact on overall treatment response and survival.

Inequalities in neighbourhood features within children's 20-minute neighbourhoods and variation in time spent locally, measured using GPS.

There has been a growing interest in policies that encourage local living by promoting accessible and walkable communities, such as the 20-minute neighbourhood concept. Despite the widespread adoption of this policy in cities worldwide, little research has been conducted on the characteristics of children's 20-minute neighbourhoods and their association with time spent locally. This study aimed to explore the features of Scottish children's 20-minute neighbourhoods by analysing an 800-meter road and path network buffer surrounding 687 children's homes. Based on existing literature, the study identified key features associated with children's time spent locally and the 20-minute neighbourhood policy. The study then examined variations in these features by socioeconomic status, urbanicity, and gender. The findings revealed significant inequalities in the presence of health-benefiting (e.g., green spaces, recreational facilities, healthy food outlets) and health-harming (e.g., major roads, unhealthy commodity retailers) environments within children's 20-minute neighbourhoods. Children from more deprived areas had access to more of both types of environments. The study also found that having a school within a 20-minute neighbourhood was associated with an increased amount of time spent locally (IRR 1.62, 95% CI 1.5 to 1.8, p<0.001). The study suggests that the 20-minute neighbourhood policy should extend beyond mere access to local amenities and prioritise creating healthy 20-minute neighbourhoods, particularly in socioeconomically deprived areas. The research highlights the importance of promoting equal access to quality local environments, which can contribute to improved health and well-being outcomes for children.

Inequities in the physical activity of disabled young people in Aotearoa New Zealand: a stakeholder SWOT analysis of the physical activity sector.

AIMS: Disabled people, particularly children and adolescents, tend to participate in less physical activity than their non-disabled peers on average. However, disabled children and youth (i.e., young people [YP]) are typically underrepresented in physical activity (PA) research, with little data available in Aotearoa New Zealand to guide policy makers to alter societal factors that contribute to disability inequities. The purpose of this study was to conduct a Strengths, Weaknesses, Opportunities, and Threats (SWOT) analysis of the PA sector in Aotearoa New Zealand with respect to PA participation and promotion among disabled YP. METHODS: Focus group discussions, underpinned by the SWOT framework, were facilitated with stakeholders (n=11) engaged in the Aotearoa New Zealand PA sector. Data were transcribed and analysed using content analysis. Desirable and accessible opportunities were essential enablers of PA in disabled YP. RESULTS: Communication, transport, equipment costs, awareness of activities, and social support were identified as factors that influence PA participation. Schools also have a considerable influence on PA participation among disabled YP, while greater funding for and cohesion/collaboration among PA providers is key to continued growth in PA participation. CONCLUSIONS: Communication, accessibility, funding, and collaborative/coordinated multi-level efforts were identified as areas in need of strengthening to provide equitable opportunities for disabled YP in Aotearoa New Zealand to participate in PA.

How I treat refractory CRS and ICANS after CAR T-cell therapy.

The clinical use of chimeric antigen receptor (CAR) T-cell therapy is growing rapidly because of the expanding indications for standard-of-care treatment and the development of new investigational products. The establishment of consensus diagnostic criteria for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), alongside the steady use of both tocilizumab and corticosteroids for treatment, have been essential in facilitating the widespread use. Preemptive interventions to prevent more severe toxicities have improved safety, facilitating CAR T-cell therapy in medically frail populations and in those at high risk of severe CRS/ICANS. Nonetheless, the development of persistent or progressive CRS and ICANS remains problematic because it impairs patient outcomes and is challenging to treat. In this case-based discussion, we highlight a series of cases of CRS and/or ICANS refractory to front-line interventions. We discuss our approach to managing refractory toxicities that persist or progress beyond initial tocilizumab or corticosteroid administration, delineate risk factors for severe toxicities, highlight the emerging use of anakinra, and review mitigation strategies and supportive care measures to improve outcomes in patients who develop these refractory toxicities.

Differences in physical activity participation among young adults in Aotearoa New Zealand.

