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Increased COVID-19-related morbidity and mortality have been reported in solid organ transplant recipients (SOTRs). Most studies are underpowered for rigorous matching. We report infections, hospitalization, ICU care, mortality from COVID-19, and pertinent vaccination data in Swedish SOTRs 2020-2021. We conducted a nationwide cohort study, encompassing all Swedish residents. SOTRs were identified with ICD-10 codes and immunosuppressant prescriptions. Comparison cohorts were weighted based on a propensity score built from potential confounders (age, sex, comorbidities, socioeconomic factors, and geography), which achieved a good balance between SOTRs and non-SOTR groups. We included 10,372,033 individuals, including 9073 SOTRs. Of the SARS-CoV-2 infected, 47.3% of SOTRs and 19% of weighted comparator individuals were hospitalized. ICU care was given to 8% of infected SOTRs and 2% of weighted comparators. The case fatality rate was 7.7% in SOTRs, 6.2% in the weighted comparison cohort, and 1.3% in the unweighted comparison cohort. SOTRs had an increased risk of contracting COVID-19 (HR = 1.15 p < 0.001), being hospitalized (HR = 2.89 p < 0.001), receiving ICU care (HR = 4.59 p < 0.001), and dying (HR = 1.42 p < 0.001). SOTRs had much higher morbidity and mortality than the general population during 2020-2021. Also compared with weighted comparators, SOTRs had an increased risk of contracting COVID-19, being hospitalized, receiving ICU care, and dying. In Sweden, SOTRs were vaccinated earlier than weighted comparators. Lung transplant recipients had the worst outcomes. Excess mortality among SOTRs was concentrated in the second half of 2021.

Objectives: To explore the National Fatality Review Case Reporting System (NFR-CRS) as a new data source to (1) characterize pediatric vehicular heatstroke (PVH) deaths among children <15 years of age reviewed by Child Death Review teams, and (2) identify factors independently associated with common PVH scenarios and incident locations., Methods: Data for 2005-2019 were used to characterize 296 PVH deaths. Frequencies and percentages were calculated to describe child, supervisor, and incident characteristics. Multiple logistic regression with and without imputation were carried out to identify factors associated with the two outcomes of interest: PVH scenario (left in vehicle vs. gained access) and incident place (supervisor workplace vs. other locations). Odds ratios and 95% confidence intervals (OR, 95% CI) were calculated., Results: Most children had been left unattended in vehicles ( N  = 225, 76.0%) and 13.5% ( N  = 40) had gained access independently. Children were most often male ( N  = 168, 56.8%), non-Hispanic White ( N  = 131, 44.3%), and <2 years of age ( N  = 172, 58.1%). Disability or chronic illness was noted for 4.7% ( N  = 14), 13.9% ( N  = 41) had a history of maltreatment, and 6.1% ( N  = 18) an open CPS case at the time of incident. Children left unattended were more likely to be <2 years of age (adjusted imputed OR 26.7, CI 7.3-97.2) and less likely to have an open CPS case (0.2, 0.0-0.4) and for the incident to occur at home (0.2, 0.1-0.9) compared to children who gained access. PVH deaths occurring at the supervisor's workplace were more likely to be <2 years of age (6.2, 2.4-15.8), to have occurred on a weekday (5.9, 1.7-20.9), and to have been supervised by their parent at the incident time (2.7, 1.1-6.7) compared to other locations., Conclusions: The results align with previous PVH findings and added new information on child race/ethnicity, CPS action, disability/chronic illness, and maltreatment. With the exception of parents being more likely to be the supervisor in incidents occurring at home, which was expected, neither supervisor characteristics nor child race/ethnicity or sex were independently significant in multiple regression, suggesting that PVH is pervasive and that education campaigns should be similarly broad.

Neutrophils act as critical mediators of innate immunity, which depends on their rapid responses to chemokines followed by their migration towards sites of infection during chemotaxis. Chemokine receptors expressed on the surface of neutrophils mediate chemotaxis by activating contractile machinery as the cells escape from capillary beds and then attack pathogens. Neutrophils also contribute to inflammatory responses, which support pathogen destruction but can lead to acute and chronic inflammatory disorders. CXCR2, a G-protein-coupled chemokine receptor expressed on both myeloid and epithelial cells, is well-characterized for its capacities to bind multiple chemokines, including interleukin-8 and growth-related oncogene alpha in humans or keratinocyte chemokine (KC) in mice. Here we show that a small molecule CXCR2 antagonist termed RIST4721 can effectively inhibit KC-stimulated chemotaxis by neutrophils derived from ex vivo-cultured mouse bone marrow in a potent and dose-dependent manner. Antagonistic properties of RIST4721 are thoroughly characterized, including the maximal, half-maximal and minimum concentrations required to inhibit chemotaxis. Importantly, RIST4721-treated neutrophils exhibit robust phagocytosis and reactive oxygen species production, confirming drug specificity to chemotaxis inhibition. Together our data indicate that RIST4721 acts to inhibit inflammation mediated and potentiated by neutrophils and therefore promises to facilitate treatment of a host of inflammatory conditions.

