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.

A Scoping Review of Safety and Health Interventions in the High-Risk Dairy Industry: Gaps in Evidence Point to Future Directions in Research.

The occupational injury rate of the dairy industry (6.6 per 100 full-time workers) is twice that of the national average across all industries (3.3 per 100 full-time workers). While dairy farms are becoming larger in size and fewer in number, this rate has not changed. A scoping review was conducted to identify published reports of occupational safety interventions in the dairy industry. An additional criterion was that the study included an evaluation of the intervention. Out of 22 articles that met the first criterion (discussion of interventions specific to the dairy industry), 19 met the second of having an evaluative component. These 19 articles corresponded to 16 unique studies, because 4 articles corresponded to the same study. Of the 16 unique studies, only 3 had a comparison of treatment vs. control effects, and none measured the impact of the intervention on injuries and fatalities. Of the 16 interventions, 6 were focused on training or informational campaigns in which the evaluations primarily measured knowledge acquisition. Additionally, none of these studies had a sufficient sample size to compare injury rates as an outcome. Our study demonstrates that the literature lacks any rigorous evaluation of whether dairy safety interventions are making an impact on injury prevention. Given this, it is not possible to determine how work-related injuries and deaths can be prevented in the dairy industry. Recommendations for future research include incorporating rigorous evaluation into research designs and attempting to develop low-cost, unobtrusive methods for collecting data on intermediate and final outcomes.

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.

Coding agricultural injury: Factors affecting coder agreement.

OBJECTIVES: To determine coders' agreement level for the Occupational Injury and Illness Classification System (OIICS) source of injury and injury event codes, and the Farm and Agricultural Injury Classification (FAIC) code in the AgInjuryNews.org and to determine the effects of supplemental information and follow-up discussion in final code assignments. METHODS: Two independent researchers initially coded 1304 injury cases from AgInjurynews.org using the OIICS and the FAIC coding schemes. Code agreement levels for injury source, event, and FAIC and the effect of supplemental information and follow-up discussions on final coding was assessed. RESULTS: Coders' agreement levels were almost perfect for OIICS source and event categories at the 3-digit level, with lower agreement at the 4-digit level. By using supplemental information and follow-up discussion, coders improved the coding accuracy by an average 20% for FAIC. Supplemental information and follow-up discussions had helped finalize the disagreed codes 55% of the time for OIICS source coding assignments and 40% of time for OIICS event coding assignments for most detailed 4-digit levels. Five key themes emerged regarding accurate and consistent coding of the agricultural injuries: inclusion/exclusion based on industry classification system; inconsistent/discrepant reports; incomplete/nonspecific reports; effects of supplemental information on coding; and differing interpretations of code selection rules. Practical applications: Quantifying the level of agreement for agricultural injuries will lead to a better understanding of coding discrepancies and may uncover areas for improvement to coding scheme itself. High level of initial and final agreement with FAIC and OIICS codes suggest that these coding schemes are user-friendly and amenable to widespread use.

Factors Controlling Calanoid Copepod Biomass and Distribution in the Upper San Francisco Estuary and Implications for Managing the Imperiled Delta Smelt (Hypomesus transpacificus).

Delta smelt struggle to persist in a dramatically altered estuarine environment. Complex and incompletely understood relationships between food availability, environmental stressors, other components of the species' habitat, and the abundance of delta smelt impede the effective management and recovery of the species. The empirical modeling presented in this study quantitatively describes spatial-temporal biomass values of calanoid copepods, a key prey item for delta smelt, in relation to multiple potential controlling factors. The results underscore the role that river flows through the estuary have in determining prey availability, and demonstrate contributions of water temperature, salinity, and macronutrients in determining copepod biomass. The analysis also shows the importance of non-native, invasive bivalves in determining copepod biomass. Importantly, the analysis describes spatial-temporal shifts in the relative importance of modeled covariates across sampling locations in the Delta. Model results indicate that increasing flows in the fall of wetter years adversely affected copepod biomass, while increases in flows in the spring of drier years provided regional increases in biomass. The results of this analysis can inform resource management decisions and contribute to a comprehensive model that can meaningfully guide efforts to recover the imperiled delta smelt.

