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OBJECTIVE: The authors examined the long-term health effects of occupational exposure to acrylamide among production and polymerisation workers. METHODS: An earlier study of 371 acrylamide workers was expanded to include employees hired since 1979. In this updated study, 696 acrylamide workers were followed from 1955 through 2001 to ascertain vital status and cause of death. Exposure to acrylamide was retrospectively assessed based on personal samples from the 1970s onwards and area samples over the whole study period. RESULTS: Fewer of the acrylamide workers died (n = 141) compared to an expected number of 172.1 (SMR 81.9, 95% CI 69.0 to 96.6). No cause-specific SMR for any of the investigated types of cancer was exposure related. The authors did, however, find more pancreatic cancer deaths than expected (SMR 222.2, 95% CI 72.1 to 518.5). With respect to non-malignant disease, more diabetes deaths were observed than expected (SMR 288.7, 95% CI 138.4 to 531.0). To assess the influence of regional factors, the analysis was repeated with an internal reference population. The elevated SMR for diabetes persisted. CONCLUSION: This study provides little evidence for a cancer risk from occupational exposure to acrylamide at production facilities. However, the increased rates of pancreatic cancer in this study and another larger study of acrylamide production workers indicate that caution is needed to rule out a cancer risk. The authors believe that the excess of diabetes mortality in this study is most likely not related to acrylamide exposure, because a larger study of acrylamide workers reported a deficit in this cause of death. The authors conclude that the increased SMR for diabetes mortality is probably not related to regional influences. [ABSTRACT FROM AUTHOR]

We observed 42,076 men and 11,706 women first employed at the Michigan locations of The Dow Chemical Company between 1940 and 1994. Follow-up was 98% complete, and we identified 16,242 deaths. Significant deficits in standardized mortality ratios were observed for all causes, all malignant neoplasms, and more than a dozen other causes of death when compared with rates in the United States. We observed significant elevations for several causes of death among employees of a magnesium foundry. There is little modern exposure information, because the foundry was sold nearly 40 years ago. This routine surveillance activity provided a generally favorable overview of the health experience of our employees and did not suggest a need for an additional focused study. [ABSTRACT FROM AUTHOR]

Objective: To update and add to a previously identified cohort of employees potentially exposed to the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D). The putative association between 2,4-D and non-Hodgkin's lymphoma has been debated for more than a decade.Methods: Cohort members were male employees of The Dow Chemical Company who manufactured or formulated 2,4-D any time from 1945 to the end of 1994. Their mortality experience was compared with national rates and with more than 40 000 other company employees who worked at the same location.Results: 330 Deaths were observed among 1517 people compared with 365 expected (standardised mortality ratio (SMR)=0.90, 95% confidence interval (95% CI) 0.81 to 1.01). There were no significantly increased SMRs for any of the causes of death analyzed. When compared with the United States rates, the SMR for non-Hodgkin's lymphoma (NHL) was 1.00 (95% CI 0.21 to 2.92). The internal comparison with other Dow employees showed a non-significant relative risk of 2.63, (95% CI 0.85 to 8.33). Death was attributed to amyotrophic lateral sclerosis (ALS) for three cohort members. Compared with the other company employees, the relative risk was 3.45 (95% CI 1.10 to 11.11). The cases were employed in the manufacture or formulation of 2,4-D at different periods (1947-9, 1950-1, and 1968-86), and for varying durations of time (1.3, 1.8, and 12.5 years).Conclusion: There was no evidence of a causal association between exposure to 2,4-D and mortality due to all causes and total malignant neoplasms. No significant risk due to NHL was found. Although not an initial hypothesis, an increased relative risk of ALS was noted. This finding is unsupported by other animal and human studies. [ABSTRACT FROM AUTHOR]

