Novel WRN Helicase Inhibitors Selectively Target Microsatellite Unstable Cancer Cells.

Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n-dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumours, and WRN inhibitors are in development. Here, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target. Fragment-based screening led to the development of potent and highly selective WRN helicase covalent inhibitors. These compounds selectively suppressed MSI model growth In vitro and In vivo by mimicking WRN loss, inducing DNA double-strand breaks at expanded TA-repeats and DNA damage. Assessment of biomarkers in preclinical models linked TA-repeat expansions and mismatch repair (MMR) alterations to compound activity. Efficacy was confirmed in immunotherapy-resistant organoids and patient-derived xenograft (PDX) models. The discovery of potent, selective covalent WRN inhibitors provides proof of concept for synthetic-lethal targeting of WRN in MSI cancer and tools to dissect WRN biology.

Agricultural youth injuries: An updated review of cases from U.S. news media reports, 2016-2021.

Introduction: Fatal and non-fatal youth (ages 0-17) injuries in U.S. agriculture continue to be a significant public health concern. Despite sustained work and attention from federally supported research programming, we continue to observe an unacceptably high number of life-altering and life-ending traumatic injuries to youth in agricultural environments. Likewise, there is still a gap in stringent systematic agricultural injury and/or illness surveillance at the federal level. This paper will provide an updated review of child agricultural injuries from U.S. news media reports, expanding upon this author team's initial 2018 report. Methods: Data collection from 2016 to 2021 occurred as part of the AgInjuryNews initiative, and data were coded according to the Farm and Agricultural Injury Classification (FAIC) system and the Occupational Injury and Illness Classification System (OIICS). The AgInjuryNews system primarily contains news media reports. Categorical variables were analyzed and compared using a chi-square test. In addition, the Jonckheere-Terpstra test for trend was used to test the yearly change in the number of youth injuries. Results: We observed a general decrease in agricultural injuries compared to the original 2015-2017 dataset. Younger children (<5 years-old) and males were more often injured and more fatally injured than older children and females, respectively. Males and older victims were more likely to suffer an occupational-related injury compared to females and younger victims, respectively. Vehicles remained a major source of injuries, with tractors comprising 28%, and ATVs/UTVs comprising 26% of all injuries. Roadway incidents involving tractors and UTVs were less often fatal compared to non-roadway incidents, while ATVs were more fatal on roadways. Discussion: This updated review shows childhood agricultural injuries and fatalities continue to be a major public health concern within the US. It is unclear if the trend downward in injuries is due to reporting, data capture methods, or a true decrease in injuries. These data continue to be of interest to stakeholders in academia, public health, government, and private industry-user groups who regularly and consistently seek this type of information, often from multiple data sources, including as registered users on AgInjuryNews.org. These data identify emerging issues within the industry and further inform national and international planning committees' work.

What about the Rest of Them? Fatal Injuries Related to Production Agriculture Not Captured by the Bureau of Labor Statistics (BLS) Census of Fatal Occupational Injuries (CFOI).

Surveillance of injuries in production agriculture is necessary to inform stakeholders about workplace hazards and risks in order to improve and advance injury prevention policies and practices for this dangerous industry. The most comprehensive fatal injury surveillance effort currently in the United States is the Bureau of Labor Statistics (BLS) Census of Fatal Occupational Injuries (CFOI), which covers occupational fatalities in all U.S. industries, including production agriculture. However, this surveillance does not include many categories of fatalities that occur during agricultural work or on production agriculture worksites. To better capture the human cost of production agriculture, the authors of this paper call for the collection of additional data with a broader scope that supplements, not replaces, the current CFOI. This paper describes challenges in surveillance, highlights key procedural gaps, and offers recommendations for advancing national surveillance of fatal traumatic injuries associated with production agriculture.

Redesigning a Sentinel Surveillance System for Collecting and Disseminating Near Real-Time Agricultural Injury Reports: System Usability Study.

