Acute Pain Management in a Multi-site Trauma Patient.

Pain management is often difficult in the setting of multi-site trauma such as that caused by motor vehicle accidents (MVA), which is especially compounded in the setting of polysubstance abuse. This often results in patients with poor pain tolerance requiring escalating doses of opioid therapy, which creates a vicious cycle. The use of peripheral nerve blocks (PNB) has been shown to decrease overall opioid consumption and can be used effectively to manage postoperative pain in this patient population. Our case report aims to highlight the importance of PNBs as part of a multimodal approach to pain management in patients with polytrauma in the setting of polysubstance abuse.

Serum Levels of Bupivacaine After Bilateral Ultrasound-Guided Deep Parasternal Intercostal Plane Block in Cardiac Surgery with Median Sternotomy.

OBJECTIVE: To evaluate systemic levels of bupivacaine after bilateral ultrasound-guided deep parasternal intercostal plan (PIP) block in cardiac surgical patients undergoing median sternotomy. DESIGN: Prospective, observational study SETTING: Single institution; academic university hospital PARTICIPANTS: Twenty-eight adult patients undergoing cardiac surgery with median sternotomy received a PIP block with 2.5 mg/kg bupivacaine with or without dexamethasone and dexmedetomidine. MEASUREMENTS: Arterial blood samples were analyzed for total serum bupivacaine concentration at 5, 15, 30, 45, 60, 90, 120, and 150 minutes after placement of PIP. Local anesthetic volume, local anesthetic adjuncts, time to extubation, postoperative pain scores, and opioid consumption were recorded. MAIN RESULTS: The mean peak bupivacaine concentration was 0.60 ± 0.62 µg/mL, and the mean time to maximum concentration (Tmax) was 16.92 ± 12.97 minutes. Two patients (7.1%) had a concentration >2.0 µg/mL within 15 minutes of block placement. The mean Tmax of bupivacaine was significantly greater in patients who did not receive additives compared to those patients who did (22.86 ± 14.77 minutes v 10.0 ± 5.22 minutes; p = .004). The times to extubation and postoperative pain were not improved with additives. CONCLUSIONS: Bilateral PIP placed at the end of cardiac surgery resulted in low systemic bupivacaine levels. The inclusion of additives shortened Tmax without improving outcome.

A single center descriptive study of local anesthetic dose in knee arthroplasty: Was there evidence of local anesthetic systemic toxicity?

STUDY OBJECTIVE: Describe dosing of local anesthetic when both a periarticular injection (PAI) and peripheral nerve block (PNB) are utilized for knee arthroplasty analgesia, and compare the dosing of local to suggested maximum dosing, and look for evidence of local anesthetic systemic toxicity (LAST). DESIGN: A single center retrospective cohort study between May 2018 and November 2022. SETTING: A major academic hospital. PATIENTS: Patients who had both a PAI and PNB while undergoing primary, revision, total, partial, unilateral, or bilateral knee arthroplasty. INTERVENTIONS: None. MEASUREMENTS: Calculate the dose of local anesthetic given via PAI, PNB, and both routes combined as based on lean body weight and compare that to the suggested maximum dosing. Look for medications, clinical interventions, and critical event notes suggestive of a LAST event. MAIN RESULTS: There were 4527 knee arthroplasties where both a PAI and PNB were performed during the study period. When combining PAI and PNB doses, >75% of patients received more than the suggested maximum dose of 3 mg/kg lean body weight. The median local anesthetic dosing over the study period, 4.4 mg/kg (IQR 3.5,5.9), was 147% of the suggested maximum dose (IQR 117,197). There was no conclusive evidence of LAST among any of the patients in the study. CONCLUSIONS: Over the course of our study, we had 4527 knee arthroplasties with a median PAI and PNB local anesthetic dose that was 147% of the suggested maximum without any clear clinical evidence of a LAST event.

The Impact of the Combined Effect of Inhalation Anesthetics and Iron Dextran on Rats' Systemic Toxicity.