A Novel Tripod Percutaneous Reconstruction Technique in Periacetabular Lesions Caused by Metastatic Cancer.

BACKGROUND: Metastatic lesions in the periacetabular region can cause pain and immobility. Symptomatic patients are often treated surgically with a total hip replacement using various modified Harrington methods. These open surgical procedures confer inherent risks. Prolonged recovery and potential complications may delay adjuvant radiation and systemic therapy. METHODS: We describe a novel technique for acetabular reconstruction. Three large-bore cannulated screws are placed percutaneously under fluoroscopy in a tripod configuration to reinforce the mechanical axes of the acetabulum. Increased stability improves pain control and permits weight-bearing. RESULTS: Twenty consecutive patients with periacetabular metastases were treated using the tripod technique. Eighteen patients (90%) had Harrington class-III lesions, and 2 patients had Harrington class-II lesions. The mean surgical time was 2.3 hours. Sixteen patients (80%) were able to get out of bed on postoperative day 1. At 3 months postoperatively, there was significant improvement in pain as documented on their visual analog scale (p < 0.01) and in functionality as measured by the Eastern Cooperative Oncology Group score (p < 0.01). The mean follow-up time was 7 months (range, 0.6 to 20 months). At the most recent follow-up, only 3 among the 16 surviving patients were using opioids chronically for pain. Total hip arthroplasty was performed in 4 patients (20%) in a staged fashion using the previously placed screws as support for a cemented cup and obviating the need for a cage device. Of the 16 patients, 15 could walk either independently (6 patients) or using an ambulatory aid (9 patients). Eight patients with the primary tripod reconstruction survived >6 months postoperatively. They were found to have either new bone formation filling the defects or healing of the pathological fractures. There has been no implant loosening or failure. CONCLUSIONS: The tripod technique is a novel application to provide safe and effective pain relief in the context of periacetabular metastatic disease. It can be easily converted to support a cemented acetabular cup for a total hip replacement should disease progression occur. This technique provides an alternative to open surgery as currently practiced in these patients. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

General personality dimensions, impairment and treatment response in obsessive-compulsive disorder.

General personality dimensions are associated with clinical severity and treatment response in individuals with depression and many anxiety disorders, but little is known about these relationships in individuals with obsessive-compulsive disorder (OCD). Individuals in the current study included 705 adults with OCD who had participated in family and genetic studies of the disorder. Participants self-completed the Neuroticism, Extraversion, Openness Personality Inventory or Neuroticism, Extraversion, Openness Five-Factor Inventory-3. Relationships between personality scores, and subjective impairment and OCD treatment response, were evaluated. The odds of subjective impairment increased with (unit increase in) the neuroticism score (odds ratio, OR = 1.03; 95% CI = 1.01-1.04; p < 0.01) and decreased with extraversion scores (OR = 0.98; 95% CI = 0.96-0.99; p < 0.01). The odds of reporting a good response to serotonin/selective serotonin reuptake inhibitors (OR = 1.02; 95% CI = 1.01-1.04; p < 0.01) or cognitive behavioural therapy (OR = 1.03; 95% CI = 1.01-1.05; p < 0.01) increased with the extraversion score. The magnitude of these relationships did not change appreciably after adjusting for other clinical features related to one or more of the personality dimensions. The findings suggest that neuroticism and extraversion are associated with subjective impairment, and that extraversion is associated with self-reported treatment response, in individuals with OCD. © 2019 John Wiley & Sons, Ltd.

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.

Agricultural Youth Injuries: A Review of 2015-2017 Cases from U.S. News Media Reports.