BACKGROUND: Injury data and reports provide valuable information for both public and private organizations to guide programming, policy, and prevention, but in the increasingly complex and dangerous industry of US agriculture, the injury surveillance needed to produce this data is lacking. To address the gap, AgInjuryNews was established in 2015. The system includes fatal and nonfatal injury cases derived from publicly available reports, including occupational and nonoccupational injuries, occurring in the agricultural, forestry, and fishing (AFF) industry. OBJECTIVE: The study aimed to develop a stakeholder-engaged redesign of the interactive, up-to-date, and publicly available dataset of US AFF injury and fatality reports. METHODS: Instructor-led heuristic evaluations within a 15-student undergraduate course, data from 8 student participants of laboratory-based usability testing and 2016 and 2017 AgInjuryNews-registered user surveys, coupled with input from the National Steering Committee informed the development priorities for 2018. An interdisciplinary team employed an agile methodology of 2-week sprints developing in ASP.NET and Structured Query Language to deliver an intuitive frontend and a flexible, yet structured, backend, including a case report input form for capturing more than 50 data points on each injury report. RESULTS: AgInjuryNews produced 17,714 page views from 43 countries in 2018 captured via Google Analytics, whereas 623 injury reports were coded and loaded, totaling more than 31,000 data points. Newly designed features include customizable email alerts, an interactive map, and expanded search and filter options. User groups such as the Bureau of Labor Statistics and the Agricultural Safety and Health Council of America have endorsed the system within their networks. News media have cited or referenced the system in national outlets such as the New York Times, Politico, and the Washington Post. CONCLUSIONS: The new system's features, functions, and improved data granularity have sparked innovative lines of research and increased collaborative interest domestically and abroad. It is anticipated that this nontraditional sentinel surveillance system and its dataset will continue to serve many purposes for public and private agricultural safety and health stakeholders in the years to come. .

Novel pH Selective, Highly Lytic Peptides Based on a Chimeric Influenza Hemagglutinin Peptide/Cell Penetrating Peptide Motif.

Delivery of macromolecular cargos such as siRNA to the cytosol after endocytosis remains a critical challenge. Numerous approaches including viruses, lipid nanoparticles, polymeric constructs, and various peptide-based approaches have yet to yield a general solution to this delivery issue. In this manuscript, we describe our efforts to design novel endosomolytic peptides that could be used to facilitate the release of cargos from a late endosomal compartment. These amphiphilic peptides, based on a chimeric influenza hemagglutinin peptide/cell-penetrating peptide (CPP) template, utilize a pH-triggering mechanism in which the peptides are protonated after acidification of the endosome, and thereby adopt an alpha-helical conformation. The helical forms of the peptides are lytically active, while the non-protonated forms are much less or non-lytically active at physiological pH. Starting from an initial lead peptide (INF7-Tat), we systematically modified the sequence of the chimeric peptides to obtain peptides with greatly enhanced lytic activity that maintain good pH selectivity in a red blood cell hemolysis assay.

Leadership and Funding: Changes Ahead for Agricultural Safety and Health.

For the last several decades, financial support for agricultural safety and health programs and professionals has primarily been covered by public dollars through federal and state government grant programs and appropriations. This federal and state funding provided a tremendous boost to farm safety and health professionals and program efforts for 30+ years and has provided the foundation and structure for current agricultural safety and health efforts and activities. However, there is reason to question long-term sustainability of a sufficient level of federal and state dollars for agricultural safety and health. Public funding for agricultural safety and health has never quite kept up to inflation, but even more ominous is that the entire agricultural safety and health program has been proposed for elimination each year by the White House budget beginning with the fiscal year 2012. It seems prudent, perhaps even imperative, for the agricultural safety and health community to find alternative support mechanisms. We suggest that now is a great time for agricultural businesses, services, and organizations to step up their financial support. Fortunately, several positive examples have recently surfaced within the agricultural community. As the agricultural industry continues to be a dominant enterprise in the United States, the integration of significant funding and the role of leadership from within the industry must continue to expand.

Operator Exposure to Hydrogen Sulfide from Dairy Manure Storages Containing Gypsum Bedding.

Dairy manure storages containing gypsum-based bedding have been linked anecdotally with injury and death due to presumed dangerous levels of gases released. Recycled gypsum products are used as a cost-effective bedding alternative to improve animal welfare and provide agronomic benefits to manure recycled back to the land. Sulfur contained in gypsum (calcium sulfate) can contribute to hydrogen sulfide (H2S) gas formation under the anaerobic storage conditions typical of dairy manure slurry. Disturbance of stored manure during agitation releases a burst of volatile gases. On-farm monitoring was conducted to document conditions during manure storage agitation relative to gas concentration and operator safety. One objective was to document operator exposure to H2S levels; therefore, each operator wore a personal gas monitor while performing tasks associated with manure storage agitation. Data from three dairy bedding management categories on ten farms were compared: (1) traditional organic bedding, (2) gypsum bedding, and (3) gypsum bedding plus a manure additive thought to reduce H2S formation and/or release. Portable meters placed around the perimeter of dairy manure storages recorded H2S concentrations prior to and during 19 agitation events. Results show that farms using gypsum bedding produced higher H2S concentrations during manure storage agitation than farms using traditional bedding. In most cases, gypsum-containing manure storages produced H2S levels above recognized safe thresholds for both livestock and humans. Farm operators were most at risk during activities in close proximity to the manure storage during agitation, and conditions 10 m away from the storage were above the 20 ppm H2S threshold on some farms using gypsum bedding. Although H2S concentrations rose to dangerous levels, only two of 18 operators were exposed to >50 ppm H2S during the first 60 min of manure storage agitation. Operators who are aware of the risk of high H2S concentrations near gypsum-laden manure storages can reduce their exposure risk by working upwind and away from the H2S plume within a closed tractor cab.