Disruption of any stage of iron homeostasis, including uptake, utilization, efflux, and storage, can cause progressive damage to peripheral organs. The health hazards associated with occupational exposure to inhalation anesthetics (IA) in combination with chronic iron overload are not well documented. This study aimed to investigate changes in the concentration of essential metals in the peripheral organs of rats after iron overload in combination with IA. The aim was also to determine how iron overload in combination with IA affects tissue metal homeostasis, hepcidin-ferritin levels, and MMP levels according to physiological, functional, and tissue features. According to the obtained results, iron accumulation was most pronounced in the liver (19×), spleen (6.7×), lungs (3.1×), and kidneys (2.5×) compared to control. Iron accumulation is associated with elevated heavy metal levels and impaired essential metal concentrations due to oxidative stress (OS). Notably, the use of IA increases the iron overload toxicity, especially after Isoflurane exposure. The results show that the regulation of iron homeostasis is based on the interaction of hepcidin, ferritin, and other proteins regulated by inflammation, OS, free iron levels, erythropoiesis, and hypoxia. Long-term exposure to IA and iron leads to the development of numerous adaptation mechanisms in response to toxicity, OS, and inflammation. These adaptive mechanisms of iron regulation lead to the inhibition of MMP activity and reduction of oxidative stress, protecting the organism from possible damage.

Local Anesthetic Systemic Toxicity (LAST): More Common Than You Think.

The number of anesthetic body procedures in the United States is rapidly increasing, with many being performed on an outpatient basis. These procedures are advertised as being safe, and many times the serious complications may not be discussed. Although local anesthetic systemic toxicity is a rare complication, it is associated with an increase in morbidity. The emergency department staff should be aware of the possibility of this rare complication, as well as the variety of resulting symptoms (from minor to severe), potential sequelae, and appropriate management for patients who have undergone an outpatient anesthetic body procedure. Multiple factors contribute to the development of local anesthetic systemic toxicity, resulting in life-threatening effects on the neurologic and cardiovascular systems. Also, the site of administration, along with the local anesthetic agent used, can impact the risk of the development of local anesthetic systemic toxicity. To minimize the risk and ensure the best possible outcome for these patients, emergency department staff must be highly aware of the mechanisms, risk factors, prevention, and management/treatment of local anesthetic systemic toxicity.

The road to virtual control groups and the importance of proper body-weight selection.

Virtual control groups (VCGs) created from historical control data (HCD) can reduce the number of concurrent control group animals needed in regulatory toxicity studies by up to 25%. This study investigates the performance of VCGs on statistical outcomes of body weight development between treatment and control groups in legacy studies. The objective is to reproduce the statistical outcomes of 28-day sub-chronic studies (legacy studies) after replacing the concurrent control group with virtual ones. In rodent toxicity studies initial body weight is used as surrogate for the age of animals. For the assessment of VCG-sampling methods three different approaches are explored: (i) sampling VCGs from the entire HCD ignoring initial body weight information of the legacy study, (ii) sampling from HCD matching the legacy study's initial body weights, and (iii) sampling from HCD with assigned statistical weights derived from legacy study initial body weight information. It is shown that the ability to reproduce statistical outcomes by virtual controls is mainly determined by the congruence between the legacy study and the HCD weight distribution: regardless of the chosen approach, the ability to reproduce statistical outcomes was well for VCGs when the legacy study's initial-body-weight distribution was similar to the HCD's. When the initial body weight range of the legacy study was at the extreme ends of the HCD's distribution, the weighted-sampling approach was superior. This article highlights the importance of proper HCD-matching by the legacy study's initial body weight and discusses required conditions to accurately reproduce body weight development.

Animal control data from past studies performed in a standardized manner can be used to create virtual control groups (VCGs) to use in new studies instead of control animals. This approach can reduce the number of study animals by up to 25%. This study assesses the performance of VCGs selected by body weight in rat studies. The objective was to reproduce the original study results as closely as possible after replacing the original control group values with VCGs from a pool of historical control values. Several methods for selecting control animal data to create VCGs were compared. Among these, assigning statistical weights to the sampling pool yielded the best performance. Ideally the body weight distributions on day 1 of the study should be similar between the VCG and the original study animals. This article shows that proper selection VCGs can yield reliable study data with fewer animals.

Revolutionizing developmental neurotoxicity testing - a journey from animal models to advanced in vitro systems.