On 1 January 2021, the United Kingdom formally exited the European Union (EU; Brexit) and ceased to be subject to EU chemical regulation requirements. Before Brexit, UK chemical policy was regulated largely by the EU. With its large internal market, sophisticated regulatory capability, and stringent regulatory framework, the EU has become the world's leading regulatory state, regularly influencing global industrial decisions and practices. At the time of writing, there has been limited academic analysis of the implications of Brexit for UK chemical regulation. More than two years post-Brexit, we have the opportunity to assess UK chemical regulation and revisit early expectations about regulatory divergence. This article takes the EU's Regulation on the Registration, Evaluation, Authorisation, and Restriction of Chemicals (REACH) as a case study to analyze patterns of post-Brexit regulatory divergence, thereby providing one of the first analyses of the implications of Brexit on UK chemical regulation. Through the analysis and review of key documents and reports (n = 99), this article assesses the extent to which UK and EU regulatory (REACH) regimes are beginning to diverge and discusses the potential implications of any divergence for the United Kingdom. We find that the UK and EU chemical regulatory regimes are now evolving independently and provide clear, empirical evidence of an emerging divergence in regulatory decisions, ambitions, and approaches. The evidence suggests that the United Kingdom is currently unable to keep pace with EU developments, lacking the capacity, expertise, and capability of its EU counterparts, raising the prospect of further divergence in the future. Integr Environ Assess Manag 2024;20:1529-1538. © 2024 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC)., (© 2024 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).)

We conducted a literature review of urinary 2,4-D in populations not associated with a herbicide application. Of the 33 studies identified, the median/mean concentrations were similar for children, adults, and pregnant women regardless of geography. Individuals with highest concentrations may have had opportunities to directly contact 2,4-D outside of an application. Most studies were conducted in populations in North America and did not examine potential sources of 2,4-D, or what factors might influence higher or lower urinary 2,4-D concentrations. In the future, prioritizing the examination of 2,4-D biomonitoring in other regions and collecting information on sources and factors influencing exposures would better our understanding of 2,4-D exposures globally. In all the studies reviewed the concentrations of urinary 2,4-D observed were orders of magnitude below the US regulatory endpoints, suggesting that people are not being exposed to 2,4-D at levels high enough to result in adverse health effects., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The literature search and data extraction were conducted while one of the authors (DB) was an employee of Corteva AgriScience. CJB is retired from The Dow Chemical Company, a manufacturer of 2,4-D. The writing of the report, which is reflected in the review, synthesis, and conclusions are the exclusive professional work product of the authors and do not necessarily represent the views of the Corteva AgriScience. A courtesy copy of the draft manuscript was provided to Corteva AgriScience., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: This study compared a novel topical hydrogel burn dressing (CI-PRJ012) to standard of care (silver sulfadiazine) and to untreated control in a swine thermal burn model, to assess for wound healing properties both in the presence and absence of concomitant bacterial inoculation., Methods: Eight equal burn wounds were created on six Yorkshire swine. Half the wounds were randomized to post-burn bacterial inoculation. Wounds were subsequently randomized to three treatments groups: no intervention, CI-PRJ012, or silver sulfadiazine cream. At study end, a blinded pathologist evaluated wounds for necrosis and bacterial colonization., Results: When comparing CI-PRJ012 and silver sulfadiazine cream to no treatment, both agents significantly reduced the amount of necrosis and bacteria at 7 days after wound creation (p < 0.01, independently for both). Further, CI-PRJ012 was found to be significantly better than silver sulfadiazine (p < 0.02) in reducing bacterial colonization. For wound necrosis, no significant difference was found between silver sulfadiazine cream and CI-PRJ012 (p = 0.33)., Conclusions: CI-PRJ012 decreases necrosis and bacterial colonization