Objectives: To describe the epidemiology of battery-related emergency department (ED) visits among children aged <18 years in the United States from 2010 to 2019 and compare with previous study findings., Methods: Data on ED visits were obtained from the National Electronic Injury Surveillance System. Using narrative descriptions and diagnosis codes, battery-related cases were coded into four exposure routes: (1) ingestion, (2) mouth exposure, (3) ear insertion, and (4) nasal insertion., Results: An estimated 70 322 (95% confidence interval: 51 275-89 369) battery-related ED visits among children aged <18 years occurred during the study period, or 9.5 per 100 000 children annually. Button batteries were implicated in 84.7% of visits where battery type was described. A statistically significant increase in the ED visit rate occurred from 2010 to 2017 (P = .03), followed by a nonstatistically significant decrease from 2017 to 2019. The ED visit rate was highest among children aged ≤5 years compared with those 6 to 17 years (24.5 and 2.2 per 100 000 children, respectively). The mean patient age was 3.2 years (95% confidence interval: 2.9-3.4). Ingestions accounted for 90.0% of ED visits, followed by nasal insertions (5.7%), ear insertions (2.5%), and mouth exposures (1.8%)., Conclusions: Pediatric battery-related ED visit rates continued to significantly increase from 2010 to 2017, with children aged ≤5 years having the highest rates. Prevention efforts have not significantly reduced injury rates; therefore, regulatory efforts are needed. Ultimately, hazard reduction or elimination through safer button battery design is critical and should be adopted by the battery industry., (Copyright © 2022 by the American Academy of Pediatrics.)

Background: Due to organ shortage, many patients do not receive donor organs. The present novel thrombolytic technique utilizes organs from donors with uncontrolled donation after circulatory deaths (uDCD), with up to 4-5 h warm ischemia, without advanced cardiopulmonary resuscitation (aCPR) or extracorporeal circulation (EC) after death., Methods: The study group of pigs (n = 21) underwent simulated circulatory death. After 2 h, an ice slush was inserted into the abdomen. Kidneys were retrieved 4.5 h after death. Lys-plasminogen, antithrombin-III (ATIII), and alteplase (tPA) were injected through the renal arteries on the back table. Subsequent ex vivo perfusion at 15 °C was continued for 3 h, followed by 3 h with red blood cells (RBCs) at 32 °C. Perfusion outcome and histology were compared between uDCD kidneys, receiving no thrombolytic treatment (n = 8), and live donor kidneys (n = 7). The study kidneys were then transplanted into pigs as autologous grafts with a single functioning autologous kidney as the only renal support. uDCD control pigs (n = 8), receiving no ex vivo perfusion, served as controls., Results: Vascular resistance decreased to <200 mmHg/mL/min ( P < 0.0023) and arterial flow increased to >100 mL/100 g/min ( P < 0.00019) compared to controls. In total 13/21 study pigs survived for >10 days, while all uDCD control pigs died. Histology was preserved after reconditioning, and the creatinine level after 10 days was next to normal., Conclusions: Kidneys from extended uDCD, not receiving aCPR/EC, can be salvaged using thrombolytic treatment to remove fibrin thrombi while preserving histology and enabling transplantation with a clinically acceptable early function., Competing Interests: M.O. is the inventor of several patents within the field of transplantation. The other authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

For many decades, the international tobacco industry has set its sights on Asia, due to the large population numbers, the high prevalence of male smokers who might shift to its brands, and the extremely low number of female smokers who could possibly be induced into starting smoking. Because of US trade threats against several Asian countries in the 1980s, Asia became quickly aware that tobacco control involved politics, legislation, economics and trade. Several Asian jurisdictions pioneered tobacco control measures, and the Western Pacific is still the only WHO region where all countries have ratified the WHO Framework Convention on Tobacco Control (FCTC). Progress needs to be accelerated to reduce the still high male smoking prevalence and maintain the low female prevalence by fully implementing the WHO FCTC as part of achieving sustainable development, even while grappling with the looming epidemic of new products, holding the companies accountable, and protecting tobacco control policies against constant industry interference., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Although it is known that solid organ transplant recipients fare worse after COVID-19 infection, data on the impact of COVID-19 on clinical outcomes and allograft function in lung transplant (LTx) recipients are limited and based mainly on reports with short follow-up. In this nationwide study, all LTx recipients with COVID-19 diagnosed from 1 February 2020 to 30 April 2021 were included. The patients were followed until 1 August 2021 or death. We analysed demographics, clinical features, therapeutic management and outcomes, including lung function. Forty-seven patients were identified: median age was 59 (10-78) years, 53.1% were male, and median follow-up was 194 (23-509) days. COVID-19 was asymptomatic or mild at presentation in 48.9%. Nine patients (19.1%) were vaccinated pre-COVID infection. Two patients (4.3%) died within 28 days of testing positive, and the overall survival rate was 85.1%. The patients with asymptomatic or mild symptoms had a higher median % expected forced expiratory volume during the first second than the patients with worse symptoms (P = 0.004). LTx recipients develop the entire spectrum of COVID-19, and in addition to previously acknowledged risk factors, lower pre-COVID lung function was associated with more severe disease presentation., (© 2021 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)