Developmental neurotoxicity (DNT) testing has seen enormous progress over the last two decades. Preceding even the publication of the animal-based OECD test guideline for DNT testing in 2007, a series of non-animal technology workshops and conferences (starting in 2005) shaped a community that has delivered a comprehensive battery of in vitro test methods (IVB). Its data interpretation is covered by a very recent OECD test guidance (No. 377). Here, we aim to overview the progress in the field, focusing on the evolution of testing strategies, the role of emerging technologies, and the impact of OECD test guidelines on DNT testing. In particular, this is an example of a targeted development of an animal-free testing approach for one of the most complex hazards of chemicals to human health. These developments started literally from a blank slate, with no proposed alternative methods available. Over two decades, cutting-edge science enabled the design of a testing approach that spares animals and enables throughput for this challenging hazard. While it is evident that the field needs guidance and regulation, the massive economic impact of decreased human cognitive capacity caused by chemical exposure should be prioritized more highly. Beyond this, the claim to fame of DNT in vitro testing is the enormous scientific progress it has brought for understanding the human brain, its development, and how it can be perturbed.

Developmental neurotoxicity (DNT) testing predicts the hazard of exposure to chemicals to human brain development. Comprehensive advanced non-animal testing strategies using cutting-edge technology can now replace animal-based approaches to assess this complex hazard. These strategies can assess large numbers of chemicals more accurately and efficiently than the animal-based approach. Recent OECD test guidance has formalized this battery of in vitro test methods for DNT, marking a pivotal achievement in the field. The shift towards non-animal testing reflects both a commitment to animal welfare and a growing recognition of the economic and public health impacts associated with impaired cognitive function caused by chemical exposures. These innovations ultimately contribute to safer chemical management and better protection of human health, especially during the vulnerable stages of brain development.

Acute Systemic Toxicity Caused by Topical Application of EMLA Cream on a Leg Ulcer: Case Report and Review of Literature.

INTRODUCTION: Systemic toxicity of eutectic mixture of local anesthetics (EMLA) cream is rare and is most commonly observed in children, for example, upon extensive application, and rarely occurs in adults with certain dispositions. CASE REPORT: We report the case of a 71-year-old man who developed methemoglobinemia and systemic intoxication upon topical application of EMLA cream for leg ulcer and stasis dermatitis prior to surgical debridement. Approximately 45 min after application, the patient was found to be in a somnolent state, was unable to articulate, and showed peripheral cyanosis. The blood concentration of methemoglobin (MetHb) was 15.1%, and therefore, a diagnosis of systemic toxicity of EMLA due to methemoglobinemia was established. After removal of the cream, oxygen was applied, and further observation revealed that the patient's condition rapidly improved without any residue. In the following, we also discuss literature related to systemic EMLA intoxication. CONCLUSION: EMLA cream may cause severe systemic toxicity even in adults under certain conditions, for example, when applied on damaged skin or in extensive amounts.

Local Anesthetic Systemic Toxicity: Ensuring Sustained Nursing Knowledge in a High-Volume Outpatient Surgery Center.

PURPOSE: Local anesthetic systemic toxicity (LAST) is a low-frequency, high-risk event that can occur within minutes of a patient receiving a local anesthetic. The goals of this project were to standardize LAST care management across an academic medical center and sustain an improvement in nurses' knowledge of how to recognize signs and symptoms of LAST and how to competently manage a LAST scenario. DESIGN: We used a quantitative design to accomplish the goals of the project. METHODS: Our interdisciplinary team developed a clinical practice guideline based on the LAST Checklist published by the American Society of Regional Anesthesia and Pain Medicine, and used a simulation scaffolded by multimodal education and system changes to ensure sustained knowledge. We measured improvement using a graded knowledge assessment as well as qualitative feedback. FINDINGS: Scores on the assessment increased from 4.76 to 6.34 (out of seven points) following the intervention and remained significantly higher than the baseline 9 months after the educational intervention (9-month score = 6.19, t = 2.99, P = .004). Nurses reported feeling more confident and knowledgeable following the intervention and requested to have regular sessions of the simulation. To sustain improvements, we developed a computer-based learning module. The module and simulation were integrated into nursing orientation and an annual competency. CONCLUSIONS: While standardizing LAST care in accordance with evidence-based guidance is critical to patient safety due to its infrequent occurrence, nurses should consider implementing simulation supplemented with multimodal education and system changes to ensure sustained knowledge.

Enhanced anti-glioma activity of annonaceous acetogenins based on a novel liposomal co-delivery system with ginsenoside Rh2.

