Addressing Gaps in Our Understanding of the Epidemiology of Drowning at the Global, National, and Local Level

Introduction: The World Health Organization (WHO) estimates that there are at least 372,000 deaths by drowning each year, making drowning the third leading cause of unintentional injury death worldwide. Despite its global impact, drowning remains a neglected public health issue and relatively under-researched area. Objective: (1) To conduct a comprehensive epidemiological investigation and address gaps in our understanding of the drowning problem at the global, national, and local level; and (2) to provide policy-makers and advocates with comprehensive information to inform their drowning prevention efforts. Methods: This study involved retrospective reviews of five data sources: (1) global drowning data were extracted from the WHO mortality database for all countries that reported deaths using ICD-10 drowning codes; (2) data on non-fatal drowning victims who required hospital admission in Canada were obtained from the Canadian Institute for Health Information (CIHI)s Discharge Abstract Database; (3) data on non-fatal drowning victims who required an emergency department visit were obtained from CIHIs National Ambulatory Care Reporting System; (4) data on unintentional fatal drowning deaths in Canada were obtained from the Drowning Prevention Research Centre (DPRC) database; (5) data on child drowning fatalities in private backyard pools in Ontario were collected from the case files at the Office of the Chief Coroner for Ontario using a structured questionnaire. Results: The results presented in this dissertation can inform drowning prevention globally, nationally, and locally. Internationally, official data categorization methods contribute to an underestimation of the burden of fatal drowning. In Canada, fatal drowning is only part of the problem; non-fatal drowning presents a substantial burden and the characteristics of non-fatal drowning differ significantly from fatal drowning. Further, although bystander intervention plays an important role in the survival of a drowning person, non-professional bystanders often intervene with high-risk, contact rescues, or do not attempt a rescue at all. Finally, children who drown in private backyard pools in Ontario often access the pool directly from the residence, yet most municipalities have not enacted isolation fencing bylaws. Conclusion: Addressing gaps in epidemiological drowning research at the global, national, and local level revealed several recommendations for policy, prevention, and future research

Exploring the burden of fatal drowning and data characteristics in three high income countries: Australia, Canada and New Zealand

Background: Drowning is a leading and preventable cause of death that has suffered an attention deficit. Improving drowning data in countries would assist the understanding of the full extent and circumstances of drowning, to target interventions and evaluate their effectiveness. The World Health Organization identifies data collection as a key strategy underpinning effective interventions. This study compares unintentional fatal drowning data collection, management and comparison using the databases of Australia, Canada and New Zealand. Methods: Cases of fatal unintentional drowning between 1-January-2005 and 31-December-2014 were extracted. Cases were combined into a single dataset and univariate and chi square analysis (p < 0.01) were undertaken. Location and activity variables were mapped and combined. Variables consistently collected across the three countries were compared to the ILCOR Drowning Data Guideline. The authors also recommend variables for a minimum core dataset. Results: Of 55 total variables, 19 were consistent and 13 could be compared across the three databases. When mapped against the ILCOR Drowning Data Guideline, six variables were consistently collected by all countries, with five compared within this study. The authors recommend a minimum core dataset of 11 variables including age, sex, location, activity, date of incident, and alcohol and drug involvement). There were 8176 drowning deaths (Australia 34.1%, Canada 55.9%, New Zealand 9.9%). All countries achieved reductions in crude drowning rates (Australia - 10.2%, Canada - 20.4%, New Zealand - 24.7%). Location and activity prior to drowning differed significantly across the three countries. Beaches (X2 = 1151.0;p < 0.001) and ocean/harbour locations (X2 = 300.5;p < 0.001) were common in Australia and New Zealand, while lakes/ponds (X2 = 826.5;p < 0.001) and bathtubs (X2 = 27.7;p < 0.001) were common drowning locations in Canada. Boating prior to drowning was common in Canada (X2 = 66.3;p < 0.001). Conclusions: The comparison of data across the three countries was complex. Work was required to merge categories within the 20% of variables collected that were comparable, thus reducing the fidelity of data available. Data sources, collection and coding varied by country, with the widest diversity seen in location and activity variables. This study highlights the need for universally agreed and consistently applied categories and definitions to allow for global comparisons and proposes a core minimum dataset

World Conference on Drowning Prevention 2019, Durban, South Africa

No Abstract

Observation of an α-synuclein liquid droplet state and its maturation into Lewy body-like assemblies.