Background: Solid organ transplant (SOT) recipients may be more vulnerable to coronavirus disease 2019 (COVID-19). Data on the clinical course of COVID-19 in immunosuppressed patients are limited, and the optimal management strategy for these patients is yet unclear., Methods: We present 53 SOT recipients (31 kidney transplant recipients, 8 liver transplant recipients, 5 heart transplant recipients, 5 lung transplant recipients, 3 liver-kidney transplant recipients, and 1 kidney-after-heart transplant recipient), transplanted at a Swedish high-volume transplant center and each diagnosed with COVID-19 between February 21, 2020 and June 22, 2020. Demographic, clinical, and treatment data were extracted from the electronic patient files., Results: Patients reported fever (61%), cough (43%), diarrhea (31%), and upper respiratory symptoms (29%). The median age was 56 years, and 57% were male. According to severity, 55% had mild, 13% had moderate, 19% had severe, and 13% had critical disease. Thirty-seven patients (70%) were hospitalized, with 8 requiring intensive care. Thirteen of the 37 patients were initially managed as outpatients but later hospitalized. One patient received hydroxychloroquine, and no patients received antivirals. Antimetabolites and calcineurin inhibitors were held or reduced in two-thirds. Twenty-seven of 37 hospitalized patients (73%) received low-molecular-weight heparin. Five (13.5%) hospitalized patients died. Overall survival for the entire cohort was 90.5%. No rejection episodes were noted., Conclusions: Hospitalization, lowering of immunosuppression, and prophylactic anticoagulation were the most common therapeutic interventions for SOT recipients with COVID-19. A significant proportion of patients could be managed on an outpatient basis, while keeping a low threshold for admission. Mild and moderate disease forms seem to have a good outcome., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Coronavirus disease 2019 (COVID-19) ranges from a mild illness to acute respiratory distress syndrome (ARDS), multiorgan dysfunction, and death. Transplant recipients are vulnerable due to comorbidities and immunosuppressants that render them susceptible to infections. The information on COVID-19 in kidney transplant recipients remains limited to small case series., Methods: A systematic literature search was conducted, and 12 case series totalling 204 kidney transplant recipients with COVID-19 were identified. Data were extracted, pooled and analysed., Results: Most patients (74%) were men. The most frequent symptoms were fever (76%), cough (64%) and dyspnoea (43%). At admission, over 70% of the patients had abnormal radiological findings. Leukocyte counts were in the lower normal range. C-reactive protein, ferritin, and D-dimer were consistently increased. Treatments included lowering immunosuppression, hydroxychloroquine, antivirals, tocilizumab and intravenous immunoglobulins. Thirty-one percent of the patients were admitted to intensive care units (ICUs), and 16% required intubation. The overall mortality was 21.2%. Patients who died were significantly older than those who survived (61 ± 12 vs. 51 ± 15, p  < .01). Logistic regression revealed that the odds for death increased by 4.3% for each additional year of age (odds ratio [OR] 1.043, 95% confidence interval [CI] 1.005-1.083, p value = .0265)., Conclusions: No substantial conclusions could be drawn on the efficacy of any particular treatment. More rigorous patient stratification is needed when analysing and reporting data to facilitate future meta-analyses.

Background: Motor vehicle crashes are the third-leading cause of death to American children aged 1-5 years. When installed correctly, child restraints (car seats) reduce risk of serious injury and death. However, most restraints are installed incorrectly. The current gold standard for correct installation is systematic car seat checks, where certified technicians help parents, but car seat checks are highly underused due to barriers in access, scheduling and resources., Methods: The present study protocol describes plans to evaluate use of interactive virtual presence technology (interactive merged reality)-joint, simultaneous remote verbal and visual interaction and exposure to the same 3D stimuli-to assist remotely located parents installing child restraints. If effective, this technology could supplement or replace in-person checks and revolutionise how government, industry and non-profits help parents install child restraints properly. Building from preliminary studies, we propose a randomised non-inferiority trial to evaluate whether parents who install child restraints while communicating with remote expert technicians via interactive virtual presence on their smartphones achieve installations and learning not inferior in safety to parents who install restraints with on-site technicians. We will randomly assign 1476 caregivers at 7 US sites to install child restraints either via interactive virtual presence or live technicians. Correctness of installation will be assessed using objective checklists, both following installation and again 4 months later., Conclusion: We aim to demonstrate that child restraint installation is accurate (>90% correct) when conducted remotely, that such installations are not inferior to installation accuracy with live experts and that parents learn and retain information about child restraint installation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Organs from older donors are believed to withstand ischemia worse than those from younger donors. The effect of age on the development of intestinal preservation injury (IPI) is unclear., Methods: We compared the development of IPI in intestines from young (3 mo), adult (14 mo), and old (20 mo) rat donors and assessed if luminal preservation (LP) is effective in delaying IPI. Small intestines were perfused with, and stored in, preservation solution (Custodiol) with or without LP solution (polyethylene glycol 3350). IPI was studied using histology (Chiu score, Alcian blue staining), Western blot, and electrophysiological assessment (Ussing chamber) at 4, 8, and 14 hours., Results: Intestines of old rats did not show major histological alterations, whereas their aortas and kidneys revealed typical age-related changes (arteriosclerosis and glomerulosclerosis). Intestines from old rats fared similarly to their younger counterparts at all time points regarding preservation injury and goblet cells count. Intestines undergoing LP showed fewer histological signs of damage and higher goblet cells count when compared with samples without LP, regardless of donor age. Ussing chamber experiments indicated a time-dependent deterioration of all parameters studied, which was delayed by the use of LP., Conclusions: Older intestines did not convincingly demonstrate a faster IPI compared with intestines from adult and young donors. The small differences between the age groups were nullified by the use of LP. LP significantly delayed the IPI in all age groups and may allow for longer preservation periods without an increased risk of mucosal damage.

Objectives: Evidence that health interventions work is not enough to ensure implementation into policy and practice. The complexity of public health systems requires more diverse actions. This paper proposes a conceptual model to enhance understanding of interlinking factors that influence the evidence implementation process., Methods: A literature review was conducted to explore factors that influence the process of evidence implementation in complex public health systems, including research findings and observations from 32 case studies of injury prevention interventions underway in 24 countries and results from evidence research networks. Concepts and themes identified through a critical review were organised, ordered and interlinked to build the model., Results: An Evidence Implementation Model for Public Health Systems and four concepts or themes: Evidence implementation target; Actors involved in implementation; Knowledge transfer; and Barriers and facilitators to evidence implementation were developed to provide a simplified, yet broad framework that highlights multiple factors and back and forth inter-linkages within and between the concepts that influence the uptake of evidence into public health systems policy and practice., Conclusions: Understanding the factors discussed within and amongst the four concepts of this model should ultimately help to positively influence the uptake of evidence into real world public health systems. This model has relevance for decision makers, researchers, knowledge brokers, and implementers.