Annonaceous acetogenins (ACGs) have potent anti-tumor activity, and the problems of their low solubility, hemolysis, and in vivo delivery have been solved by encapsulation into nanoparticles. However, the high toxicity still limits their application in clinic. In this paper, the co-delivery strategy was tried to enhance the in vivo anti-tumor efficacy and reduce the toxic effects of ACGs. Ginsenoside Rh2, a naturally derived biologically active compound, which was reported to have synergistic effect with paclitaxel, was selected to co-deliver with ACGs. And due to its similarity with cholesterol in chemical structure, the co-loading liposomes, (ACGs + Rh2)-Lipo, were successfully constructed using Rh2 instead of cholesterol as the membrane material. The obtained (ACGs + Rh2)-Lipo and ACGs-Lipo had similar mean particle size (about 80 nm), similar encapsulation efficiency (EE, about 97%) and good stability. The MTS assay indicated that (ACGs + Rh2)-Lipo had stronger toxicity in vitro. In the in vivo study, in contrast to ACGs-Lipo, (ACGs + Rh2)-Lipo demonstrated an improved tumor targetability (3.3-fold in relative tumor targeting index) and significantly enhanced the antitumor efficacy (tumor inhibition rate, 72.9 ± 5.4% vs. 60.5 ± 5.4%, p < .05). The body weight change, liver index, and spleen index of tumor-bearing mice showed that Rh2 can attenuate the side effects of ACGs themselves. In conclusion, (ACGs + Rh2)-Lipo not only alleviated the toxicity of ACGs to the organism, but also enhanced their anti-tumor activity, which is expected to break through their bottleneck.

Association of free maternal and fetal ropivacaine after epidural analgesia for intrapartum caesarean delivery: a prospective observational trial.

BACKGROUND: Ropivacaine is present in plasma in both protein-bound and free forms. The free form is responsible for the occurrence of toxic side effects. During obstetric epidural analgesia, free ropivacaine enters the fetal circulation depending on various factors. The aim of this study was to analyse a potential association between ropivacaine concentrations in maternal and fetal plasma and hence the extent of fetal exposure to ropivacaine. METHODS: In this prospective monocentre study, parturients who met the following criteria were included in the study: 1. epidural administration as part of obstetric anaesthesia, and 2. subsequent intrapartum caesarean delivery, which 3. was performed after an epidural bolus administration of ropivacaine within the existing epidural analgesia. Total and free ropivacaine concentrations were analysed in maternal blood at baseline, prior to epidural bolus administration for caesarean delivery, and in maternal and fetal (umbilical venous, oxygenated) blood at delivery. The results are presented as mean ±â€¯SD or median (25/75th percentile). RESULTS: We screened 128 parturients who went into labour at term and requested epidural analgesia, of whom 39 were ultimately included in the study. An intrapartum caesarean delivery was performed after the epidural application of 207 (166/276) mg ropivacaine during an epidural treatment period of 577 (360/1010) min. Total and free ropivacaine concentrations were 1402 ±â€¯357 ng/ml and 53 ±â€¯46 ng/ml, respectively, in maternal venous blood and 457 ±â€¯243 ng/ml and 43 ±â€¯27 ng/ml, respectively, in fetal blood. The maternal total and free ropivacaine concentrations were significantly correlated (r = 0.873; P < 0.0001). CONCLUSION: The results of the present study suggest that determining the concentration of free ropivacaine in maternal blood may be a feasible option for estimating neonatal exposure to ropivacaine.

Can exposure to lisdexamfetamine dimesylate from juvenile period to peripubertal compromise male reproductive parameters in adult rats?

Lisdexamfetamine (LDX) is a d-amphetamine prodrug used to treat attention deficit and hyperactivity disorder, a common neurodevelopmental disorder in children and adolescents. Due to its action mediated by elevated levels of catecholamines, mainly dopamine and noradrenaline, which influence hormonal regulation and directly affect the gonads, this drug may potentially disrupt reproductive performance. This study evaluated the effects of exposure to LDX from the juvenile to peripubertal period (critical stages of development) on systemic and reproductive toxicity parameters in male rats. Male Wistar rats (23 days old) were treated with 0; 5.2; 8.6 or 12.1 mg/kg/day of LDX from post-natal day (PND) 23 to 53, by gavage. LDX treatment led to reduced daily food and water consumption, as well as a decrease in social behaviors. The day of preputial separation remained unaltered, although the treated animals exhibited reduced weight. At PND 54, the treated animals presented signs of systemic toxicity, evidenced by a reduction in body weight gain, increase in the relative weight of the liver, spleen, and seminal gland, reduction in erythrocyte and leukocyte counts, reduced total protein levels, and disruptions in oxidative parameters. In adulthood, there was an increase in immobile sperm, reduced sperm count, morphometric changes in the testis, and altered oxidative parameters, without compromising male sexual behavior and fertility. These findings showed that LDX-treatment during the juvenile and peripubertal periods induced immediate systemic toxicity and adversely influenced reproductive function in adult life, indicating that caution is necessary when prescribing this drug during the peripubertal phase.