Misfolded α-synuclein is a major component of Lewy bodies, which are a hallmark of Parkinson's disease (PD). A large body of evidence shows that α-synuclein can aggregate into amyloid fibrils, but the relationship between α-synuclein self-assembly and Lewy body formation remains unclear. Here, we show, both in vitro and in a Caenorhabditis elegans model of PD, that α-synuclein undergoes liquid‒liquid phase separation by forming a liquid droplet state, which converts into an amyloid-rich hydrogel with Lewy-body-like properties. This maturation process towards the amyloid state is delayed in the presence of model synaptic vesicles in vitro. Taken together, these results suggest that the formation of Lewy bodies may be linked to the arrested maturation of α-synuclein condensates in the presence of lipids and other cellular components.Wellcome Trust (065807/Z/01/Z) (203249/Z/16/Z). Also, the UK Medical Research Council (MRC) (MR/K02292X/1), Alzheimer Research UK (ARUK) (ARUK-PG013-14), Michael J Fox Foundation (16238) and from Infinitus China Ltd

Observation of an α-synuclein liquid droplet state and its maturation into Lewy body-like assemblies.

Misfolded α-synuclein is a major component of Lewy bodies, which are a hallmark of Parkinson's disease (PD). A large body of evidence shows that α-synuclein can aggregate into amyloid fibrils, but the relationship between α-synuclein self-assembly and Lewy body formation remains unclear. Here, we show, both in vitro and in a Caenorhabditis elegans model of PD, that α-synuclein undergoes liquid‒liquid phase separation by forming a liquid droplet state, which converts into an amyloid-rich hydrogel with Lewy-body-like properties. This maturation process towards the amyloid state is delayed in the presence of model synaptic vesicles in vitro. Taken together, these results suggest that the formation of Lewy bodies may be linked to the arrested maturation of α-synuclein condensates in the presence of lipids and other cellular components.Wellcome Trust (065807/Z/01/Z) (203249/Z/16/Z). Also, the UK Medical Research Council (MRC) (MR/K02292X/1), Alzheimer Research UK (ARUK) (ARUK-PG013-14), Michael J Fox Foundation (16238) and from Infinitus China Ltd

Fast Fluorescence Lifetime Imaging Reveals the Aggregation Processes of α-Synuclein and Polyglutamine in Aging Caenorhabditis elegans.

The nematode worm Caenorhabditis elegans has emerged as an important model organism in the study of the molecular mechanisms of protein misfolding diseases associated with amyloid formation because of its small size, ease of genetic manipulation, and optical transparency. Obtaining a reliable and quantitative read-out of protein aggregation in this system, however, remains a challenge. To address this problem, we here present a fast time-gated fluorescence lifetime imaging (TG-FLIM) method and show that it provides functional insights into the process of protein aggregation in living animals by enabling the rapid characterization of different types of aggregates. Specifically, in longitudinal studies of C. elegans models of Parkinson's and Huntington's diseases, we observed marked differences in the aggregation kinetics and the nature of the protein inclusions formed by α-synuclein and polyglutamine. In particular, we found that α-synuclein inclusions do not display amyloid-like features until late in the life of the worms, whereas polyglutamine forms amyloid characteristics rapidly in early adulthood. Furthermore, we show that the TG-FLIM method is capable of imaging live and non-anaesthetized worms moving in specially designed agarose microchambers. Taken together, our results show that the TG-FLIM method enables high-throughput functional imaging of living C. elegans that can be used to study in vivo mechanisms of protein aggregation and that has the potential to aid the search for therapeutic modifiers of protein aggregation and toxicity

