Next steps for drowning prevention in rural and remote Australia: A systematic review of the literature.

OBJECTIVE: To examine unintentional drowning by remoteness in Australia. DESIGN: A systematic review of both peer-reviewed and grey literature published between January 1990 and December 2019 (inclusive). METHOD: Using Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, MEDLINE (Ovid), PubMed, EMBASE, Scopus, PsycINFO (ProQuest), SPORTDiscus and Google Scholar were searched for studies exploring fatal and non-fatal unintentional drowning by remoteness. Epidemiological data, common factors and prevention strategies were extracted and mapped to Australian standard geographical classifications (major cities, inner regional, outer regional, remote and very remote). Level of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation and prevention strategies aligned to the hierarchy of control. RESULT: Thirty-two studies satisfied inclusion criteria (66% reporting epidemiology; 59% risk factors; and 44% prevention strategies). All (100%) included studies were assessed very low against Grading of Recommendations Assessment, Development and Evaluation. Findings indicate rural populations (ie, excluding major cities) have higher rates of drowning positively correlated with increasing remoteness. Common factors included age (child), natural water bodies, undertaking boating and watercraft activities and alcohol consumption. While a range of prevention strategies has been proposed, only one study outlined a rural drowning prevention strategy which had been implemented and evaluated. Strategies were generally low on the hierarchy of control. CONCLUSION: Rural populations are proportionately overrepresented in drowning statistics. Proposed prevention strategies have unknown efficacy. Greater research into rural drowning of Australians is needed especially exploring behavioural motivations, program delivery, cost-effectiveness and evaluation. Development and use of a standard definition for remoteness are recommended. Rural populations use water extensively; therefore, there is an urgent need to keep them safe.

Pre-Existing Medical Conditions: A Systematic Literature Review of a Silent Contributor to Adult Drowning.

Medical conditions can increase drowning risk. No prior study has systematically reviewed the published evidence globally regarding medical conditions and drowning risk for adults. MEDLINE (Ovid), PubMed, EMBASE, Scopus, PsycINFO (ProQuest) and SPORTDiscus databases were searched for original research published between 1 January 2005 and 31 October 2021 that reported adult (≥15 years) fatal or non-fatal drowning of all intents and pre-existing medical conditions. Conditions were grouped into the relevant International Classifications of Diseases (ICD) codes. Eighty-three studies were included (85.5% high-income countries; 38.6% East Asia and Pacific region; 75.9% evidence level III-3). Diseases of the nervous system (n = 32 studies; 38.6%), mental and behavioural conditions (n = 31; 37.3%) and diseases of the circulatory system (n = 25; 30.1%) were the most common categories of conditions. Epilepsy was found to increase the relative risk of drowning by 3.8 to 82 times, with suggested preventive approaches regarding supervised bathing or showering. Drowning is a common suicide method for those with schizophrenia, psychotic disorders and dementia. Review findings indicate people with pre-existing medical conditions drown, yet relatively few studies have documented the risk. There is a need for further population-level research to more accurately quantify drowning risk for pre-existing medical conditions in adults, as well as implementing and evaluating population-level attributable risk and prevention strategies.

Paediatric Strategy Forum for medicinal product development of chimeric antigen receptor T-cells in children and adolescents with cancer: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

The seventh multi-stakeholder Paediatric Strategy Forum focused on chimeric antigen receptor (CAR) T-cells for children and adolescents with cancer. The development of CAR T-cells for patients with haematological malignancies, especially B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), has been spectacular. However, currently, there are scientific, clinical and logistical challenges for use of CAR T-cells in BCP-ALL and other paediatric malignancies, particularly in acute myeloid leukaemia (AML), lymphomas and solid tumours. The aims of the Forum were to summarise the current landscape of CAR T-cell therapy development in paediatrics, too identify current challenges and future directions, with consideration of other immune effector modalities and ascertain the best strategies to accelerate their development and availability to children. Although the effect is of limited duration in about half of the patients, anti-CD19 CAR T-cells produce high response rates in relapsed/refractory BCP-ALL and this has highlighted previously unknown mechanisms of relapse. CAR T-cell treatment as first- or second-line therapy could also potentially benefit patients whose disease has high-risk features associated with relapse and failure of conventional therapies. Identifying patients with very early and early relapse in whom CAR T-cell therapy may replace haematopoietic stem cell transplantation and be definitive therapy versus those in whom it provides a more effective bridge to haematopoietic stem cell transplantation is a very high priority. Development of approaches to improve persistence, either by improving T cell fitness or using more humanised/fully humanised products and co-targeting of multiple antigens to prevent antigen escape, could potentially further optimise therapy. Many differences exist between paediatric B-cell non-Hodgkin lymphomas (B-NHL) and BCP-ALL. In view of the very small patient numbers with relapsed lymphoma, careful prioritisation is needed to evaluate CAR T-cells in children with Burkitt lymphoma, primary mediastinal B cell lymphoma and other NHL subtypes. Combination trials of alternative targets to CD19 (CD20 or CD22) should also be explored as a priority to improve efficacy in this population. Development of CD30 CAR T-cell immunotherapy strategies in patients with relapsed/refractory Hodgkin lymphoma will likely be most efficiently accomplished by joint paediatric and adult trials. CAR T-cell approaches are early in development for AML and T-ALL, given the unique challenges of successful immunotherapy actualisation in these diseases. At this time, CD33 and CD123 appear to be the most universal targets in AML and CD7 in T-ALL. The results of ongoing or planned first-in-human studies are required to facilitate further understanding. There are promising early results in solid tumours, particularly with GD2 targeting cell therapies in neuroblastoma and central nervous system gliomas that represent significant unmet clinical needs. Further understanding of biology is critical to success. The comparative benefits of autologous versus allogeneic CAR T-cells, T-cells engineered with T cell receptors T-cells engineered with T cell receptor fusion constructs, CAR Natural Killer (NK)-cell products, bispecific T-cell engager antibodies and antibody-drug conjugates require evaluation in paediatric malignancies. Early and proactive academia and multi-company engagement are mandatory to advance cellular immunotherapies in paediatric oncology. Regulatory advice should be sought very early in the design and preparation of clinical trials of innovative medicines, for which regulatory approval may ultimately be sought. Aligning strategic, scientific, regulatory, health technology and funding requirements from the inception of a clinical trial is especially important as these are very expensive therapies. The model for drug development for cell therapy in paediatric oncology could also involve a 'later stage handoff' to industry after early development in academic hands. Finally, and very importantly, strategies must evolve to ensure appropriate ease of access for children who need and could potentially benefit from these therapies.