Capitalizing on Federal Agencies' Intentions To Protect Youth Working in Agriculture.

Nearly 750,000 youth work on farms across the United States. The U.S. Department of Labor's (U.S. DOL) Fair Labor Standards Act (FLSA) Hazardous Occupations Orders for Agriculture (HOOA) applies to approximately 37% of these youth. The HOOA regulations had not been updated since their inception in the late 1960s and the early 1970s. An attempt by U.S. DOL to update the regulations in 2011 was met with fierce opposition by the agricultural community, and the proposed updated regulations were withdrawn. One impactful outcome of these two events was a rededication by USDA and the farm community to address agricultural youth farm safety through education rather than through regulation. An agriculturally based National Steering Committee has developed consensus Belief Statements and Guiding Principles to proactively influence agricultural youth safety. In this case, USDA was clearly a 'sphere of influence' for youth agricultural safety.

Injury risks for on-road farm equipment and horse and buggy crashes in Pennsylvania: 2010-2013.

OBJECTIVE: The purpose of this study was to investigate characteristics associated with farm equipment and horse and buggy roadway crashes in relation to person, incident, and injury characteristics to identify appropriate points for injury incident prevention. METHODS: Information on crashes occurring on public roads during the years 2010-2013 was obtained from the Pennsylvania Department of Transportation (PennDOT) and analyzed. RESULTS: There were 344 farm equipment and 246 horse and buggy crashes during the 4-year study period. These crashes involved 666 and 504 vehicles and 780 and 838 people, respectively. In incidents with farm equipment, the non-farm equipment drivers had an almost 2 times greater injury risk than farm equipment operators. Horse and buggy crashes were almost 3 times more injurious to the horse and buggy drivers than the drivers of the other vehicles. CONCLUSIONS: The average crash rate for farm equipment was 198.4 crashes per 100,000 farm population and for horse and buggy the crash rate was calculated as 89.4 crashes per 100,000 Amish population per year. This study suggests that road safety and public health programs should focus not only on farm equipment operators and horse and buggy drivers but on other motorists sharing the roadway with them.

Apneic events - A proposed new target for respiratory safety pharmacology.

Current practice in respiratory safety pharmacology generally follows the regulatory guidance provided by the ICH document S7A and focuses on measures of pulmonary ventilation. What these measures do not account for is the ability of drugs to cause ventilatory instability or interruptions in ventilatory rhythm. Ventilatory instability can be identified by the presence of prolonged end-expiratory pauses or apneic periods. An apneic event has been defined as an apneic period of sufficient duration to cause hypoxia (i.e., decrease in hemoglobin oxygen saturation ≥ 3%). Repeated apneic events are often referred to as intermittent hypoxia. Characterizing ventilatory instability is important since (1) occurrence of apneic events in humans can lead to serious adverse outcomes such as systemic and pulmonary hypertension, cardiac arrhythmia, stroke, CNS dysfunction, metabolic disorders, enhanced tumor growth and death, (2) drugs are known to cause or exacerbate apneic events in humans, and (3) there is a preexisting condition of ventilatory instability referred to as sleep apnea that is prevalent in the human population. Evaluating this new target in respiratory safety pharmacology studies is needed to ensure that the potential for new drugs to cause or exacerbate apneic events can be identified and the impact on patient safety characterized.

Online Design Aid for Evaluating Manure Pit Ventilation Systems to Reduce Entry Risk.