BACKGROUND: The purpose of this study was to examine socio-demographic differences in physical activity (aerobic and muscle-strengthening) among young adults (18-24 years). METHODS: Data collected between 2017-2019 as a part of Sport New Zealand's Active NZ survey were examined using logistic regression analyses to determine the odds of participants meeting aerobic, muscle-strengthening and combined physical activity recommendations. Gender, ethnicity, employment/student status, disability status, and socio-economic deprivation were included as explanatory variables in analyses. RESULTS: The proportion of young adults meeting recommendations varied according to physical activity type (aerobic:63.2%; strength:40.1%; combined:37.2%). Young adults not employed/studying had lower odds of meeting recommendations than those full-time employed (OR = 0.43 [0.34-0.54]). Physical activity levels differ according to gender and this intersects with ethnicity, employment/student status, and social deprivation. For example, the odds of Pasifika young adults meeting combined physical activity recommendations compared to Europeans were not different (OR = 0.95 [0.76-1.19]), but when stratified by gender the odds were significantly higher for men (OR = 1.55 [1.11-2.16]) and significantly lower for women (OR = 0.64 [0.47-0.89]. Similarly, young adults in high deprivation areas had lower odds of meeting combined physical activity recommendations than those in low deprivation areas (OR = 0.81 [0.68-0.95]), but this was mainly due to the difference among women (OR = 0.68 [0.54-0.85]) as there was no difference among men (OR = 0.97 [0.76-1.25]). CONCLUSIONS: Intersections between socio-demographic characteristics should be considered when promoting physical activity among young adults in Aotearoa New Zealand, particularly young adults not employed/studying, and young women who live in deprived areas or identify as Asian or Pasifika. Tailored approaches according to activity type for each of these groups are required.

Results from Aotearoa New Zealand's 2022 Report Card on Physical Activity for Children and Youth: A call to address inequities in health-promoting activities.

Background: This article reports the methods and findings for Aotearoa New Zealand's 2022 Report Card on Physical Activity for Children and Youth indicators, and on inequities within these indicators. Methods: Grades were assigned to indicators using the Active Healthy Kids Global Alliance criteria depending on data availability, and inequities reported based on gender, ethnicity, disability status, area-level socioeconomic deprivation, urbanicity, and school year. Two additional indicators were included in this report card: Sleep, and Physical literacy. Results: Grades were assigned to indicators as follows: Overall physical activity: C+, Organised sport and physical activity: B-, Physical literacy: B, Active transportation: D, Sedentary behaviours: C-, Sleep: B+, Whanau (family) and peers: D, School: C+, Government: A. Inequities across all socio-demographic variables were observed. An 'inconclusive' grade was assigned to the Active play, Physical fitness, and Community and Environment indicators due to insufficient data. Conclusion: It is imperative that targeted, comprehensive, and population-specific approaches are implemented to support health-promoting physical activity behaviours and reduce inequities among children and youth in Aotearoa. There is a need to promote all dimensions of physical activity (overall activity, active play, recreation, organised sport, active transportation) and the reduction of screen time through policy, research, evidence-based social marketing campaigns, and urban design. Regular, nationally representative surveys that enable the consistent and regular measurement of key Report Card indicators are needed.

Burnout in US hematologists and oncologists: impact of compensation models and advanced practice provider support.

Burnout is prevalent throughout medicine. Few large-scale studies have examined the impact of physician compensation or clinical support staff on burnout among hematologists and oncologists. In 2019, the American Society of Hematology conducted a practice survey of hematologists and oncologists in the AMA (American Medical Association) Masterfile; burnout was measured using a validated, single-item burnout instrument from the Physician Work-Life Study, while satisfaction was assessed in several domains using a 5-point Likert scale. The overall survey response rate was 25.2% (n = 631). Of 411 respondents with complete responses in the final analysis, 36.7% (n = 151) were from academic practices and 63.3% (n = 260) from community practices; 29.0% (n = 119) were female. Over one-third (36.5%; n = 150) reported burnout, while 12.0% (n = 50) had a high level of burnout. In weighted multivariate logistic regression models incorporating numerous variables, compensation plans based entirely on relative value unit (RVU) generation were significantly associated with high burnout among academic and community physicians, while the combination of RVU + salary compensation showed no significant association. Female gender was associated with high burnout among academic physicians. High advanced practice provider utilization was inversely associated with high burnout among community physicians. Distinct patterns of career dissatisfaction were observed between academic and community physicians. We propose that the implementation of compensation models not based entirely on clinical productivity increased support for women in academic medicine, and expansion of advanced practice provider support in community practices may address burnout among hematologists and oncologists.

More-Than-Human: A Cross-Sectional Study Exploring Children's Perceptions of Health and Health-Promoting Neighbourhoods in Aotearoa New Zealand.

