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Abstract Background “Herbarium X-ray Fluorescence (XRF) Ionomics” is a new quantitative approach for extracting the elemental concentrations from herbarium specimens using handheld XRF devices. These instruments are principally designed for dense sample material of infinite thickness (such as rock or soil powder), and their built-in algorithms and factory calibrations perform poorly on the thin dry plant leaves encountered in herbaria. While empirical calibrations have been used for ‘correcting’ measured XRF values post hoc, this approach has major shortcomings. As such, a universal independent data analysis pipeline permitting full control and transparency throughout the quantification process is highly desirable. Here we have developed such a pipeline based on Dynamic Analysis as implemented in the GeoPIXE package, employing a Fundamental Parameters approach requiring only a description of the measurement hardware and derivation of the sample areal density, based on a universal standard. Results The new pipeline was tested on potassium, calcium, manganese, iron, cobalt, nickel, and zinc concentrations in dry plant leaves. The Dynamic Analysis method can correct for complex X-ray interactions and performs better than both the built-in instrument algorithms and the empirical calibration approach. The new pipeline is also able to identify and quantify elements that are not detected and reported by the device built-in algorithms and provides good estimates of elemental concentrations where empirical calibrations are not straightforward. Conclusions The new pipeline for processing XRF data of herbarium specimens has a greater accuracy and is more robust than the device built-in algorithms and empirical calibrations. It also gives access to all elements detected in the XRF spectrum. The new analysis pipeline has made Herbarium XRF approach even more powerful to study the metallome of existing plant collections.

Background: Delivering ethical care in global plastic surgery is challenging due to the unique complexities of resource-limited settings. Additionally, the rise of medical tourism has highlighted the importance of informed consent and awareness of the potential risks that are associated with seeking medical care in foreign countries. This article aims to consider core medical ethics principles and apply them in the context of delivering global plastic surgery., Methods: This article examines the application of the four core medical ethics principles in a framework set forth by Beauchamp and Childress, namely autonomy, beneficence, nonmaleficence, and justice, in the context of delivering plastic surgery in international settings. A literature review was performed, where all potential global plastic surgery articles were reviewed to better understand the application of the four core medical ethics framework in this context., Results: Increased communication between visiting surgeons and local healthcare providers; heightened education of surgeons traveling to low-to-middle-income countries regarding local medical practices, resource availability, and cultural norms before providing surgical education; and a greater emphasis on collecting and publishing data analyzing short- and long-term outcomes in low-to-middle-income countries are all likely to improve the success of international medical missions, ensuring that all patients receive medical treatment in a manner that upholds Beauchamp and Childress' four core medical ethics principles., Conclusion: Providing plastic and reconstructive surgery abroad can be done ethically if the four main principles of medical ethics (respect for autonomy, beneficence, nonmaleficence, and justice) are used., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