Background: The hazardous nature of the agricultural environment, reflected in the numerous injuries and deaths to children who live, work and play on farms, coupled with the lack of a comprehensive national surveillance system in the United States, highlights the need for making the best use of publicly available youth agricultural injury data. Objective: The purpose of this study was to describe a 3-year collection of youth agricultural injuries using the publicly available injury and fatality data from AgInjuryNews.org and present recommendations for future injury prevention strategies. Methods: Data were obtained from AgInjuryNews.org, a web-based collection of U.S. news reports of agricultural injuries. We analyzed cases from 2015 to 2017 for youth aged 0-17. We classified injuries as occupational and non-occupational related, based on the Farm and Agricultural Injury Classification (FAIC) code. Each case was also coded for source and event using the Occupational Injury and Illness Classification System (OIICS). Results: Of the 348 injury reports reviewed, 51% were fatal, and about one-third of the victims were 6 years old or younger. Most injuries were non-occupational, and the most frequent injury sources were vehicles (includes tractors and all-terrain vehicles) and machinery. Youth operators, extra riders, roadway operations, and unsupervised youth playing near or in a worksite were four key contributing factors associated with vehicle and machinery related injuries. Conclusions: This study reaffirms that youth agricultural-related injuries and fatalities are still a persistent problem in the United States. The hypothesis generating AgInjuryNews system can provide more current data than traditional surveillance datasets as a tool for understanding the sources of youth agricultural injuries, monitoring injury trends, and informing policy efforts and prevention strategies. Future studies should continue to explore and evaluate the comprehensiveness of this system's data and the impact of its dissemination, as well as similar rural health informatics solutions for integration into sustainable interventions that can be customized and delivered domestically and abroad.

Independent Scientific Review under the Endangered Species Act.

The directive from Congress in the Endangered Species Act obliging the US Fish and Wildlife Service and National Marine Fisheries Service along with other federal agencies to use the best available scientific information in their determinations-and calls from stakeholder communities to show that they have done so-have led the federal wildlife agencies to seek external, expert review of their determinations with increasing frequency over time. In the present article, we survey the agency determinations that may be subject to independent science review and the technical tasks embedded in those determinations that can benefit from such review. We go on to identify common failures in scientific review that compromise the quality and reliability of agency determinations and then describe the attributes of independent scientific reviews that enable the agencies to discharge their statutory duties while seeking to conserve threatened and endangered species and the ecosystems on which they depend.

Correction: Behavioral and synaptic alterations relevant to obsessivecompulsive disorder in mice with increased EAAT3 expression.

The original version of this Article contained an error in the spelling of the author Anna K Radke, which was incorrectly given as Anna R Radke. This has now been corrected in both the PDF and HTML versions of the Article.

Behavioral and synaptic alterations relevant to obsessive-compulsive disorder in mice with increased EAAT3 expression.

Obsessive-compulsive disorder (OCD) is a severe, chronic neuropsychiatric disorder with a strong genetic component. The SLC1A1 gene encoding the neuronal glutamate transporter EAAT3 has been proposed as a candidate gene for this disorder. Gene variants affecting SLC1A1 expression in human brain tissue have been associated with OCD. Several mouse models fully or partially lacking EAAT3 have shown no alterations in baseline anxiety-like or repetitive behaviors. We generated a transgenic mouse model (EAAT3glo) to achieve conditional, Cre-dependent EAAT3 overexpression and evaluated the overall impact of increased EAAT3 expression at behavioral and synaptic levels. Mice with EAAT3 overexpression driven by CaMKIIα-promoter (EAAT3glo/CMKII) displayed increased anxiety-like and repetitive behaviors that were both restored by chronic, but not acute, treatment with fluoxetine or clomipramine. EAAT3glo/CMKII mice also displayed greater spontaneous recovery of conditioned fear. Electrophysiological and biochemical analyses at corticostriatal synapses of EAAT3glo/CMKII mice revealed changes in NMDA receptor subunit composition and altered NMDA-dependent synaptic plasticity. By recapitulating relevant behavioral, neurophysiological, and psychopharmacological aspects, our results provide support for the glutamatergic hypothesis of OCD, particularly for the increased EAAT3 function, and provide a valuable animal model that may open novel therapeutic approaches to treat this devastating disorder.

Using multiple coding schemes for classification and coding of agricultural injury.

BACKGROUND: Agricultural safety and health researchers have used a variety of classification and coding schemes to identify and categorize injury, illness, and disease associated with agricultural hazards. This paper demonstrates how the Farm and Agricultural Injury Classification (FAIC) and Occupational Injury and Illness Classification System (OIICS) coding schemes can be used in tandem for all agricultural injuries. METHODS: Specific cases from the AgInjuryNews.org database were selected to illustrate how the FAIC and OIICS codes can be applied to agricultural injury, and to illustrate limitations that still exist with each coding scheme. RESULTS: Using the FAIC and OIICS together provided a clearer picture of an injury incident by combining more explicit occupational and non-occupational exposures with incident type details in a single table. CONCLUSIONS: Both FAIC and OIICS coding schemes depend on sufficient information being available from injury reports. This paper concluded with suggestions for improving coding of agricultural injury.