[Principles of the pharmacology of local anesthetics]. / Grundlagen der Pharmakologie von Lokalanästhetika.

The development of local anesthetics revolutionized the performance of painful interventions. Local anesthetics have an effect on voltage-gated sodium channels in nerve fibers and modulate the conduction of impulses. With respect to the chemical structure, local anesthetics can be divided into amide and ester types. The structural differences of local anesthetics have an influence on the duration of action, the degradation pathways and specific side effects. Severe adverse events include cardiotoxicity and neurotoxicity. In addition to basic measures, such as the monitoring and securing of vital parameters, lipid infusion represents a treatment option in cases of intoxication. The recent developments of local anesthetics are particularly concerned with the reduction of toxicity and prolonging the duration of action.

Developmental Impacts of Epigenetics and Metabolism in COVID-19.

Developmental biology is intricately regulated by epigenetics and metabolism but the mechanisms are not completely understood. The situation becomes even more complicated during diseases where all three phenomena are dysregulated. A salient example is COVID-19, where the death toll exceeded 6.96 million in 4 years, while the virus continues to mutate into different variants and infect people. Early evidence during the pandemic showed that the host's immune and inflammatory responses to COVID-19 (like the cytokine storm) impacted the host's metabolism, causing damage to the host's organs and overall physiology. The involvement of angiotensin-converting enzyme 2 (ACE2), the pivotal host receptor for the SARS-CoV-2 virus, was identified and linked to epigenetic abnormalities along with other contributing factors. Recently, studies have revealed stronger connections between epigenetics and metabolism in COVID-19 that impact development and accelerate aging. Patients manifest systemic toxicity, immune dysfunction and multi-organ failure. Single-cell multiomics and other state-of-the-art high-throughput studies are only just beginning to demonstrate the extent of dysregulation and damage. As epigenetics and metabolism directly impact development, there is a crucial need for research implementing cutting-edge technology, next-generation sequencing, bioinformatics analysis, the identification of biomarkers and clinical trials to help with prevention and therapeutic interventions against similar threats in the future.

Controlled Refolding of Denatured IL-12 Using In Situ Antigen-Capturing Nanochaperone Remarkably Reduces the Systemic Toxicity and Enhances Cancer Immunotherapy.

Cytokines are powerful in cancer immunotherapy, however, their therapeutic potential is limited by the severe systemic toxicity. Here a potent strategy to reduce the toxicity of systemic cytokine therapy by delivering its denatured form using a finely designed nanochaperone, is described. It is demonstrated that even if the denatured protein cargos are occasionally released under normal physiological conditions they are still misfolded, while can effectively refold into native states and release to function in tumor microenvironment. Consequently, the systemic toxicity of cytokines is nearly completely overcome. Moreover, an immunogenic cell death (ICD)-inducing chemotherapeutic is further loaded and delivered to tumor using this nanochaperone to trigger the release of tumor-associated antigens (TAAs) that are subsequently captured in situ by nanochaperone and then reflows into lymph nodes (LNs) to promote antigen cross-presentation. This optimized personalized nanochaperone-vaccine demonstrates unprecedented suppressive effects against large, advanced tumors, and in combination with immune checkpoint blockade (ICB) therapy results in a significant abscopal effect and inhibition of postoperative tumor recurrence and metastasis. Hence, this approach provides a simple and universal delivery strategy to reduce the systemic toxicities of cytokines, as well as provides a robust personalized cancer vaccination platform, which may find wide applications in cancer immunotherapy.

The short-term toxicity and metabolome of dicyclopentadiene.