In this ecological study, we attempt to quantify the extent to which differences in homicide and suicide death rates between three countries, and among states/provinces within those countries, may be explained by differences in their social, economic, and structural characteristics. We examine the relationship between state/province level measures of societal risk factors and state/province level rates of violent death (homicide and suicide) across Australia, Canada, and the United States. Census and mortality data from each of these three countries were used. Rates of societal level characteristics were assessed and included residential instability, self-employment, income inequality, gender economic inequity, economic stress, alcohol outlet density, and employment opportunities). Residential instability, self-employment, and income inequality were associated with rates of both homicide and suicide and gender economic inequity was associated with rates of suicide only. This study opens lines of inquiry around what contributes to the overall burden of violence-related injuries in societies and provides preliminary findings on potential societal characteristics that are associated with differences in injury and violence rates across populations.

Advanced preservation injury (PI) after intestinal transplantation has deleterious short- and long-term effects and constitutes a major research topic. Logistics and costs favor rodent studies, whereas clinical translation mandates studies in larger animals or using human material. Despite diverging reports, no direct comparison between the development of intestinal PI in rats, pigs, and humans is available. We compared the development of PI in rat, porcine, and human intestines. Intestinal procurement and cold storage (CS) using histidine-tryptophan-ketoglutarate solution was performed in rats, pigs, and humans. Tissue samples were obtained after 8, 14, and 24 h of CS), and PI was assessed morphologically and at the molecular level (cleaved caspase-3, zonula occludens, claudin-3 and 4, tricellulin, occludin, cytokeratin-8) using immunohistochemistry and Western blot. Intestinal PI developed slower in pigs compared to rats and humans. Tissue injury and apoptosis were significantly higher in rats. Tight junction proteins showed quantitative and qualitative changes differing between species. Significant interspecies differences exist between rats, pigs, and humans regarding intestinal PI progression at tissue and molecular levels. These differences should be taken into account both with regards to study design and the interpretation of findings when relating them to the clinical setting.

Unintentional injury remains an important global public health issue, and efforts to address it are often hampered by a lack of visibility, leadership, funding, infrastructure, capacity and evidence of effective solutions. The growing support for a socioecological model and a systems approach to prevention-along with the acknowledgement that injury prevention can be a byproduct of salutogenic design and activities-has increased opportunities to integrate unintentional injury prevention into other health promotion and disease prevention agendas. It has also helped to integrate it into the broader human development agenda through the Sustainable Development Goals. This growing support provides new opportunities to use a human rights-based approach to address the issue. The human rights-based approach is based on the idea that all members of society have social, economic and cultural rights and that governments are responsible and accountable for upholding those rights. It incorporates a systems approach, addresses inequity and places an emphasis on the most vulnerable corners of humanity. It also leverages legal statutes and provides organisations with the opportunity to build existing international goals and benchmarks into their monitoring efforts. This paper describes the approach and highlights how it can leverage attention and investment to address current challenges for unintentional injury., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Over the past decade, evidence has accumulated to suggest that bisexual people experience higher rates of poor mental health outcomes compared to both heterosexual and gay/lesbian individuals. However, no previous meta-analyses have been conducted to establish the magnitude of these disparities. To address this research gap, we conducted a systematic review and meta-analysis of studies that reported bisexual-specific data on standardized measures of depression or anxiety. Of the 1,074 full-text articles reviewed, 1,023 were ineligible, predominantly because they did not report separate data for bisexual people (n = 562 studies). Ultimately, 52 eligible studies could be pooled in the analysis. Results indicate that across both outcomes, there is a consistent pattern of lowest rates of depression and anxiety among heterosexual people, while bisexual people exhibit higher or equivalent rates in comparison to lesbian/gay people. On the basis of empirical and theoretical literature, we propose three interrelated contributors to these disparities: experiences of sexual orientation-based discrimination, bisexual invisibility/erasure, and lack of bisexual-affirmative support. Implications for interventions to improve the health and well-being of bisexual people are proposed.

Objectives: The aim of this study was to highlight the differences in injury rates between populations through a descriptive epidemiological study of population-level trends in injury mortality for the high-income countries of Australia, Canada and the United States., Methods: Mortality data were available for the US from 2000 to 2014, and for Canada and Australia from 2000 to 2012. Injury causes were defined using the International Classification of Diseases, Tenth Revision external cause codes, and were grouped into major causes. Rates were direct-method age-adjusted using the US 2000 projected population as the standard age distribution., Results: US motor vehicle injury mortality rates declined from 2000 to 2014 but remained markedly higher than those of Australia or Canada. In all three countries, fall injury mortality rates increased from 2000 to 2014. US homicide mortality rates declined, but remained higher than those of Australia and Canada. While the US had the lowest suicide rate in 2000, it increased by 24% during 2000-2014, and by 2012 was about 14% higher than that in Australia and Canada. The poisoning mortality rate in the US increased dramatically from 2000 to 2014., Conclusion: Results show marked differences and striking similarities in injury mortality between the countries and within countries over time. The observed trends differed by injury cause category. The substantial differences in injury rates between similarly resourced populations raises important questions about the role of societal-level factors as underlying causes of the differential distribution of injury in our communities.