The scientific and ethical issues associated with the use of animal-derived antibodies in research can be overcome by the use of animal-free, sequence-defined recombinant antibodies, whose benefits are well documented. Here, we describe progress made following a 2019 expert meeting focused on improving the quality and reproducibility of biomedical research by accelerating the production and use of animal-free recombinant antibodies in the USA. In the five intervening years since the meeting, participants have established multifaceted initiatives to tackle the next steps outlined during the meeting. These initiatives include: prioritising the replacement of ascites-derived and polyclonal antibodies; distributing educational materials describing recombinant antibodies; fostering public-private partnerships to increase access to recombinant antibodies; and increasing the availability of funding for recombinant antibody development. Given the widescale use of antibodies across scientific disciplines, a transition to modern antibody production methods relies on a commitment from government agencies, universities, industry and funding organisations, to initiatives such as those outlined here., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Toxicants with the potential to bioaccumulate in humans and animals have long been a cause for concern, particularly due to their association with multiple diseases and organ injuries. Per- and polyfluoro alkyl substances (PFAS) and polycyclic aromatic hydrocarbons (PAH) are two such classes of chemicals that bioaccumulate and have been associated with steatosis in the liver. Although PFAS and PAH are classified as chemicals of concern, their molecular mechanisms of toxicity remain to be explored in detail. In this study, we aimed to identify potential mechanisms by which an acute exposure to PFAS and PAH chemicals can induce lipid accumulation and whether the responses depend on chemical class, dose, and sex. To this end, we analyzed mechanisms beginning with the binding of the chemical to a molecular initiating event (MIE) and the consequent transcriptomic alterations. We collated potential MIEs using predictions from our previously developed ToxProfiler tool and from published steatosis adverse outcome pathways. Most of the MIEs are transcription factors, and we collected their target genes by mining the TRRUST database. To analyze the effects of PFAS and PAH on the steatosis mechanisms, we performed a computational MIE-target gene analysis on high-throughput transcriptomic measurements of liver tissue from male and female rats exposed to either a PFAS or PAH. The results showed peroxisome proliferator-activated receptor (PPAR)-α targets to be the most dysregulated, with most of the genes being upregulated. Furthermore, PFAS exposure disrupted several lipid metabolism genes, including upregulation of fatty acid oxidation genes ( Acadm , Acox1 , Cpt2 , Cyp4a1 - 3 ) and downregulation of lipid transport genes ( Apoa1 , Apoa5 , Pltp ). We also identified multiple genes with sex-specific behavior. Notably, the rate-limiting genes of gluconeogenesis ( Pck1 ) and bile acid synthesis ( Cyp7a1 ) were specifically downregulated in male rats compared to female rats, while the rate-limiting gene of lipid synthesis ( Scd ) showed a PFAS-specific upregulation. The results suggest that the PPAR signaling pathway plays a major role in PFAS-induced lipid accumulation in rats. Together, these results show that PFAS exposure induces a sex-specific multi-factorial mechanism involving rate-limiting genes of gluconeogenesis and bile acid synthesis that could lead to activation of an adverse outcome pathway for steatosis., Competing Interests: Authors AH, MA, and VP were employed by The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Authors MB-M, DM, DP, ES, and RS were employed by Sciome LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Hari, AbdulHameed, Balik-Meisner, Mav, Phadke, Scholl, Shah, Casey, Auerbach, Wallqvist and Pannala.)

Objective: This study investigates Enhanced Recovery After Surgery (ERAS®) protocols' impact on long-term opioid and sedative use following mastectomy with or without implant-based breast reconstruction (IBBR)., Summary Background Data: ERAS® protocols for patients undergoing mastectomy with or without IBBR are associated with decreased length of stay, increased rate of same-day discharge, decreased postoperative pain, and decreased postoperative opioid requirements. However, less is known about their effect on opioid and sedative use beyond 90 days after surgery., Methods: A retrospective review of all patients undergoing mastectomy with or without IBBR at a single institution between January 2013 and December 2019. Mastectomy ERAS® protocols were implemented in February 2017, creating two groups: pre-ERAS® and ERAS®. Baseline characteristics and prevalence of chronic opioid and sedative use were compared. Univariable and multivariable logistic regression predicted factors associated with increased odds of chronic opioid and sedative use., Results: 756 patients were evaluated: 405 pre-ERAS® and 351 ERAS®. Post-ERAS®, chronic opioid use decreased in opioid-naïve (40% vs. 30%, P=0.024) and opioid-tolerant patients (58% vs. 37%, P=0.002), with no increase in chronic sedative use. There were decreased odds of chronic opioid use for all ERAS® patients (OR=0.57, 95% CI: 0.42-0.76)), and of IBBR patients, those receiving subcutaneous implants (OR=0.31, 95% CI: 0.20-0.48). There was increased chronic opioid-use odds if undergoing bilateral surgery (OR=1.54, 95% CI: 1.14-2.08), two-stage reconstruction (OR=9.78, 95% CI: 5.94-16.09), and for patients with higher PACU pain scores (OR=1.09, 95% CI: 1.03-1.14) or >150 discharge OMEs (OR=2.63, 95% CI: 1.48-4.68)., Conclusion: ERAS® protocols for mastectomy patients with or without IBR are associated with decreases in chronic opioid use, without concomitant increases in chronic sedative use., Competing Interests: Disclosures/ Funding: The authors have no financial or other conflicts of interest pertaining to this research to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The eukaryotic lineage has enjoyed a long-term "stable" mutualism between nucleus and mitochondrion, since mitochondrial endosymbiosis began about 2 billion years ago. This mostly cooperative interaction has provided the basis for eukaryotic expansion and diversification, which has profoundly altered the forms of life on Earth. While we ignore the exact biochemical details of how the alpha-proteobacterial ancestor of mitochondria entered into endosymbiosis with a proto-eukaryote, in more general terms, we present a signaling games perspective of how the cooperative relationship became established, and has been maintained. While games are used to understand organismal evolution, information-asymmetric games at the molecular level promise novel insights into endosymbiosis. Using a previously devised biomolecular signaling games approach, we model a sender-receiver information asymmetric game, in which the informed mitochondrial sender signals and the uninformed nuclear receiver may take actions (involving for example apoptosis, senescence, regeneration and autophagy/mitophagy). The simulation shows that cellularization is a stabilizing mechanism for Pareto efficient sender/receiver strategic interaction. In stark contrast, the extracellular environment struggles to maintain efficient outcomes, as senders are indifferent to the effects of their signals upon the receiver. Our hypothesis has translational implications, such as in cellular therapy, as mitochondrial medicine matures. It also inspires speculative conjectures about how an analogous human-AI endosymbiosis may be engineered.