compared to no treatment in a swine model. CI-PRJ012 appeared to perform comparably to silver sulfadiazine. CI-PRJ012, which is easily removed with the application of room-temperature water, may provide clinical advantages over silver sulfadiazine., Competing Interests: Declaration of Competing Interest TLG and JDR have no conflicts of interest to declare. CJB, JT, and DAT were paid consultants on this project. RID, TCF, OJB, JSC, DG, NNC, and JKA are employees of Critical Innovations. RID, TCF, OJB, JSC, NNC, and JKA are inventors of CI-PRJ012 technology, with related intellectual property rights., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Polyethylene glycol (PEG) is a synthetic, biodegradable, and hyperosmotic material promising in the treatment of acute peripheral nerve injuries. Our team set out to investigate the impact of fibrin glue upon PEG fusion in a rat model., Methods: Eighteen rats underwent sciatic nerve transection and PEG fusion. Electrophysiologic testing was performed to measure nerve function and distal muscle twitch. Fibrin glue was applied and testing repeated. Due to preliminary findings, fibrin glue was applied to an uncut nerve in five rodents and testing was conducted before and after glue application. Mann-Whitney U tests were used to compare median values between outcome measures. A Shapiro-Wilk test was used to determine normality of data for each comparison, significance set at a P value less than 0.05., Results: PEG fusion was confirmed in 13 nerves with no significant change in amplitude ( P = 0.054), latency ( P = 0.114), or conduction velocity ( P = 0.114). Stimulation of nerves following PEG fusion produced distal muscle contraction in 100% of nerves. Following application of fibrin glue, there was a significant reduction in latency ( P = 0.023), amplitude ( P < 0.001), and conduction velocity ( P = 0.023). Stimulation of the nerve after application of fibrin glue did not produce distal muscle twitch. Five uncut nerves with fibrin glue application blocked distal muscle contraction following stimulation., Conclusions: Our data suggest that fibrin glue alters the nerve's function. The immediate confirmation of PEG fusion via distal muscle twitch is blocked with application fibrin glue in this experimental model. Survival and functional outcome studies are necessary to understand if this has implications on the long-term functional outcomes., Competing Interests: The authors have no financial interest to declare in relation to the content of this article. This project received grant funding from the AFSH resident fast track grant., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Air pollution accountability studies examine the relationship(s) between an intervention, regulation, or event and the resulting downstream impacts, if any, on emissions, exposure, and/or health. The sequence of events has been schematically described as an accountability chain. Here, we update the existing framework to capture real-life complexities and to highlight important factors that fall outside the linear chain. This new "accountability web" is intended to convey the intricacies associated with conducting an accountability study to various audiences, including researchers, policy makers, and stakeholders. We also identify data considerations for planning and completing a robust accountability study, including those relevant to novel and innovative air pollution and exposure data. Finally, we present a series of recommendations for the accountability research community that can serve as a guide for the next generation of accountability studies., Competing Interests: Support for the Workshop was provided by the 10.13039/100011253American Petroleum Institute (API). API was not involved in the Workshop deliberations nor in the preparation or approval of the manuscript. The authors retain sole responsibility for the writing and content of this paper, which represent the professional opinions of the authors and not necessarily those of API or its member companies. As Workshop facilitators, CJB, JEG, and JSL received compensation and travel support from 10.13039/100011253API. Travel support was also provided to all authors except AMR, HSE, and SL. Honoraria were provided to SE, LRFH, MN, AGR, and JWH. JSL, JEG, JWH, and CJB consult to governmental and private organizations, including API, on issues related to air pollution epidemiology. The views expressed in this manuscript are those of the authors and do not necessarily represent the views or policies of EPA, API (or its member companies), or co-authors' employers., (© 2023 The Authors. Published by Elsevier Inc.)