The efficiency and effectiveness of child safety interventions are determined by the quality of the implementation process. This multinational European study aimed to identify facilitators and barriers for the three phases of implementation: adoption, implementation and monitoring (AIM process). Twenty-seven participants from across the WHO European Region were invited to provide case studies of child safety interventions from their country. Cases were selected by the authors to ensure broad coverage of injury issues, age groups and governance level of implementation (eg, national, regional or local). Each participant presented their case and provided a written account according to a standardised template. Presentations and question and answer sessions were recorded. The presentation slides, written accounts and the notes taken during the workshops were analysed using thematic content analysis to elicit facilitators and barriers. Twenty-six cases (from 26 different countries) were presented and analysed. Facilitators and barriers were identified within eight general themes, applicable across the AIM process: management and collaboration; resources; leadership; nature of the intervention; political, social and cultural environment; visibility; nature of the injury problem and analysis and interpretation. The importance of the quality of the implementation process for intervention effectiveness, coupled with limited resources for child safety makes it more difficult to achieve successful actions. The findings of this study, divided by phase of the AIM process, provide practitioners with practical suggestions, where proactive planning might help increase the likelihood of effective implementation., Competing Interests: Competing interests: None., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Mortality and morbidity rates, traditionally used indicators for child injury, are limited in their ability to explain differences in child injury between countries, are inadequate in capturing actions to address the problem of child injury and do not adequately identify progress made within countries. There is a need for a broader set of indicators to help better understand the success of countries with low rates of child injury, provide guidance and benchmarks for policy makers looking to make investments to reduce their rates of fatal and non-fatal child injury and allow monitoring of progress towards achieving these goals. This article describes an assessment of national leadership, infrastructure and capacity in the context of child injury prevention in 18 countries in Europe and explores the potential of these to be used as additional indicators to support child injury prevention practice., Methods: Partners in 18 countries coordinated data collection on 21 items relating to leadership, infrastructure and capacity. Responses were coded into an overall score and scores for each of the three areas and were compared with child injury mortality rankings using Spearman's rank correlation., Results: Overall score and scores for leadership and capacity were significantly negatively correlated to child injury mortality ranking., Conclusions: Findings of this preliminary work suggest that these three policy areas may provide important guidance for the types of commitments that are needed in the policy arena to support advances in child safety and their assessment a way to measure progress.

There is considerable confusion about the nature of indicators, their use in the injury field and surprisingly little discussion about these important tools. To date discussions of injury indicators have focused on the content and presentation of health outcome measures and on the dearth of data on exposure measures. Whereas these are valuable measures and assessing the optimal use of available routinely collected data in forming indicators is important, they do not provide sufficient information to support comprehensive prevention efforts, nor do they harness the full potential of indicators as tools to support prevention efforts. This paper provides an overview of the characteristics and uses of indicators for the field of injury prevention in order to make the case for action indicators and provide a framework for their appropriate use.

The focus on evidence-based practice is critical to addressing the issue of injuries, yet advances in the science of injury prevention have not always led to advances in practice. Effective approaches are not always adopted, or when adopted and transferred from one setting to another, they do not always achieve expected results. These challenges were the basis of two breakout sessions at the second European Injury Control and Safety Promotion Conference in Paris, France (October 2008). In summarising the key issues raised during those sessions, this article describes what is meant by evidence-based practice, discusses why evidence-based practice tends not to occur and considers approaches that may facilitate the adoption and implementation of evidence-based strategies. To address the challenge, specific action is required, both on the part of the research community and those responsible for developing and implementing injury prevention policies and programmes.

Background: The aim of this study was to determine if local recurrence (LR) rates in patients with minimally invasive and advanced T3 rectal cancer are different. This may influence the use of adjuvant therapy., Methods: Consecutive patients with T3 rectal cancer undergoing curative surgery were classified into minimally invasive or advanced groups. Minimally invasive T3 was defined as a tumour that had invaded beyond the muscularis propria on microscopic examination only, whereas advanced T3 tumours had invasion beyond the muscularis propria that was obvious on macroscopic examination and confirmed histologically. Local recurrence rates of the two groups were compared by construction of Kaplan-Meier curves. The log-rank test was used to determine equivalence, and Cox regression to estimate the hazard ratio. The Grambsch- Therneau test and graphical comparison of predicted and observed Kaplan-Meier curves was used to test the proportional hazards assumption., Results: There were 222 patients in total, 74 in the minimally invasive group and 148 in the advanced. The overall LR rate was 11.2%. The LR rates in the minimally invasive and advanced groups were 5.4% and 14.2%, respectively. The log-rank test gives a P value of 0.042 for equivalence, with the minimally invasive patients doing significantly better. The hazard ratio estimated by Cox regression was 0.35 (early relative to advanced), 95% confidence intervals (0.12, 1.0). There was no evidence of confounding by age at surgery, pathology type, gender or postoperative adjuvant therapy., Conclusions: The extent of invasion into the mesorectum appears to be an independent prognostic variable. If oncologically sound surgical techniques are employed, the LR rate of patients with minimal invasion is low. Adjuvant therapy may not confer additional benefit in this group.

Community-based interventions offer a promising solution for reducing child and adolescent unintentional injuries. By focusing on altering behavior, promoting environmental change within the community, or passing and enforcing legislation, these interventions seek to change social norms about acceptable safety behaviors. This article systematically reviews 32 studies that evaluated the impact of community-based injury prevention efforts on childhood injuries, safety behaviors, and the adoption of safety devices. Interventions targeted schools, municipalities, and cities. Most relied on an educational approach, sometimes in combination with legislation or subsidies, to reduce the cost of safety devices such as bicycle helmets. Results indicate that community-based approaches are effective at increasing some safety practices, such as bicycle helmet use and car seat use among children. The evidence is less compelling that such interventions increase child pedestrian safety, increase adolescent vehicle safety by reducing drinking and driving behaviors, or reduce rates of several categories of childhood injuries. Strong evidence supporting the effectiveness of community-based interventions is lacking, in part because few studies used randomized controlled designs or examined injury rates among children and youths as outcome measures. Nonetheless, this review identifies common elements of successful community-based approaches that should be replicated in future studies. First, the use of multiple strategies grounded in a theory of behavior change is critical. Second, to maximize success, interventions should be integrated into the community and approaches should be tailored to meet unique community needs. Third, community stakeholders should be included in the development of community-based strategies. This community involvement and ownership of the intervention increases the likelihood of modeling and peer pressure, leading to widespread adoption of a safety behavior. Finally, when possible, a randomized controlled design should be used to maximize the trustworthiness of reported findings and aid decisions about where to invest resources in community-based approaches to injury prevention.