Traditionally, chemical toxicity is determined by in vivo animal studies, which are low throughput, expensive, and sometimes fail to predict compound toxicity in humans. Due to the increasing number of chemicals in use and the high rate of drug candidate failure due to toxicity, it is imperative to develop in vitro, high-throughput screening methods to determine toxicity. The Tox21 program, a unique research consortium of federal public health agencies, was established to address and identify toxicity concerns in a high-throughput, concentration-responsive manner using a battery of in vitro assays. In this article, we review the advancements in high-throughput robotic screening methodology and informatics processes to enable the generation of toxicological data, and their impact on the field; further, we discuss the future of assessing environmental toxicity utilizing efficient and scalable methods that better represent the corresponding biological and toxicodynamic processes in humans.

Background: Although the overall psychosocial benefits and body image gains of postmastectomy breast reconstruction are well-established, there is limited information on how postoperative complications affect patient quality of life (QOL)., Study Design: A single-institution cross-sectional survey analysis was performed on patients who underwent postmastectomy breast reconstruction between 2008 and 2020. QOL was assessed using the BREAST-Q and the Was It Worth It questionnaires. The results were compared among patients who had major complications, minor complications, and no complications. Responses were compared using 1-way ANOVA and chi-square tests as appropriate., Results: A total of 568 patients met inclusion criteria, and 244 patients responded (43% response rate). Most patients did not have any complications (n = 128; 52%), 41 had minor complications (17%), and 75 had major complications (31%). There were no differences in any of the BREAST-Q well-being metrics based on degree of complication. Across all 3 groups, patients reported that surgery was worthwhile (n = 212; 88%), they would choose reconstruction again (n = 203; 85%), and they would recommend it to a friend (n = 196; 82%). Overall, 77% reported that their overall experience either met or exceeded expectations, and 88% of patients had unchanged or improved overall QOL., Conclusions: Our study demonstrates that QOL and well-being are not negatively impacted by postoperative complications. Although patients who had no complications had an overall more positive experience, nearly two-thirds of all patients, no matter the degree of complication, stated that their overall experience either met or exceeded their expectations., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Chemical regulatory authorities around the world require systemic toxicity data from acute exposures via the oral, dermal, and inhalation routes for human health risk assessment. To identify opportunities for regulatory uses of non-animal replacements for these tests, we reviewed acute systemic toxicity testing requirements for jurisdictions that participate in the International Cooperation on Alternative Test Methods (ICATM): Brazil, Canada, China, the European Union, Japan, South Korea, Taiwan, and the USA. The chemical sectors included in our review of each jurisdiction were cosmetics, consumer products, industrial chemicals, pharmaceuticals, medical devices, and pesticides. We found acute systemic toxicity data were most often required for hazard assessment, classification, and labeling, and to a lesser extent quantitative risk assessment. Where animal methods were required, animal reduction methods were typically recommended. For many jurisdictions and chemical sectors, non-animal alternatives are not accepted, but several jurisdictions provide guidance to support the use of test waivers to reduce animal use for specific applications. An understanding of international regulatory requirements for acute systemic toxicity testing will inform ICATM's strategy for the development, acceptance, and implementation of non-animal alternatives to assess the health hazards and risks associated with acute toxicity.