Dicyclopentadiene (DCPD) was investigated in a 14-day oral rat toxicity study based on the OECD 407 guideline in combination with plasma metabolomics. Wistar rats received the compound daily via gavage at dose levels of 0, 50 and 150 mg/kg bw. The high dose induced transient clinical signs of toxicity and in males only reduced body weight gain. High dose liver changes were characterized by altered clinical chemistry parameters in both sexes and pathological changes in females. In high dose males an accumulation of alpha-2 u-globulin in the kidney was noted. Comparing the DCPD metabolome with previously established specific metabolome patterns in the MetaMap® Tox data base suggested that the high dose would result in liver enzyme induction leading to increased breakdown of thyroid hormones for males and females. An indication for liver toxicity in males was also noted. Metabolomics also suggested an effect on the functionality of the adrenals in high dose males, which together with published data, is suggestive of a stress related effect in this organ. The results of the present 14-day combined toxicity and metabolome investigations were qualitatively in line with literature data from subchronic oral studies in rats with DCPD. Importantly no other types of organ toxicity, or hormone dysregulation beyond the ones associated with liver enzyme induction and stress were indicated, again in line with results of published 90-day studies. It is therefore suggested that short term "smart" studies, combining classical toxicity with 'omics technologies, could be a 2 R (refine and reduce) new approach method allowing for the reduction of in vivo toxicity testing.

Impact of a Mobile App (LoAD Calc) on the Calculation of Maximum Safe Doses of Local Anesthetics: Protocol for a Randomized Controlled Trial.

BACKGROUND: Local anesthetics (LAs) are regularly used to alleviate pain during medical or surgical procedures. Their use is generally considered safe, but exceeding the maximum recommended doses can lead to LA systemic toxicity, a rare but potentially lethal complication. Determining maximum safe doses is therefore mandatory before performing local anesthesia, but rules are often unclear and the factors affecting dose calculation are numerous. Mobile health apps have been shown to help clinical decision-making, but most currently available apps present significant limitations. The Local Anesthetics Dose Calculator (LoAD Calc) app was designed to overcome these limitations by taking all relevant parameters into account. Before deploying this app in a clinical setting, it should be tested to determine its effectiveness and whether clinicians would be willing to use it. OBJECTIVE: The primary objective will be to evaluate the effectiveness of the LoAD Calc app through written simulated cases. The secondary objective will be to determine whether physicians find this app easier, faster, and safer than the methods they generally use. METHODS: We describe a parallel-group randomized controlled trial protocol. Anesthesiologists working at the Geneva University Hospitals will be invited to participate. Participants will be asked to compute the maximum dose of LA in 10 simulated clinical cases using 3 different LAs. The maximum safe dose will be determined manually using the same calculation rules that were used to develop LoAD Calc, without using the app itself. An overdose will be considered any dose higher than the correct dose, rounded to the superior integer, while an underdose will be defined as the optimal calculated dose minus 20%, rounded to the inferior integer. Randomization will be stratified according to current position (resident vs registrar). The participants allocated to the LoAD Calc (experimental) group will use the LoAD Calc app to compute the maximum safe LA doses. Those allocated to the control group will be asked to use the method they generally use. The primary outcome will be the overall overdose rate. Secondary outcomes will include the overdose rate according to ideal and actual body weight and to each specific LA, the overall underdose rate, and the time taken to complete these calculations. The app's usability will also be assessed. RESULTS: A sample size of 46 participants will be needed to detect a difference of 10% with a power of 90%. Thus, a target of 50 participants was set to allow for attrition and exclusion criteria. We expect recruitment to begin during the winter of 2023, data analysis in the spring of 2024, and results by the end of 2024. CONCLUSIONS: This study should determine whether LoAD Calc, a mobile health app designed to compute maximum safe LA doses, is safer and more efficient than traditional LA calculation methods. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/53679.

Protectiveness of NAM-based hazard assessment - which testing scope is required?

Hazard assessment (HA) requires toxicity tests to allow deriving protective points of departure (PoDs) for risk assessment irrespective of a compound's mode of action (MoA). The scope of in vitro test batteries (ivTB) thereby necessitated for systemic toxicity is still unclear. We explored the protectiveness regarding systemic toxicity of an ivTB with a scope, which was guided by previous findings from rodent studies, where examining six main targets, including liver and kidney, was sufficient to predict the guideline scope-based PoD with high probability. The ivTB comprises human in vitro models representing liver, kidney, lung and the neuronal system covering transcriptome, mitochondrial dysfunction and neuronal outgrowth. Additionally, 32 CALUX®- and 10 HepG2 BAC-GFP reporters cover a broad range of disturbance mechanisms. Eight compounds were chosen for causing adverse effects such as immunotoxicity or anemia in vivo, i.e., effects not directly covered by assays in the ivTB. PoDs derived from the ivTB and from oral repeated dose studies in rodents were extrapolated to maximum unbound plasma concentrations for comparison. The ivTB-based PoDs were one to five orders of magnitude lower than in vivo PoDs for six of eight compounds, implying that they were protective. The extent of in vitro response varied across test compounds. Especially for hematotoxic substances, the ivTB showed either no response or only cytotoxicity. Assays better capturing this type of hazard would be needed to complement the ivTB. This study highlights the potentially broad applicability of ivTBs for deriving protective PoDs of compounds with unknown MoA.