On-farm manure storage pits contain both toxic and asphyxiating gases such as hydrogen sulfide, carbon dioxide, methane, and ammonia. Farmers and service personnel occasionally need to enter these pits to conduct repair and maintenance tasks. One intervention to reduce the toxic and asphyxiating gas exposure risk to farm workers when entering manure pits is manure pit ventilation. This article describes an online computational fluid dynamics-based design aid for evaluating the effectiveness of manure pit ventilation systems to reduce the concentrations of toxic and asphyxiating gases in the manure pits. This design aid, developed by a team of agricultural engineering and agricultural safety specialists at Pennsylvania State University, represents the culmination of more than a decade of research and technology development effort. The article includes a summary of the research efforts leading to the online design aid development and describes protocols for using the online design aid, including procedures for data input and for accessing design aid results. Design aid results include gas concentration decay and oxygen replenishment curves inside the manure pit and inside the barns above the manure pits, as well as animated motion pictures of individual gas concentration decay and oxygen replenishment in selected horizontal and vertical cut plots in the manure pits and barns. These results allow the user to assess (1) how long one needs to ventilate the pits to remove toxic and asphyxiating gases from the pit and barn, (2) from which portions of the barn and pit these gases are most and least readily evacuated, and (3) whether or not animals and personnel need to be removed from portions of the barn above the manure pit being ventilated.

Evaluation of a method utilizing PhysioFlow®, a novel signal morphology-based form of impedance cardiography, to measure cardiac output in the conscious beagle.

INTRODUCTION: Currently, standard methods for measuring cardiac output are either invasive (i.e. flow probe) or are limited in terms of short measurement intervals and measurement variability (i.e. echocardiography). The ability to reliably measure cardiac output in a non-invasive manner in large animals would provide a valuable tool to expand functional cardiovascular endpoints in preclinical safety studies. PhysioFlow® is a novel method that uses waveform analysis of an impedance signal to measure cardiac output non-invasively. Unlike cardiac impedance techniques in the past, PhysioFlow® is not dependant on thoracic structure or basal thoracic impedance (Z0) and therefore this methodology is transferrable from human to animal models. METHODS: Three tool compounds with known effects on cardiac output were administered to conscious beagle dogs to determine if the non-invasive PhysioFlow® system could detect the expected changes in stroke volume and cardiac output as determined by literature references using the current standard methodologies (e.g. aortic blood flow and thermodilution). RESULTS: The PhysioFlow® system was able to detect increases in cardiac output when dosed with 20µg/kg of Dobutamine, a decrease in cardiac output when dosed with 0.1mg/kg of Acepromazine, and no significant change in cardiac output when dosed with 2mg/kg of Minoxidil. These results are within expected ranges based on published literature (Stepien et al., 1995; Taylor et al., 2007). DISCUSSION: PhysioFlow®, a signal morphology-based impedance cardiography, can be utilized to reliably and non-invasively measure cardiac output in beagle dogs.

User Perceptions of ¡Protéjase!: An Intervention Designed to Increase Protective Equipment Use Among Mexican Immigrant and Mexican American Farmworkers.

BACKGROUND: Farmworkers' exposures to pesticides are reduced when they wear personal protective equipment (PPE), and mobile health (mHealth) platforms can potentially deliver information to farmworkers to help promote PPE use. However, little is known about the feasibility of using mHealth platforms to promote farmworkers' use of PPE. OBJECTIVE: The objective of the study was to describe the development and feasibility-testing of Protect Yourself! (¡Protéjase!), an intervention designed to increase PPE use. As the vast majority of farmworkers in the United States are from Mexico, we examined the intervention in a primarily Mexican-origin farmworker population. METHODS: ¡Protéjase was developed in several steps. First, we performed ethnographic observations to understand what prevents PPE use. Next, we developed program components that met the challenges uncovered in the ethnographic observations, seeking direct feedback from farmworkers on each component. Feasibility was assessed using surveys and focus groups. Material was provided in Spanish or English at the preference of the participant. Finally, we pilot tested each component of the intervention, including: (1) PPE that was provided to each worker for their personal use during the intervention trial, and (2) delivery of an application-based tool that promoted the use of PPE through daily individualized messaging. RESULTS: 55 farmworkers enrolled in the study, but only 41 of 55 (75%) completed the entire pilot intervention trial. Results focus on the evaluation of the intervention, and include only those who completed the entire trial. Among farmworkers who completed the entire intervention trial, all but two farmworkers were born in Mexico and were Spanish speaking. Still, all study participants self-identified as Mexican or Mexican-American. When asked what changes were needed in the intervention's messaging or delivery to increase user satisfaction, 22 out of 41 participants (54%) felt that no changes were needed. However, 16 of 41 participants (39%) suggested small changes to messaging (eg, refer to long pants as pants only) to improve their understanding of the messages. Finally, a small number (3 of 41 participants, 7%) felt that messages were difficult to read, primarily due to low literacy. CONCLUSIONS: The ¡Protéjase! mHealth program demonstrated very good feasibility, satisfaction, and acceptance; potential improvements (eg, small modifications in messaging to increase farmworkers' use) were noted. Overall, the PPE provided to workers as well as the mHealth platform were both perceived as useful for promoting PPE use.