Pesticides are highly tested and regulated chemicals. There is currently great interest in the role that pesticides may play in childhood neurodevelopment. The objective was to identify and describe the body of evidence and to assess the ability to synthesize effect estimates. The epidemiologic literature from 2011 to 2022 was searched for publications on the association between pesticide exposure and neurodevelopment, behavior, and/or cognition in children. We identified 114 publications, representing 67 unique studies. While organochlorine and other insecticides were the most common classes of pesticides studied, up to 159 different metabolites or active ingredients were reported. Nine pesticides or their metabolites were reported in >10 publications. Similarly, multiple assessment methods were administered across studies to evaluate outcomes in neurodevelopment at ages which ranged from birth to 18 years of age. This scoping review reveals the heterogeneity among published studies with respect to exposures and health outcomes, in the methods used to assess and classify them, and in combinations of the two. This limits the adequacy of the evidence to evaluate specific risk estimates for a particular exposure-outcome pair. Intentional coordination among researchers to increase consistency in methodologies would facilitate the synthesis of results across studies. Research opportunities also exist to validate assumptions in exposure and outcome assessment which are implicit in many of the studies reviewed. In conclusion, there are many ongoing epidemiologic studies with a focus on pesticides and neurodevelopment. The variety of exposures, exposure assessment methods and tests for each outcome can be overwhelming. Interdisciplinary collaboration is recommended to harmonize data collection and to enable meaningful interpretation of the study results across populations., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JER is an employee of Bayer Crop Science, United States. FP is an employee of 10.13039/100004326Bayer AG, Germany. CJB consults to the private sector. CJB is a retiree and stockholder of 10.13039/100004341The Dow Chemical Company, United States., (© 2023 The Authors.)

