Mapping out strategies to further develop human-relevant, new approach methodology (NAM)-based developmental neurotoxicity (DNT) testing.

On occasion of the DNT5 meeting in Konstanz, Germany (April-2024), participants brainstormed on future challenges concerning a regulatory implementation of the developmental neurotoxicity (DNT) in vitro test battery (DNT-IVB). The five discussion topics below outline some of the key issues, opportunities and research directions for the next several years: (1) How to contextualize DNT hazard with information on potential maternal toxicity or other toxicity domains (non-DNT)? Several approaches on how to use cytotoxicity data from NAMs were discussed. (2) What opportunities exist for an immediate or near-future application of the DNT-IVB, e.

The long way from raw data to NAM-based information: Overview on data layers and processing steps.

Toxicological test methods generate raw data and provide instructions on how to use these to determine a final outcome such as a classification of test compounds as hits or non-hits. The data processing pipeline provided in the test method description is often highly complex. Usually, multiple layers of data, ranging from a machine-generated output to the final hit definition, are considered.

State of the science on assessing developmental neurotoxicity using new approach methods.

The workshop titled State of the Science on Assessing Developmental Neurotoxicity Using New Approach Methods was co-organized by University of Maryland’s Joint Institute for Food Safety and Applied Nutrition (JIFSAN) and the U.S. Food and Drug Administration’s (FDA) Center for Food Safety and Applied Nutrition (CFSAN; now called the Human Foods Program), and was hosted by FDA in College Park, MD on November 14-15, 2023.

Transcriptomic characterization of 2D and 3D human induced pluripotent stem cell-based in vitro models as New Approach Methodologies for developmental neurotoxicity testing.

The safety and developmental neurotoxicity (DNT) potential of chemicals remain critically understudied due to limitations of current in vivo testing guidelines, which are low throughput, resource-intensive, and hindered by species differences that limit their relevance to human health. To address these issues, robust New Approach Methodologies (NAMs) using deeply characterized cell models are essential. This study presents the comprehensive transcriptomic characterization of two advanced human-induced pluripotent stem cell (hiPSC)-derived models: a 2D adherent and a 3D neurosphere model of human neural progenitor cells (hiNPCs) differentiated up to 21 days.

[Reconstruction of Oncological Defects in the Pelvic-perineal Region: Report on the Consensus Workshop at the 44th Annual Meeting of the DAM 2023 in Bern, CH].

The surgical-oncological treatment of pelvic and perineal malignancies is associated with a high complication rate and morbidity for patients. Modern multimodal treatment modalities, such as neoadjuvant radio-chemotherapy for anal or rectal cancer, increase the long-term survival rate while reducing the risk of local recurrence. Simultaneously, the increasing surgical radicality and higher oncological safety with wide resection margins is inevitably associated with larger and, due to radiation, more complex tissue defects in the perineal and sacral parts of the pelvic floor.

LVAs in a Pedicled SIEA Flap for the Treatment of Recurrent Lymphocele of the Groin Using Superficial Veins of the Flap for Lymphovenous Anastomosis: A Case Report and Literature Review.

Persistent lymphocele of the groin is a complication of groin surgery that can severely impact the quality of life. The restoration of the interrupted lymphatic pathway is considered by many authors the ideal treatment to prevent a recurrence. However, multiple aspiration procedures and surgical revisions can compromise the availability of local veins needed for a lymphovenular bypass surgery.

Nanoparticles Dysregulate the Human Placental Secretome with Consequences on Angiogenesis and Vascularization.

Exposure to nanoparticles (NPs) in pregnancy is increasingly linked to adverse effects on embryo-fetal development and health later in life. However, the developmental toxicity mechanisms of NPs are largely unknown, in particular potential effects on the placental secretome, which orchestrates many developmental processes pivotal for pregnancy success. This study demonstrates extensive material- and pregnancy stage-specific deregulation of placental signaling from a single exposure of human placental explants to physiologically relevant concentrations of engineered (silica (SiO) and titanium dioxide (TiO) NPs) and environmental NPs (diesel exhaust particles, DEPs).