Background: This study aimed to evaluate how enhanced recovery (ER) protocols and same-day discharge (SDD) influences patients' postoperative quality of life (QOL)., Methods: Patients who underwent mastectomy with implant-based breast reconstruction from 2008 to 2020 were identified in a prospective database. The study assessed QOL with BREAST-Q and Was It Worth It? (WIWI) questionnaires. Responses were compared between the ER and pre-ER groups and between the SDD and hospital stay (HS) groups using one-way analysis of variance (ANOVA) and chi-square tests., Results: The inclusion criteria were met by 568 patients, with a 43% response rate, and 217 patients were included for analysis. Chest physical well-being was lower for the ER cohort, but postoperative breast satisfaction was higher. Psychosocial status, sexual well-being, and satisfaction with information given did not differ significantly between the ER group and the pre-ER or SDD group. In the compared groups, QOL did not differ significantly., Conclusions: Enhanced recovery with SDD after mastectomy using implant-based reconstruction did not have an adverse impact on patient postoperative QOL., (© 2023. Society of Surgical Oncology.)

Background: We sought to evaluate the impact of mastectomy type, post-mastectomy reconstruction choice, and procedure bilaterality, on patient perceived postoperative quality of life (QoL)., Methods: Patients who underwent post-mastectomy reconstruction between 2008 and 2020 were identified in a prospective database. QoL was assessed with the BREAST-Q and the Was It Worth It (WIWI) questionnaires. The results were compared between reconstruction type, reconstruction laterality, and type of mastectomy. Responses were compared using one-way analysis of variance (ANOVA) and chi-square tests., Results: 568 patients met inclusion criteria, and 244 patients responded (43%). QoL did not significantly vary between different reconstructions selected, procedure laterality, or mastectomy type. Patients who underwent DIEP flap were significantly more satisfied with their reconstructed breasts than implant-based reconstruction. Overall, over 85% of patients experienced improved or unchanged QoL no matter what reconstruction choices were made., Conclusion: Most domains of QOL are not impacted by mastectomy type, post-mastectomy reconstruction, or laterality., Competing Interests: Declaration of competing interest All authors of “The Impact of Mastectomy and Reconstruction Technique on Patient Perceived Quality of Life” have no financial or commercial conflicts of interest to disclose., (Copyright © 2022. Published by Elsevier Inc.)

Robust and efficient processes are needed to establish scientific confidence in new approach methodologies (NAMs) if they are to be considered for regulatory applications. NAMs need to be fit for purpose, reliable and, for the assessment of human health effects, provide information relevant to human biology. They must also be independently reviewed and transparently communicated. Ideally, NAM developers should communicate with stakeholders such as regulators and industry to identify the question(s), and specified purpose that the NAM is intended to address, and the context in which it will be used. Assessment of the biological relevance of the NAM should focus on its alignment with human biology, mechanistic understanding, and ability to provide information that leads to health protective decisions, rather than solely comparing NAM-based chemical testing results with those from traditional animal test methods. However, when NAM results are compared to historical animal test results, the variability observed within animal test method results should be used to inform performance benchmarks. Building on previous efforts, this paper proposes a framework comprising five essential elements to establish scientific confidence in NAMs for regulatory use: fitness for purpose, human biological relevance, technical characterization, data integrity and transparency, and independent review. Universal uptake of this framework would facilitate the timely development and use of NAMs by the international community. While this paper focuses on NAMs for assessing human health effects of pesticides and industrial chemicals, many of the suggested elements are expected to apply to other types of chemicals and to ecotoxicological effect assessments., (© 2022. The Author(s).)

Background: Enhanced recovery after surgery (ERAS) protocols following mastectomy with or without implant-based breast reconstruction (IBBR) include ketorolac for multimodal perioperative analgesia. There are concerns that ketorolac could be associated with increased risk of postoperative hematoma formation., Methods: Retrospective review of patients undergoing mastectomy with or without IBBR between January 2013 and December 2019 at a single institution. Patients received 15 mg, 30 mg, or no ketorolac depending on ERAS protocol adherence, patient characteristics, and surgeon preference. Clinically significant hematoma was defined as requiring surgical intervention on day of surgery or postoperative day 1. Patients were compared by demographics, surgical characteristics, ketorolac dose, and hematoma prevalence. Univariable and multivariable logistic regression evaluated hematoma formation odds., Results: Eight hundred patients met inclusion criteria: 477 received ketorolac. Those who received ketorolac were younger, had lower ASA scores, were more likely to have bilateral procedures and undergo concomitant IBBR, had longer operative times, were less likely to take antiplatelet or anticoagulation medications, had higher PACU pain scores, and had higher incidence of hematomas requiring surgical intervention. Of the cohort, 4.4% had clinically significant hematomas. The 15 mg and 30 mg ketorolac groups had similar prevalence (6.0% vs 5.8%, p = 0.95). On univariable regression, there were increased odds of hematoma formation in patients who were younger, had bilateral procedures, had longer OR times, and who received ketorolac. On multivariable regression, none of the prior variables remained significant., Conclusion: After accounting for associations with longer operative times, concomitant IBBR, and bilateral procedures, ketorolac administration did not remain an independent risk factor for hematoma formation., (© 2022. Society of Surgical Oncology.)