Sexual violence (SV) is a widespread human rights issue. Survivors of SV often experience profound dehumanization and poor health outcomes when their trauma is not properly addressed, rendering it critical that they are honored and empowered within subsequent processes of healing and seeking justice. With adjudication through the criminal legal system largely underutilized due to retraumatization, scrutiny from law enforcement professionals, and high rates of case closure, restorative justice (RJ) has emerged as a promising option for survivors to repair harm and experience accountability. Little is known, however, regarding the best practices for its use in cases of SV. To meet this need, a scoping review was conducted to identify the best practices for the implementation of RJ after instances of SV experienced in adulthood. Following the search methodology outlined by the JBI Manual for Evidence Synthesis for scoping reviews, 15 articles met search criteria, including four empirical studies and 11 nonempirical research materials spanning five academic disciplines. Best practices and structures for RJ were subsequently identified, including key phases for appropriate implementation. This review can be used to create increasingly productive RJ processes for SV survivors, which is particularly important for those coming from marginalized communities facing structural inequities, as well as survivors on university campuses. As researchers, we have the power to use science to propel society toward the creation of more efficacious healing spaces for survivors of SV, and optimizing safe RJ processes plays a key role in bringing this to fruition.

Purpose: Trauma-exposed persons often experience difficulties accessing medical care, remaining engaged in treatment plans, and feeling psychologically safe when receiving care. Trauma-informed care (TIC) is an established framework for health care professionals, but best practices for TIC education remain unclear. To remedy this, the authors conducted a multidisciplinary scoping literature review to discern best practices for the design, implementation, and evaluation of TIC curricula for health care professionals., Method: The research team searched Ovid MEDLINE, Cochrane Library, Elsevier's Scopus, Elsevier's Embase, Web of Science, and the PTSDpubs database from the database inception date until May 14, 2021. Worldwide English language studies on previously implemented TIC curricula for trainees or professionals in health care were included in this review., Results: Fifty-five studies met the inclusion criteria, with medicine being the most common discipline represented. The most prevalent learning objectives were cultivating skills in screening for trauma and responding to subsequent disclosures (41 studies [74.5%]), defining trauma (34 studies [61.8%]), and understanding trauma's impact on health (33 studies [60.0%]). Fifty-one of the studies included curricular evaluations, with the most common survey items being confidence in TIC skills (38 studies [74.5%]), training content knowledge assessment (25 studies [49.0%]), participant demographic characteristics (21 studies [41.2%]), and attitudes regarding the importance of TIC (19 studies [37.3%])., Conclusions: Future curricula should be rooted in cultural humility and an understanding of the impacts of marginalization and oppression on individual and collective experiences of trauma. Moreover, curricula are needed for clinicians in more diverse specialties and across different cadres of care teams. Additional considerations include mandated reporting, medical record documentation, and vicarious trauma experienced by health care professionals., (Copyright © 2022 by the Association of American Medical Colleges.)

Background: Gender equity is a critical issue in academic medicine. Whether there is equitable access to the prestige and resources of endowed professorships merits evaluation. We investigated this question in obstetrics and gynecology, a field that focuses on the health of women and in which women are much better represented than other specialties of medicine. Materials and Methods: We compiled a list of the top 25 United States departments of obstetrics and gynecology and contacted department chairs (and used department websites) to obtain lists of faculty and their positions. Scopus, department websites, and National Institutes of Health (NIH) RePORTER were used to collect h-Index, number of publications and citations, graduation year, degrees, gender, and NIH-funding. We conducted a bivariate comparison of endowed professorship attainment by gender using a chi-square test and created a multiple variable regression model. Results: Of the 680 obstetrics and gynecology faculty across 23 departments that had endowed chairs, 64 out of 400 women (16%) and 66 out of 280 men (24%) held endowed chairs ( p  = 0.01). The multivariable model suggested no independent gender difference in attainment of an endowed chair after adjusting for covariates. Conclusion: To our knowledge, this study is the first to examine gender as a variable in endowed chair allocation in top obstetrics and gynecology academic departments. Our findings suggest a significant gender difference in the allocation of endowed chairs. That difference is driven by gender differences in academic rank, graduation year, publications, and funding. To promote the intraprofessional equity necessary to optimally advance women's health, further research and intervention are necessary.