Animal tests are used to determine which amount of a chemical is toxic ('threshold of toxicity') and which organs are affected. In principle, the threshold can also be derived solely from tests with cultured cells. However, only a limited number of cell types can practically be tested, so one challenge is to determine how many and which types shall be tested. In animal studies, only few organs including liver and kidney are regularly among those most sensitively affected. We explored whether a cell-based test battery representing these sensitive organs and covering important mechanisms of toxicity can be used to derive protective human thresholds. To challenge this approach, eight chemicals were tested that primarily cause effects in organs not directly represented in our test battery. Results provided protective thresholds for most of the investigated compounds and gave indications how to further improve the approach towards a full-fledged replacement for animal tests.

Porous NiTi Dental Implant Fabricated by a Metal Injection Molding: An in Vivo Biocompatibility Evaluation in an Animal Model.

This study assessed the corrosion resistance, intracutaneous reactivity, acute systemic toxicity, and in situ tissue effect of the implantation of porous NiTi fabricated by metal injection molding in animal models. For the intracutaneous reactivity study, five intracutaneous injections were administered per site with and without the tested extract in polar and nonpolar solutions. The extract was also delivered via intravenous and intraperitoneal routes for acute systemic toxicity. TiAl6 V4 (control) and porous NiTi were implanted in rabbit femora for a period of 13 weeks to evaluate the in situ tissue response. Corrosion was evaluated through open and cyclic polarization in PBS, while biocompatibility was investigated by assessing the general conditions, skin irritation score (edema and erythema), and histopathology. No active dissolution or hysteresis loop was observed in the corrosion study. None of the animals exhibited death, moribundity, impending death, severe pain, self-mutilation, or overgrooming. No edema was observed at injection sites. Only the positive control showed an erythematous reaction at 24, 48, and 72 h observations (p < 0.001). Porous NiTi showed a low in situ biological response for inflammation, neovascularization, and fibrosis in comparison to the control implant (p = 0.247, 0.005, and 0.011, respectively). Porous NiTi also demonstrated high pitting corrosion resistance while causing no acute hypersensitivity or acute systemic toxicity. The study concludes that porous NiTi implants were unlikely to cause local sensitization, acute systemic toxicity, or chronic inflammatory reactions in an animal model. Porous NiTi also exhibited osseointegration equivalent to Ti6AI4 V of known biocompatibility.

Toothpaste ingestion-evaluating the problem and ensuring safety: systematic review and meta-analysis.

This systematic review and meta-analysis aimed to evaluate the ingestion of toothpaste and its sequelae. The study adhered to the PRISMA guidelines and was registered in the PROSPERO database. A comprehensive search strategy was conducted across multiple databases, resulting in the inclusion of 18 relevant publications. Eligible studies encompassed various designs and included both children and adults as the study population. Data extraction was carried out systematically, and relevant information on study characteristics, interventions, and outcomes were collected. The assessment of bias was performed using the Joanna Briggs Institute's Critical Appraisal Tools showing variations of bias among the included studies. The overall risk of systemic toxicity was found to be low, and no severe or life-threatening events were reported in the included studies. Furthermore, some toothpaste formulations containing higher concentrations of fluoride were associated with an increased risk of dental fluorosis. These findings have several implications for practice and policy. Healthcare providers and dental professionals should emphasize the importance of promoting safe toothpaste use, especially in vulnerable populations such as young children who are more prone to accidental ingestion. Public health campaigns and educational initiatives should aim to raise awareness about appropriate toothpaste usage and the potential risks. In addition, toothpaste manufacturers and regulatory bodies should consider revising guidelines and regulations to ensure the safety of oral care products, including the appropriate concentration of active ingredients. Future research should focus on investigating the long-term effects of toothpaste ingestion, exploring potential interactions between different active ingredients, and evaluating the efficacy of current preventive measures.