Determination of in Vivo Enzyme Occupancy Utilizing Inhibitor Dissociation Kinetics.

During drug discovery, assessment of in vivo target occupancy by therapeutic candidates is often required for predicting clinical efficacy. Current strategies for determining target occupancy include using radiolabeled or irreversible surrogates, which can be technically challenging, and the results are often not sufficiently quantitative. We developed a straightforward method by applying slow-dissociation kinetics to quantitatively determine enzyme occupancy without using specialized reagents. We applied this method to determine occupancy of Cathepsin K inhibitors in bone tissues harvested from rabbit femurs. Tissues from dosed animals were harvested, flash frozen, lysed, then analyzed by a jump-dilution assay with substrate. The rate of substrate turnover was monitored continuously until reaching steady state and progress curves were fit with the equation [product] = vst + ((vi - vs)/kobs)(1 - exp(-kobst)). The initial rate vi represents the residual activity of the enzyme before inhibitor dissociation; vs is the reaction rate after dissociation of the inhibitor. Occupancy is derived from the ratio of vi/vs. A significant benefit of the method is that data from both the occupied and unoccupied states are obtained in the same assay under identical conditions, which provides greater consistency between studies. The Cat K inhibitor MK-0674 (in vitro IC50 1 nM) was tested in young rabbits (<6 month old) and showed a dose-dependent increase in occupancy, reaching essentially complete occupancy at 1.0 mg/kg. In addition the method enables measurement of the total Cat K in the target tissue. Results confirmed complete occupancy even as the osteoclasts responded to higher doses with increased enzyme production.

Optimizing the use of methods and measurement endpoints in respiratory safety pharmacology.

A variety of methods and measurement endpoints are currently available for evaluating respiratory function in animal models. To evaluate drug-induced effects on respiratory function, respiratory safety pharmacology studies generally emphasize the use of conscious animal models and measures of pulmonary ventilation. Respiratory rate, tidal volume and/or a measure of arterial blood gases are the standard measurement parameters. Although these parameters will provide a measure of ventilation, other ventilatory parameters, which can provide mechanistic insight or identify site of action, should also be considered. Such parameters include inspiratory and expiratory times, flows and pauses, and apneic time. Stimulation models involving exercise and exposure to elevated CO2 or reduced O2 should also be considered when enhancing measurement sensitivity or quantifying reductions in ventilatory functional reserve is desired. Although ventilatory measurements are capable of assessing the functional status of the respiratory pumping apparatus, such measurements are generally not capable of assessing the status of the other functional component of the respiratory system, namely, the gas exchange unit or lung. To characterize drug-induced effects on the gas exchange unit, measures of airway patency, lung elastic recoil and gas diffusion capacity need to be considered. The objective of this review is to discuss the value and utility of the methods and measurement endpoints currently available for assessing respiratory function to help optimize the design of respiratory safety pharmacology studies.

Respiratory safety pharmacology - current practice and future directions.

Current practice in respiratory safety pharmacology generally follows the guidance provided by the ICH document S7A and, in general, focuses on measures of pulmonary ventilation. Respiratory rate, tidal volume and/or a measure of arterial blood gases are the recommended ventilatory measurement parameters. Although these parameters will provide a measure of ventilation, other ventilatory parameters, which can provide mechanistic insight, should also be considered. Such parameters include inspiratory and expiratory times and flows and apneic time. Stimulation models involving exercise and exposure to elevated CO2 or reduced O2 should also be considered when enhancing measurement sensitivity or quantifying reductions in ventilatory functional reserve are desired. Although ventilatory measurements are capable of assessing the functional status of the respiratory pumping apparatus, such measurements are generally not capable of assessing the status of the other functional component of the respiratory system, namely, the gas exchange unit or lung. To characterize drug-induced effects on the gas exchange unit, measures of airway patency, lung elastic recoil and gas diffusion capacity need to be considered. Thus, a variety of methodologies and measurement endpoints are available for detecting and characterizing drug-induced respiratory dysfunction in animal models and should be considered when designing respiratory safety pharmacology studies.