The COVID-19 pandemic has resulted in an extraordinary incidence of morbidity and mortality, with almost 6 million deaths worldwide at the time of this writing (https://covid19.who.int/). There has been a pressing need for research that would shed light on factors - especially modifiable factors - that could reduce risks to human health. At least several hundred studies addressing the complex relationships among transmission of SARS-CoV-2, air pollution, and human health have been published. However, these investigations are limited by available and consistent data. The project goal was to seek input into opportunities to improve and fund exposure research on the confluence of air pollution and infectious agents such as SARS-CoV-2. Thirty-two scientists with expertise in exposure science, epidemiology, risk assessment, infectious diseases, and/or air pollution responded to the outreach for information. Most of the respondents expressed value in developing a set of common definitions regarding the extent and type of public health lockdown. Traffic and smoking ranked high as important sources of air pollution warranting source-specific research (in contrast with assessing overall ambient level exposures). Numerous important socioeconomic factors were also identified. Participants offered a wide array of inputs on what they considered to be essential studies to improve our understanding of exposures. These ranged from detailed mechanistic studies to improved air quality monitoring studies and prospective cohort studies. Overall, many respondents indicated that these issues require more research and better study design. As an exercise to solicit opinions, important concepts were brought forth that provide opportunities for scientific collaboration and for consideration for funding prioritization. Further conversations on these concepts are needed to advance our thinking on how to design research that moves us past the documented limitations in the current body of research and prepares us for the next pandemic., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Pyrethroid insecticides have been the subject of numerous epidemiology studies in the past two decades. We examined the pyrethroids epidemiology literature published between 2016 and 2021. Our objective with this exercise was to inform interested readers regarding information on methodological elements that strengthen a study's use for translation (i.e., use in risk assessment) and to describe aspects of future research methods that could improve utility for decision-making. We focused on the following elements: (i) study design that provided evidence that pyrethroid exposure preceded the outcome, (ii) evidence that the method used for exposure characterization was reliable and sufficiently accurate for the intended purpose, and (iii) use of a robust approach for outcome ascertainment. For each of the 74 studies identified via the literature search, we categorized the methodological elements as Acceptable or Supplemental. A study with three Acceptable elements was considered Relevant for risk assessment purposes. Based on our evaluative approach, 18 (24%) of the 74 publications were considered to be Relevant. These publications were categorized as Acceptable for all three elements assessed: confirmed exposure (N = 24), confirmed outcome (N = 64), exposure preceded the outcome (N = 44). Three of these studies were birth cohorts. There were 15 Relevant publications of adults which included 10 Agricultural Health Study cohort publications of self-reported permethrin. Overall, the majority of the reviewed studies used methods that did not permit a determination that pyrethroid exposure preceded the outcome, and/or did not utilize robust methods for exposure assessment and outcome ascertainment. There is an opportunity for investigators and research sponsors to build on the studies reviewed here and to incorporate more translational approaches to studying exposure/outcome associations related to pesticides and other chemicals., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Carol Burns and Judy LaKind consult to governmental and/or private sectors. Carol Burns is retired from The Dow Chemical Company, which manufactured and sold pesticides; albeit not pyrethroids., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Structural changes involving tissue remodelling and fibrosis are major features of many pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Abnormal deposition of extracellular matrix (ECM) proteins is a key factor in the development of tissue remodelling that results in symptoms and impaired lung function in these diseases. Tissue remodelling in the lungs is complex and differs between compartments. Some pathways are common but tissue remodelling around the airways and in the parenchyma have different morphologies. Hence it is critical to evaluate both common fibrotic pathways and those that are specific to different compartments; thereby expanding the understanding of the pathogenesis of fibrosis and remodelling in the airways and parenchyma in asthma, COPD and IPF with a view to developing therapeutic strategies for each. Here we review the current understanding of remodelling features and underlying mechanisms in these major respiratory diseases. The differences and similarities of remodelling are used to highlight potential common therapeutic targets and strategies. One central pathway in remodelling processes involves transforming growth factor (TGF)-β induced fibroblast activation and myofibroblast differentiation that increases ECM production. The current treatments and clinical trials targeting remodelling are described, as well as potential future directions. These endeavours are indicative of the renewed effort and optimism for drug discovery targeting tissue remodelling and fibrosis., Competing Interests: Declaration of Competing Interest T.C. reports grants and/or personal fees from Boehringer Ingelheim, Roche, Gilead, Bayer, Intermune, AstraZeneca, BMS, Promedior, Ad Alta. C.J.B is a director and shareholder of Amplia Therapeutics, developing anti-fibrotic drugs for the treatment of IPF. P.M.H. has received funding from Pharmaxis for the study of LOX2 inhibitors, and is on the Scientific Advisory Board of Amplia Therapeutics. J.K.B has received research funding from Boehringer Ingelheim. Other authors declare that there are no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The Matrix is designed to facilitate discussions between practitioners of risk assessment and epidemiology and, in so doing, to enhance the utility of epidemiology research for public health decision-making. The Matrix is comprised of nine fundamental "asks" of epidemiology studies, focusing on the types of information valuable to the risk assessment process., Objective: A 2,4-dichlorophenoxyacetic acid (2,4-D) case study highlights the extent to which existing epidemiology literature includes information generally needed for risk assessments and proffers suggestions that would assist in bridging the epidemiology/risk assessment gap., Methods: Thirty-one publications identified in the US Environmental Protection Agency 2,4-D epidemiology review were assessed. These studies focused on associations between 2,4-D exposure and non-Hodgkin lymphoma (NHL), respiratory effects, and birth outcomes., Results: Many of the papers met one or more specific elements of the Matrix. However, from this case study, it is clear that some aspects of risk assessment, such as evaluating source-to-intake pathways, are generally not considered in epidemiology research. Others are incorporated, but infrequently (e.g. dose-response information, harmonization of exposure categories). We indicated where additional analyses or modifications to future study design could serve to improve the translation., Discussion: Interaction with risk assessors during the study design phase and using the Matrix "asks" to guide the conversations could shape research and provide the basis for requests for funds to support these additional activities. The use of the Matrix as a foundation for communication and education across disciplines could produce more impactful and consequential epidemiology research for robust risk assessments and decision-making.