A disconnect between children's ideas and their incorporation into environmental design, in the context of rapid urbanisation and climate crises, compelled us to reflect on children's meaningful participation in positive environmental change. Our research aimed to bring new knowledge to the fore using a participatory, child-centred approach to understanding children's perceptions of health and health-promoting neighbourhoods in Aotearoa New Zealand. The cross-sectional Neighbourhoods and Health study was conducted with 93 primary school-aged children (approximate ages 8 to 10 years) from two schools in Otepoti Dunedin and two schools in Tamaki Makaurau Auckland from June 2020 to August 2021. We present a framework of twelve child-centred topics of importance for health (Healthcare and 'not getting sick', 'How you feel', and Taking care of yourself), health-promoting neighbourhoods (Proximity, safety and feel, Range of 'places to go', 'Friendly streets', and 'No smoking'), and those common to both (Connections with other humans, Healthy food and drink, Exercising and playing sport 'to keep fit', 'Nature' and 'helping the environment', and Recreational activities). The more-than-human theory was used to situate our study findings, and we explored three threads evident in children's thinking: (1) care for humans and non-humans, (2) vital interdependence of human-non-human relations, and (3) understanding complex urban environments through everyday activities. We conclude that the thriving of humans and non-humans in urban environments is important to children in Aotearoa New Zealand. We affirm that children have clear and salient ideas about health and health-promoting neighbourhoods.

Custom CARs: Leveraging the Adaptability of Allogeneic CAR Therapies to Address Current Challenges in Relapsed/Refractory DLBCL.

Cellular therapies have transformed the treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL), which typically does not respond well to salvage chemotherapy. Recently, approximately 40% of r/r DLBCL patients across three different trials achieved a complete remission at 1 year after receiving treatment with autologous chimeric antigen receptor (CAR) T cells (auto-CARs). These successes have prompted studies of auto-CARs in second-line settings, in which axicabtagene ciloleucel and lisocabtagene maraleucel both showed improved event-free survival over autologous hematopoietic cell transplantation (AHCT). While encouraging, this data also highlights that 60% of patients relapse or progress following treatment with auto-CARs. Individual disease characteristics and logistical challenges of cell engineering also limit patients' eligibility for auto-CARs. Allogeneic CAR T cells (allo-CARs) may address some of these limitations as they may mitigate delays associated with auto-CARs, thereby reducing the need for bridging chemotherapies and increasing availability of cellular products for patients with aggressive lymphomas. By being sourced from healthy donors who have never been exposed to cytotoxic chemotherapy, allo-CARs can be created from T cells with better fitness. Allo-CARs made from specific cellular subsets (e.g., stem cell memory or naïve/early memory T cells) may also have increased efficacy and long-term persistence. Additionally, allo-CARs have been successfully created from other cell types, including natural killer cells, gamma-delta T-cells and induced pluripotent stem cells. These cell types can be engineered to target viral antigens, enabling precision targeting of virally driven DLBCL. As allogeneic donor cells can be banked and cryopreserved in batches, they can be made more readily available, potentially reducing logistical hurdles and costs compared to engineering auto-CARs. This may ultimately create a more sustainable platform for cell therapies. Challenges with allo-CARs that will need to be addressed include graft versus host disease, alloimmunization, potentially decreased persistence relative to auto-CARs, and antigen escape. In short, the adaptability of allo-CARs makes them ideal for treating patients with r/r DLBCL who have progressed through standard chemotherapy, AHCT, or auto-CARs. Here, we review the published literature on patients with r/r DLBCL treated with allogeneic CAR products manufactured from various cell types as well as forthcoming allogeneic CAR technologies.

Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy.

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has led to unprecedented responses in patients with high-risk hematologic malignancies. However, up to 60% of patients still experience disease relapse and up to 80% of patients experience CAR-mediated toxicities, such as cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. We investigated the role of the intestinal microbiome on these outcomes in a multicenter study of patients with B cell lymphoma and leukemia. We found in a retrospective cohort (n = 228) that exposure to antibiotics, in particular piperacillin/tazobactam, meropenem and imipenem/cilastatin (P-I-M), in the 4 weeks before therapy was associated with worse survival and increased neurotoxicity. In stool samples from a prospective cohort of CAR T cell recipients (n = 48), the fecal microbiome was altered at baseline compared to healthy controls. Stool sample profiling by 16S ribosomal RNA and metagenomic shotgun sequencing revealed that clinical outcomes were associated with differences in specific bacterial taxa and metabolic pathways. Through both untargeted and hypothesis-driven analysis of 16S sequencing data, we identified species within the class Clostridia that were associated with day 100 complete response. We concluded that changes in the intestinal microbiome are associated with clinical outcomes after anti-CD19 CAR T cell therapy in patients with B cell malignancies.