The U.S. Department of Agriculture (USDA) regulates the potency testing of leptospirosis vaccines, which are administered to animals to protect against infection by Leptospira bacteria. Despite the long-term availability of in vitro test methods for assessing batch potency, the use of hamsters in lethal in vivo batch potency testing persists to varying degrees across leptospirosis vaccine manufacturers. For all manufacturers of these products, data collected from public USDA records show an estimated 40% decline in the annual use of hamsters from 2014 to 2020, with an estimated 55% decrease in the number of hamsters expected to have been used in leptospirosis vaccine potency tests (i.e., those in USDA Category E). An estimated 49,000 hamsters were used in 2020, with about 15,000 hamsters in Category E specifically. Based on this assessment, additional efforts are needed to fully implement in vitro batch potency testing as a replacement for the in vivo batch potency test. We propose steps that can be taken collaboratively by the USDA Center for Veterinary Biologics (CVB), manufacturers of leptospirosis vaccines, government agencies, and non-governmental organizations to accelerate broader use of the in vitro approach., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Regulatory agencies rely upon rodent in vivo acute oral toxicity data to determine hazard categorization, require appropriate precautionary labeling, and perform quantitative risk assessments. As the field of toxicology moves toward animal-free new approach methodologies (NAMs), there is a pressing need to develop a reliable, robust reference data set to characterize the reproducibility and inherent variability in the in vivo acute oral toxicity test method, which would serve to contextualize results and set expectations regarding NAM performance. Such a data set is also needed for training and evaluating computational models. To meet these needs, rat acute oral LD50 data from multiple databases were compiled, curated, and analyzed to characterize variability and reproducibility of results across a set of up to 2441 chemicals with multiple independent study records. Conditional probability analyses reveal that replicate studies only result in the same hazard categorization on average at 60% likelihood. Although we did not have sufficient study metadata to evaluate the impact of specific protocol components (eg, strain, age, or sex of rat, feed used, treatment vehicle, etc.), studies were assumed to follow standard test guidelines. We investigated, but could not attribute, various chemical properties as the sources of variability (ie, chemical structure, physiochemical properties, functional use). Thus, we conclude that inherent biological or protocol variability likely underlies the variance in the results. Based on the observed variability, we were able to quantify a margin of uncertainty of ±0.24 log10 (mg/kg) associated with discrete in vivo rat acute oral LD50 values., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Toxicology.)

Rodent cancer bioassays have been long-required studies for regulatory assessment of human cancer hazard and risk. These studies use hundreds of animals, are resource intensive, and certain aspects of these studies have limited human relevance. The past 10 years have seen an exponential growth of new technologies with the potential to effectively evaluate human cancer hazard and risk while reducing, refining, or replacing animal use. To streamline and facilitate uptake of new technologies, a workgroup comprised of scientists from government, academia, non-governmental organizations, and industry stakeholders developed a framework for waiver rationales of rodent cancer bioassays for consideration in agrochemical safety assessment. The workgroup used an iterative approach, incorporating regulatory agency feedback, and identifying critical information to be considered in a risk assessment-based weight of evidence determination of the need for rodent cancer bioassays. The reporting framework described herein was developed to support a chronic toxicity and carcinogenicity study waiver rationale, which includes information on use pattern(s), exposure scenario(s), pesticidal mode-of-action, physicochemical properties, metabolism, toxicokinetics, toxicological data including mechanistic data, and chemical read-across from similar registered pesticides. The framework could also be applied to endpoints other than chronic toxicity and carcinogenicity, and for chemicals other than agrochemicals., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)