A major antimicrobial resistance mechanism in Gram-negative bacteria is the production of β-lactamase enzymes. The increasing emergence of β-lactamase-producing multi-drug-resistant "superbugs" has resulted in increases in costly hospital Emergency Department (ED) visits and hospitalizations due to the requirement for parenteral antibiotic therapy for infections caused by these difficult-to-treat bacteria. To address the lack of outpatient treatment, we initiated an iterative program combining medicinal chemistry, biochemical testing, microbiological profiling, and evaluation of oral pharmacokinetics. Lead optimization focusing on multiple smaller, more lipophilic active compounds, followed by an exploration of oral bioavailability of a variety of their respective prodrugs, provided 36 (VNRX-7145/VNRX-5236 etzadroxil), the prodrug of the boronic acid-containing β-lactamase inhibitor 5 (VNRX-5236). In vitro and in vivo studies demonstrated that 5 restored the activity of the oral cephalosporin antibiotic ceftibuten against Enterobacterales expressing Ambler class A extended-spectrum β-lactamases, class A carbapenemases, class C cephalosporinases, and class D oxacillinases.

There is an urgent need for oral agents to combat resistant Gram-negative pathogens. Here, we describe the characterization of VNRX-5236, a broad-spectrum boronic acid β-lactamase inhibitor (BLI), and its orally bioavailable etzadroxil prodrug, VNRX-7145. VNRX-7145 is being developed in combination with ceftibuten, an oral cephalosporin, to combat strains of Enterobacterales expressing extended-spectrum β-lactamases (ESBLs) and serine carbapenemases. VNRX-5236 is a reversible covalent inhibitor of serine β-lactamases, with inactivation efficiencies on the order of 10 4 M -1 · sec -1 , and prolonged active site residence times ( t 1/2 , 5 to 46 min). The spectrum of inhibition includes Ambler class A ESBLs, class C cephalosporinases, and class A and D carbapenemases (KPC and OXA-48, respectively). Rescue of ceftibuten by VNRX-5236 (fixed at 4 μg/ml) in isogenic strains of Escherichia coli expressing class A, C, or D β-lactamases demonstrated an expanded spectrum of activity relative to oral comparators, including investigational penems, sulopenem, and tebipenem. VNRX-5236 rescued ceftibuten activity in clinical isolates of Enterobacterales expressing ESBLs (MIC 90 , 0.25 μg/ml), KPCs (MIC 90 , 1 μg/ml), class C cephalosporinases (MIC 90 , 1 μg/ml), and OXA-48-type carbapenemases (MIC 90 , 1 μg/ml). Frequency of resistance studies demonstrated a low propensity for recovery of resistant variants at 4× the MIC of the ceftibuten/VNRX-5236 combination. In vivo , whereas ceftibuten alone was ineffective (50% effective dose [ED 50 ], >128 mg/kg), ceftibuten/VNRX-7145 administered orally protected mice from lethal septicemia caused by Klebsiella pneumoniae producing KPC carbapenemase (ED 50 , 12.9 mg/kg). The data demonstrate potent, broad-spectrum rescue of ceftibuten activity by VNRX-5236 in clinical isolates of cephalosporin-resistant and carbapenem-resistant Enterobacterales .

Purpose: The aim was to identify the scope of the epidemiology literature reviewed regarding the risk of cancer as related to occupational exposure to pesticides and to compare regulatory toxicity results where feasible., Methods: Review studies of breast, lung, prostate, non-Hodgkin lymphoma, and colorectal cancer were identified from the published literature from 2010 to 2020 using a priori inclusion and exclusion criteria. Epidemiology observations were first assessed and then compared against carcinogenicity profiles derived from regulatory toxicology studies., Results: Several active ingredients were associated with specific cancer but overall, there was neither strong nor consistent epidemiologic data supportive of a positive association between pesticide exposure in occupational settings and cancer. Authors noted common themes related to the heterogeneity of exposure, study design, control for confounders, and the challenge to collect these data reliably and validly with an adequate sample size. Toxicology studies in laboratory animals that assessed carcinogenic potential did not reveal cancer outcomes that were concordant with reported epidemiologic findings., Conclusions: Farming and pesticides represent diverse exposures that are difficult to quantify in epidemiologic studies. Going forward, investigators will need creative and novel approaches for exposure assessment. Integration of epidemiologic and toxicological studies with attention to biological plausibility, mode of toxicological action and relevance to humans will increase the ability to better assess associations between pesticides and cancer.

We utilized a practical, transparent approach for systematically reviewing a chemical-specific evidence base. This approach was used for a case study of ozone inhalation exposure and adverse metabolic effects (overweight/obesity, Type 1 diabetes [T1D], Type 2 diabetes [T2D], and metabolic syndrome). We followed the basic principles of systematic review. Studies were defined as "Suitable" or "Supplemental." The evidence for Suitable studies was characterized as strong or weak. An overall causality judgment for each outcome was then determined as either causal, suggestive, insufficient, or not likely. Fifteen epidemiologic and 33 toxicologic studies were Suitable for evidence synthesis. The strength of the human evidence was weak for all outcomes. The toxicologic evidence was weak for all outcomes except two: body weight, and impaired glucose tolerance/homeostasis and fasting/baseline hyperglycemia. The combined epidemiologic and toxicologic evidence was categorized as weak for overweight/obesity, T1D, and metabolic syndrome,. The association between ozone exposure and T2D was determined to be insufficient or suggestive. The streamlined approach described in this paper is transparent and focuses on key elements. As systematic review guidelines are becoming increasingly complex, it is worth exploring the extent to which related health outcomes should be combined or kept distinct, and the merits of focusing on critical elements to select studies suitable for causal inference. We recommend that systematic review results be used to target discussions around specific research needs for advancing causal determinations.