Brain hyperserotonemia causes autism-relevant social deficits in mice.

Background: Hyperserotonemia in the brain is suspected to be an endophenotype of autism spectrum disorder (ASD). Reducing serotonin levels in the brain through modulation of serotonin transporter function may improve ASD symptoms. Methods: We analyzed behavior and gene expression to unveil the causal mechanism of ASD-relevant social deficits using serotonin transporter (Sert) knockout mice. Results: Social deficits were observed in both heterozygous knockout mice (HZ) and homozygous knockout mice (KO), but increases in general anxiety were only observed in KO mice. Two weeks of dietary restriction of the serotonin precursor tryptophan ameliorated both brain hyperserotonemia and ASD-relevant social deficits in Sert HZ and KO mice. The expression of rather distinct sets of genes was altered in Sert HZ and KO mice, and a substantial portion of these genes was also affected by tryptophan depletion. Tryptophan depletion in Sert HZ and KO mice was associated with alterations in the expression of genes involved in signal transduction pathways initiated by changes in extracellular serotonin or melatonin, a derivative of serotonin. Only expression of the AU015836 gene was altered in both Sert HZ and KO mice. AU015836 expression and ASD-relevant social deficits normalized after dietary tryptophan restriction. Conclusions: These findings reveal a Sert gene dose-dependent effect on brain hyperserotonemia and related behavioral sequelae in ASD and a possible therapeutic target to normalize brain hyperserotonemia and ASD-relevant social deficits.

Technology Use Among Youth While Operating Farm Equipment.

Distracted driving by using modern technologies has been linked with increased risk of injuries, however, the current research has focused primarily on the use of technology while operating roadway vehicles. The purpose of this study was to explore the use of technology while operating farm equipment among members of an agricultural youth organization (Pennsylvania FFA Association members). An online survey was used to examine the use of technology while operating a tractor, ATV/UTV, skid steer, and truck/car. Survey responses with 10 types of technology use were analyzed in relation to a wide variety of factors including frequency of use, safety beliefs, safety concern, and seeing others using technology. One hundred forty-three youth completed the questionnaire in 2017. Eighty-eight percent of youth surveyed used technology to some extent while operating farm equipment. Self-reported technology use was most influenced by safety beliefs and seeing others using technology while operating farm equipment regardless of the farm equipment type. Findings from this study provide insights into factors behind technology use while engaged in farm work-related driving by youth.

National Research and Extension Agenda for Agricultural Safety and Health Assessment.

This brief report for the Journal of Agromedicine presents key findings of a systematic review of scholarly products produced between 2004 and 2015 associated with agricultural safety and health priority areas. This brief report is derived from "A review of the National Research and Extension Agenda for Agricultural Safety and Health". The purpose of this report is to provide a synopsis of extension and research safety efforts and provide recommendations for extension. The scholarly products were classified into three main groups: peer-reviewed journal articles, technical conference papers, and educational products. It was found that more scholarly products were produced in the priority areas in more recent years, and more educational products were produced than peer-reviewed journal articles. Land-grant universities alone produce almost one-half of the total scholarly products within the priority areas.

Analysis of Limiting Factors Across the Life Cycle of Delta Smelt (Hypomesus transpacificus).

We developed a mechanistic life-cycle model derived from the elicitation of multiple factors influencing the success of individual life-stages of the imperiled delta smelt (Hypomesus transpacificus). We discuss the relevance of limiting factors in population ecology and problems with additive models in detecting them. We identify limiting factors and assess their significance using a non-linear optimization routine, combined with traditional metrics to assess the value of covariates and model performance. After reviewing previous conceptual models and multivariate analyses, we identified a set of factors that were consistent with conceptual models and useful in explaining the erratic fluctuations in a common abundance index: food at certain times in certain locations, predation by introduced species primarily in the spring, and entrainment. The analytical approach provides a transparent and intuitive framework in which to consider the contribution of covariates and consequences for population trends, and has the potential to assist with the evaluation of proposed recovery measures.