Antimony trioxide (Sb2O3, CAS 1309-64-4) has been examined in a range of in vitro and in vivo genotoxicity assays. Negative results were obtained with the Salmonella/microsome assay and the L5178Y mutation assay, but a positive response was observed in the in vitro cytogenetic assay using isolated human peripheral lymphocytes. However, in vivo, antimony trioxide was non-clastogenic in the mouse bone marrow micronucleus assay, following oral gavage administration for 1, 7, 14 or 21 days at dose levels of up to 5000 mg/kg (single dose) or 1000 mg/kg (repeat dose). A negative result was also obtained in the in vivo rat liver DNA repair (unscheduled DNA synthesis) assay following a single oral gavage administration of doses up to 5000 mg/kg. These data show no genotoxicity for antimony trioxide in vivo and do not confirm a previous report of clastogenicity in the mouse on repeated dosing. It is concluded that antimony trioxide is not genotoxic in vivo and does not present a genotoxic hazard to humans.

While sodium hypochlorite is widely used as a disinfectant for municipal sewage effluents and power station cooling waters discharged into coastal environments, there is limited information on the potential in vivo genotoxicity of such disinfection procedures to marine organisms. Using a recently developed test system based on the marine polychaete Platynereis dumerilii, we have evaluated impacts based on embryo-larval development, cytotoxicity and genotoxicity following exposure to disinfected settled (primary) effluent from a municipal sewage treatment works (STW). Sewage samples were collected from Newton Abbot STW, Devon, UK and then disinfected with sodium hypochlorite based on standard operational procedures. Exposure of polychaetes to dilutions of disinfected sewage in seawater (20 +/- 1 degree C) led to a marked reduction in normal embryo-larval development (7 h EC50 from 0.57-1.88% (v/v), n = 4), with a simultaneous increase in cytotoxicity. Following the calculation of the Maximum Tolerated Dose (MTD), based on developmental and cytotoxic effects, the organisms were also analysed for the induction of chromosomal aberrations. This investigation demonstrated the absence of genotoxicity in polychaetes exposed in vivo to sewage disinfected with sodium hypochlorite. These observations extend our previously published studies in which polychaetes exposed to non-disinfected sewage, while showing developmental toxicity and cytotoxicity, did not exhibit any evidence of cytogenetic damage.

Aneuploidy plays a significant role in adverse human health conditions including birth defects, pregnancy wastage and cancer. Although there is clear evidence of chemically induced aneuploidy in experimental systems, to date there are insufficient data to determine with certainty if chemically induced aneuploidy contributes to human disease. However, since there is no reason to assume that chemically induced aneuploidy will not occur in human beings, it is prudent to address the aneugenic potential of chemicals in the safety assessment process. A wide range of methods has been described for the detection of chemically induced aneuploidy including subcellular systems, tests with fungi, plants and Drosophila as well as in vitro mammalian systems and in vivo mammalian somatic and germ cell assays. However, none of these methods is sufficiently validated or widely used in routine screening. Underlying the efforts to develop aneuploidy-specific assays is the presumption that current genetic toxicology tests do not detected chemicals that have aneuploidy-inducing potential. To address this, we have critically evaluated data from standard genetic toxicology assays for 16 known or suspected aneugens. The conclusions from the review are listed below. 1. At present there are only nine chemicals that can be classified as definitive aneugens, as determined by positive results in in vivo rodent assays. 2. As expected, the majority of definitive and suspected aneugens are negative in the bacterial mutation assay. 3. The majority of definitive aneugens evaluated induce polyploidy in vitro. With few exception, they also induced structural chromosome aberrations in vitro. 4. All of the definitive aneugens that have been sufficiently tested induce micronuclei in rodent bone marrow cells in vivo. A number of these chemicals also induced structural chromosome aberrations in vivo. 5. There is no evidence for a unique germ cell aneugen, that is a chemical that induces aneuploidy in germ cells and not in somatic cells. Furthermore, an analysis of several databases indicates the proportion of chemicals which induce polyploidy and not chromosome aberrations in vitro is low. Based on these conclusions, the following recommendations are made: for screening purposes, a standard genotoxicity test battery (including an in vitro cytogenetic assay with an assessment of polyploidy and clastogenicity at the same harvest time) should be performed; in the absence of polyploidy induction in vitro no further evaluation of aneuploidy-inducing potential is needed; if polyploidy is observed, in vitro follow-up testing to investigate further the aneuploidy-inducing potential should be conducted; such follow-up testing will generally start with the conduct of a standard in vivo somatic cell micronucleus assay; if the in vivo somatic cell micronucleus assay is negative, with adequate evidence of exposure of the bone marrow to the test compound, no further testing of aneuploidy-inducing potential is needed; if the in vivo somatic cell micronucleus assay is positive, further information on mechanisms of micronucleus induction can be obtained by using kinetochore/centromeric staining in vitro and/or in vivo; an assessment of potential germ cell aneuploidy activity may then be considered; aneuploidy induction which does not involve the direct interaction of a chemical or its metabolite(s) with DNA is expected to have a threshold. This must be considered in the risk assessment of such chemicals; this is not addressed by current risk assessment guidelines.