Using social marketing to address barriers and motivators to agricultural safety and health best practices.

Social marketing is an intervention development strategy that pays considerable attention to barriers to and motivators for behavioral change or adoption of recommended behaviors. Barriers are obstacles that prevent individuals from changing or adopting behaviors and are often referred to as the "cons" or "costs" of doing something. Motivators, on the other hand, are factors that encourage individuals to change or adopt behaviors and are often referred to as the "pros," "benefits," or "influencing factors" of doing something. Importantly, social marketing does not target education or knowledge change as an end point; rather, it targets behavior change. Studies across several types of desired behaviors (e.g., smoking cessation, weight control, more exercise, sunscreen use, radon testing) using the Stages of Change model have found systematic relationships between stages of change and pros and cons of changing behavior. A review of literature identifies numerous research and intervention studies that directly reference social marketing in agricultural safety and health, studies that identify reasons why parents allow their children to be exposed to hazardous situations on the farm, and reasons why youth engage in risky behaviors, but only two studies were found that show evidence of systematically researching specific behavioral change motivating factors. The authors offer several suggestions to help address issues relating to social marketing and agricultural safety and health.

A selective Akt inhibitor produces hypotension and bradycardia in conscious rats due to inhibition of the autonomic nervous system.

Akt is a serine-threonine kinase that is amplified in a variety of human cancers, and as with other anticancer agents, some Akt inhibitors have produced functional cardiovascular effects such as marked hypotension that may limit their clinical benefit. Although identified in preclinical studies, the mechanism(s) responsible for these effects are often not fully characterized; potential targets include Akt signaling disruption in cardiac tissue, vascular smooth muscle, and/or autonomic system signaling. A selective Akt inhibitor was found to produce a rapid and marked hypotension and bradycardia in conscious rats. Isolated right atrial tissue and isolated thoracic aortic rings were used to examine direct effects of Akt inhibition on cardiac and vascular tissues, respectively. In addition, rats surgically prepared with telemetry units for monitoring blood pressure and heart rate were used to investigate potential effects on the autonomic nervous system (ANS). Whereas this Akt inhibitor did not produce any significant effect on atrial tissue, it did cause vasorelaxation of aortic rings. More significantly, in conscious rats, the Akt inhibitor inhibited the neural pressor response to the known nicotinic acetylcholine receptor (nAchR) agonist dimethylphenylpiperazinium (DMPP). In fact, the response observed was comparable to the response observed with the known ganglionic blocker hexamethonium. Thus, the hypotension and bradycardia produced by the Akt inhibitor is primarily due to blockade of nAchRs in autonomic ganglia. This finding highlights the importance of evaluating the ANS for cardiovascular effects associated with new chemical entities as well as suggesting a novel direct effect of an Akt inhibitor on nAchRs.

Tractors and rollover protection in the United States.

There are approximately 4.2 million tractors on farms and ranches across the United States. The average age of tractors is over 25 years and some of the oldest models are the most popular. Older tractors are less safe than newer tractors, and many older tractors are operated by individuals with increased risk of being injured or killed on a tractor. A key tractor safety device, a rollover protective structure (ROPS), is missing from most tractors manufactured before 1985. Data from the US Department of Labor's Census of Fatal Occupational Injuries (CFOI) suggest that the production agriculture sector accounts for approximately 70.3% of the 3299 work deaths in the Agriculture, Forestry, and Fishing industry between 2003 and 2007. Nearly 900 of these incidents involve farm tractors and of these, approximately 43% were from tractor overturns. Efforts to reduce both the number of tractor overturn fatalities and injuries have been underway for years. These efforts primarily encompass worker education/training programs and activities, ROPS design and engineering applications, and research on more effective ways of encouraging tractor owners to retrofit their older tractors with ROPS. This paper reviews various approaches available to reduce the fatalities, serious injuries, and economic burden associated with tractor overturns. Past and current efforts to promote ROPS in the United States and in other countries, current safe tractor operations education and training programs, and ROPS-related safety engineering projects are discussed. Recommendations for advancing safe tractor operation and the number of tractors protected by ROPS are given. This review was prepared for the Agricultural Safety and Health Council of America/National Institute for Occupational Safety and Health conference, "Be Safe, Be Profitable: Protecting Workers in Agriculture," January 2010.