Increased winter drownings in ice-covered regions with warmer winters

Winter activities on ice are culturally important for many countries, yet they constitute a high safety risk depending upon the stability of the ice. Because consistently cold periods are required to form stable and thick ice, warmer winters could degrade ice conditions and increase the likelihood of falling through the ice. This study provides the first large-scale assessment of winter drowning from 10 Northern Hemisphere countries. We documented over 4000 winter drowning events. Winter drownings increased exponentially in regions with warmer winters when air temperatures neared 0 ̊C. The largest number of drownings occurred when winter air temperatures were between -5 ̊C and 0 ̊C, when ice is less stable, and also in regions where indigenous traditions and livelihood require extended time on ice. Rates of drowning were greatest late in the winter season when ice stability declines. Children and adults up to the age of 39 were at the highest risk of winter drownings. Beyond temperature, differences in cultures, regulations, and human behaviours can be important additional risk factors. Our findings indicate the potential for increased human mortality with warmer winter air temperatures. Incorporating drowning prevention plans would improve adaptation strategies to a changing climate.Funding was provided to SS by the Ontario Ministry of Research, Innovation and Science Early Researcher Award and York University Research Chair programme. Funding support for BAD was provided by Kempestiftelserna. AL was supported by Estonian Research Council Grant PSG 32. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Funding was provided to SS by the Ontario Ministry of Research, Innovation and Science Early Researcher Award and York University Research Chair programme. Funding support for BAD was provided by Kempestiftelserna. AL was supported by Estonian Research Council Grant PSG 32. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

MET-receptor targeted fluorescent imaging and spectroscopy to detect multifocal papillary thyroid cancer

Purpose: Multifocal disease in PTC is associated with an increased recurrence rate. Multifocal disease (MD) is underdiagnosed with the current gold standard of pre-operative ultrasound staging. Here, we evaluate the use of EMI-137 targeted molecular fluorescence-guided imaging (MFGI) and spectroscopy as a tool for the intra-operative detection of uni- and multifocal papillary thyroid cancer (PTC) aiming to improve disease staging and treatment selection. Methods: A phase-1 study (NCT03470259) with EMI-137 was conducted to evaluate the possibility of detecting PTC using MFGI and quantitative fiber-optic spectroscopy. Results: Fourteen patients underwent hemi- or total thyroidectomy (TTX) after administration of 0.09 mg/kg (n = 1), 0.13 mg/kg (n = 8), or 0.18 mg/kg (n = 5) EMI-137. Both MFGI and spectroscopy could differentiate PTC from healthy thyroid tissue after administration of EMI-137, which binds selectively to MET in PTC. 0.13 mg/kg was the lowest dosage EMI-137 that allowed for differentiation between PTC and healthy thyroid tissue. The smallest PTC focus detected by MFGI was 1.4 mm. MFGI restaged 80% of patients from unifocal to multifocal PTC compared to ultrasound. Conclusion: EMI-137-guided MFGI and spectroscopy can be used to detect multifocal PTC. This may improve disease staging and treatment selection between hemi- and total thyroidectomy by better differentiation between unifocal and multifocal disease. Trial registration: NCT03470259.</p

Intraoperative MET-receptor targeted fluorescent imaging and spectroscopy for lymph node detection in papillary thyroid cancer:novel diagnostic tools for more selective central lymph node compartment dissection

PURPOSE: Patients undergoing prophylactic central compartment dissection (PCLND) for papillary thyroid cancer (PTC) are often overtreated. This study aimed to determine if molecular fluorescence-guided imaging (MFGI) and spectroscopy can be useful for detecting PTC nodal metastases (NM) and to identify negative central compartments intraoperatively. METHODS: We used a data-driven prioritization strategy based on transcriptomic profiles of 97 primary PTCs and 80 normal thyroid tissues (NTT) to identify tumor-specific antigens for a clinically available near-infrared fluorescent tracer. Protein expression of the top prioritized antigen was immunohistochemically validated with a tissue microarray containing primary PTC (n = 741) and NTT (n = 108). Staining intensity was correlated with 10-year locoregional recurrence-free survival (LRFS). A phase 1 study (NCT03470259) with EMI-137, targeting MET, was conducted to evaluate safety, optimal dosage for detecting PTC NM with MFGI, feasibility of NM detection with quantitative fiber-optic spectroscopy, and selective binding of EMI-137 for MET. RESULTS: MET was selected as the most promising antigen. A worse LRFS was observed in patients with positive versus negative MET staining (81.9% versus 93.2%; p = 0.02). In 19 patients, no adverse events related to EMI-137 occurred. 0.13 mg/kg EMI-137 was selected as optimal dosage for differentiating NM from normal lymph nodes using MFGI (p < 0.0001) and spectroscopy (p < 0.0001). MFGI identified 5/19 levels (26.3%) without NM. EMI-137 binds selectively to MET. CONCLUSION: MET is overexpressed in PTC and associated with increased locoregional recurrence rates. Perioperative administration of EMI-137 is safe and facilitates NM detection using MFGI and spectroscopy, potentially reducing the number of negative PCLNDs with more than 25%. CLINICAL TRIAL REGISTRATION: NCT03470259