Samples of settled (primary) effluent were collected from a municipal sewage treatment works at Newton Abbot, Devon, UK, a site which discharges primary effluent via long sea pipeline into the English Channel (minimum of 200-fold initial dilution). Sewage samples were collected during the period February-April 1995 and were analysed for standard physico-chemical parameters (ammonia, chemical oxygen demand, conductivity, non-purgeable organic carbon and settled solids). Samples were also tested for cytotoxicity, genotoxicity, and for developmental effects in the embryo-larval stages of the marine worm, Platynereis dumerilii. Exposure to sewage concentrations of > or = 10% (v/v) in seawater at 20 +/- 1 degrees C led to a marked reduction in normal embryo-larval development (7 h EC50 values from 10% to 18% v/v, n = 5). There was also evidence of a simultaneous delay in the cell cycle progression (as determined by sister chromatid differential staining) following embryo-larval exposures to sewage concentrations of > or = 10% (v/v). Following the calculation of the Maximum Tolerated Dose (MTD), based on cytotoxic and developmental effects, cells from the same embryo-larvae were analysed for chromosomal aberrations (CAs). Results were consistent for all samples tested, demonstrating the absence of cytogenetic damage following the in vivo exposure of polychaete embryo-larvae to settled sewage.

CI Solvent Yellow 14 has been reported to be carcinogenic in the rat, inducing neoplastic liver nodules, but non-carcinogenic in the mouse. The present experiments have extended previously reported investigations on the activity of CI Solvent Yellow 14 in in vivo genotoxicity assays. CI Solvent Yellow 14 has been examined for genotoxicity in vivo in the bone marrow micronucleus assay in both the rat and the mouse, and in the rat liver unscheduled DNA synthesis (DNA repair) assay, to limit doses of 5000 and 2000 mg/kg respectively, by oral gavage. CI Solvent Yellow 14 showed evidence of clastogenic activity in both the rat and mouse bone marrow (clear effect in the rat; weak effect in the mouse), but no evidence of DNA repair in the rat liver. In view of the latter finding, the contribution, if any, of the genotoxicity expressed by the micronucleus assay to the formation of liver nodules on chronic administration of the compound, is unclear.

An in vivo genotoxicity test system has been developed using the embryo-larval stages of the marine annelid, Platynereis dumerilii (Polychaeta: Nereidae). This species is representative of an ecologically important group of marine invertebrates, it is amenable to laboratory culture and has a well defined and stable karyotype (2n=28) which is suitable for the analysis of a range of cytogenetic endpoints, including chromosomal aberrations (CAs) and sister chromatid exchanges (SCEs). An evaluation of the cell cycle kinetics using the embryo-larval stages allowed selection of exposure times for cytogenetic work. Subsequently, 12-h-old embryos were exposed to reference mutagens, dissolved in sea water, in the presence of 5-bromodeoxyuridine (BrdU) for 12 h (SCE analysis) or 8 h (CA analysis) at 15 +/- 1 degree C, by which time they had reached the first larval stage (20-24h). Dose response-relationships for cytotoxicity, SCEs and CAs were observed for both direct acting mutagens (methyl methanesulfonate, mitomycin C) and mutagens which require metabolic activation (cyclophosphamide, benzo[a]pyrene). The sensitivity of the embryo-larval stages of P. dumerilii to both direct and indirect acting mutagens, their suitability for laboratory culture, together with the presence of a good karyotype and chromosome morphology for cytogenetic analyses, makes this species a potentially valuable in vivo model for marine genotoxicity testing.

A series of bacterial mutation, mammalian cell (L5178Y) gene mutation and in vitro cytogenetic assays were performed to compare the efficacy of using S9 fractions prepared from rats induced with a combination of phenobarbital (PB) and beta-naphthoflavone (beta NF), with S9 fractions from rats treated with the general enzyme inducer Aroclor 1254. Although some quantitative differences in the magnitudes of the mutagenic/clastogenic effects were observed between the two induction regimes, no qualitative differences were observed. The use of a combined PB/beta NF induction regime using oral dosing is therefore considered to be a suitable substitute for Aroclor 1254.

Trichloroacetic acid (TCA) was tested for its ability to induce chromosomal damage in cultured human peripheral blood lymphocytes and in bone marrow cells of male and female C57BL/6JfBL10/Alpk mice. Two in vitro cytogenetic assays were conducted with TCA. In the first TCA, as free acid, was added to whole blood cultures at final concentrations of 500, 2000 and 3500 micrograms/ml in the presence and absence of an auxiliary metabolic activation system (rat liver S9-mix). Statistically significant increases in the percentage of aberrant cells compared with solvent control values were observed in cultures treated with TCA at 2000 and 5000 mu/ml. Investigation into the effects of TCA on the pH of the culture medium revealed significant reductions in pH at both these TCA concentrations. Neutralized TCA was then tested at concentrations of 500, 2,000 and 5000 micrograms/ml, also in the presence and absence of S9-mix. No statistically or biologically significant increases in the percentage of aberrant cells were observed in any of these cultures. In the mouse micronucleus test, neutralized TCA was administered in two equal intraperitoneal doses 24 h apart to C57BL/6JfBL10/Alpk mice (337, 675 and 1080 mg/kg in males; 405, 810 and 1300mg/kg in females). These dose levels represent 25%, 50% and 80% of the median lethal dose (MLD) in this strain of mouse. Bone marrow samples were taken 6 and 24 h after the second dose and the chromosomal damage assessed by analysis of the bone marrow for micronuclei. No statistically or biologically significant increases in the incidence of micronucleated polychromatic erythrocytes compared with the solvent control dosed animals were observed in either sex at the 6 h sampling time or in the females at the 24 h sampling time. A small but statistically significant increase in micronucleated polychromatic erythrocytes was observed in male mice 24 h after a dose of 675 mg/kg (50% MLD). Since no increases were noted at the 25 or 80% MLD, and the levels recorded are within the range of the concurrent solvent control values, the small increase observed in the males at the 50% MLD is considered not to be biologically significant. Flow cytometric studies on suspensions of isolated liver cell nuclei revealed that changes in FITC binding (indicating altered chromatin conformation) were induced by pH changes alone and were not caused by neutralized TCA.(ABSTRACT TRUNCATED AT 400 WORDS)

The development of assays to detect numerical chromosome aberrations has not kept pace with that for assays used to detect other genotoxicity endpoints such as gene mutations and structural chromosome aberrations, even though the importance of aneuploidy in relation to heritable defects in germ cells and to carcinogenesis in somatic cells is acknowledged. Regulatory bodies at present have no formal requirements concerning aneuploidy detection and decisions are made on a case-by-case basis. The aim of this review is to indicate which assays are available for the detection of chemically induced aneuploidy and what aspects should be taken into account when testing for chemically induced aneuploidy using in vitro, in vivo somatic and in vivo germ cell assays without dictating exact protocols. Our recommendations concentrate on systems that, to date, have been most extensively used and we indicate where future developments may lie. It is important that the currently available and future tests for chemically induced aneuploidy should be adequately validated before being implemented into screening strategies or regulatory guidelines. This requirement has not yet been met and is confounded by the lack of a well defined reference database of animal and human chemical aneugens.

The rodent liver carcinogen and hepatic peroxisome proliferator methylclofenapate (MCP) has been evaluated for genetic toxicity in a range of in vitro and rodent genotoxicity assays. It gave a negative response in each of the following assays: mutagenicity to S. typhimurium and E. coli (+/- S9 mix, plate and pre-incubation assays), clastogenicity to cultured human lymphocytes and CHO cells (+/- S9 mix), a mouse bone marrow micronucleus assay (24h and 48h sampling), a rat liver assay for UDS in vivo (12h sampling), assays for lac I (Big Blue) and lac Z (Muta Mouse) mutations in the liver of transgenic mice, and an assay of the ability of MCP to modify the mutagenicity to the liver of dimethylnitrosamine in both transgenic mutation assays. The micronucleus and UDS assays were conducted using a single administration of MCP at its maximum tolerated dose, while the transgenic assays were conducted using nine daily administrations of MCP at its cancer bioassay dose level. These nine daily administrations were shown to double the weight of the liver of non-transgenic, Big Blue and Muta Mice, as well as leading to a dramatic proliferation of peroxisomes (electron microscopy) in the livers of each strain. These changed parameters had returned to control levels when the mutation analyses were conducted (10 days after the final dose of MCP). Despite the liver enlargement observed following MCP administration, no evidence of mitotic activity was observed in treated livers, although an increased number of cells were undergoing replicative DNA synthesis during the final 3 days of the 9 days of administration (BUdR assessment of S-phase). Liver biochemistry parameters (ALT, AST, AP, CK, GGT and albumin) were unaffected by the chronic (9 day) administration of MCP indicating an absence of hepatic toxicity. These combined observations favour a non-genotoxic mechanism of action for the hepatic carcinogenicity of MCP. The clastogenicity in vitro of the perixisome proliferator Wyeth 14,643 has been confirmed in CHO cells, but it is noted that this chemical is more soluble than is MCP. In particular, at the highest dose level at which MCP could be tested, Wy 14,643 was also non-clastogenic.

De Flora et al. (1991a) have demonstrated a marked protective effect afforded by N-acetylcysteine (NAC) to the liver and lung of rats exposed to benzo[a]pyrene (BP) by intratracheal injection. Due to the protocol used by De Flora et al., BP was inactive in the bone marrow micronucleus assay and, consequently, the possible protective effect of NAC in this tissue could not be assessed. In the present study, three daily administrations of 7,12-dimethylbenzanthracene (DMBA; 15 or 25 mg/kg/day via oral gavage) resulted in the expected increased in micronucleated polychromatic erythrocytes (MPE) in the bone marrow of male C57BL/6 mice 24 h after the final dose. Pretreatment of similar groups of mice with NAC (1 g/kg/day via oral gavage) 5 h before each administration of DMBA had no effect on MPE frequencies. It is concluded that NAC does not have a protective effect on the mouse bone marrow.

World experience has shown the crucial need for government commitment, funding, and action in reducing the tobacco epidemic. It is recommended that each country establish a national council on tobacco or health to coordinate a comprehensive tobacco control program. This program should incorporate data collection including evaluation of specific anti-tobacco measures; legislative measures including strong, rotating health warnings, limits on harmful substances, establishment of smoke-free areas, bans on any new forms of tobacco use, and a total ban on all promotion of tobacco products; health education campaigns; and taxation and price policies. The support and involvement of the medical profession are vital. Obstacles to success include cultural factors, the intertia of governments and the medical profession, but most importantly the tobacco industry, the largest, wealthiest, most determined, and strongest opposition to tobacco control worldwide.

In countries where prolonged smoking of manufactured cigarettes is a widely established habit, it is responsible for about 90% of lung cancer. As lung cancer is usually incurable, even with expensive technology, the key to its control lies in prevention. World experience has shown the crucial need for government commitment, funding and action in controlling the epidemic of tobacco-related disease. It is recommended that each country establish a national council of 'tobacco or health' to coordinate a comprehensive tobacco control programme. This programme should incorporate data collection, including evaluation of specific anti-tobacco measures; legislative measures, including strong, rotating health warnings, limits on harmful substances, establishment of smoke-free areas, bans on any new forms of tobacco use, and a total ban on all direct or indirect promotion of tobacco products; health education campaigns; and taxation and price policies. The support and involvement of the medical profession is vital. Obstacles to success include the effect of advertising revenue in silencing the media, the inertia of governments and the medical profession, but most importantly the tobacco industry--the largest, wealthiest, most determined and strongest opposition to tobacco control worldwide.

The presence of sickle cell trait and the prevalence and severity of retinopathy were assessed in 124 Negro diabetics. Sickle cell trait had no adverse effect on diabetic retinopathy.