Comprehensive mapping of the AOP-Wiki database: identifying biological and disease gaps.

The Adverse Outcome Pathway (AOP) concept facilitates rapid hazard assessment for human health risks. AOPs are constantly evolving, their number is growing, and they are referenced in the AOP-Wiki database, which is supported by the OECD. Here, we present a study that aims at identifying well-defined biological areas, as well as gaps within the AOP-Wiki for future research needs.

Report of the First ONTOX Stakeholder Network Meeting: Digging Under the Surface of ONTOX Together With the Stakeholders.

The first Stakeholder Network Meeting of the EU Horizon 2020-funded ONTOX project was held on 13-14 March 2023, in Brussels, Belgium. The discussion centred around identifying specific challenges, barriers and drivers in relation to the implementation of non-animal new approach methodologies (NAMs) and probabilistic risk assessment (PRA), in order to help address the issues and rank them according to their associated level of difficulty. ONTOX aims to advance the assessment of chemical risk to humans, without the use of animal testing, by developing non-animal NAMs and PRA in line with 21st century toxicity testing principles.

Using in vitro data to derive acceptable exposure levels: A case study on PBDE developmental neurotoxicity.

Background: Current acceptable chemical exposure levels (e.g., tolerable daily intake) are mainly based on animal experiments, which are costly, time-consuming, considered non-ethical by many, and may poorly predict adverse outcomes in humans.

The probable future of toxicology - probabilistic risk assessment.

Both because of the shortcomings of existing risk assessment methodologies, as well as newly available tools to predict hazard and risk with machine learning approaches, there has been an emerging emphasis on probabilistic risk assessment. Increasingly sophisticated AI models can be applied to a plethora of exposure and hazard data to obtain not only predictions for particular endpoints but also to estimate the uncertainty of the risk assessment outcome. This provides the basis for a shift from deterministic to more probabilistic approaches but comes at the cost of an increased complexity of the process as it requires more resources and human expertise.

Developmental neurotoxicity evaluation of three Chinese herbal medicines in zebrafish larvae by means of two behavioral assays: Touch-evoked response and light/dark transition.

Chinese herbal medicine (CHM) is used among pregnant women. However, the question of its safety during pregnancy remains unclear. The use of these products relies on history of use data but there are specific toxicities like developmental neurotoxicity that are clearly understudied.

Complex reconstruction of the clavicle with a prefabricated medial femur condyle chimeric flap including a superficial circumflex iliac artery perforator flap: A case report.

The medial femur condyle (MFC) cortico-periosteal flap is a popular flap for bone reconstruction. The use of a chimeric version of this flap with a skin island has been described, but anatomical arterial variation can occur that prevent its harvest. Furthermore, the donor area of the skin paddle has been debated as poor because of the scarring in a visible area and because of the difficulty in obtaining pliable thin skin.

Innovative tools and methods for toxicity testing within PARC work package 5 on hazard assessment.

New approach methodologies (NAMs) have the potential to become a major component of regulatory risk assessment, however, their actual implementation is challenging. The European Partnership for the Assessment of Risks from Chemicals (PARC) was designed to address many of the challenges that exist for the development and implementation of NAMs in modern chemical risk assessment. PARC's proximity to national and European regulatory agencies is envisioned to ensure that all the research and innovation projects that are initiated within PARC agree with actual regulatory needs.

The impact of biostatistics on hazard characterization using in vitro developmental neurotoxicity assays.

In chemical safety assessment, benchmark concentrations (BMC) and their associated uncertainty are needed for the toxicological evaluation of in vitro data sets. A BMC estimation is derived from concentration-response modelling and results from various statistical decisions, which depend on factors such as experimental design and assay endpoint features. In current data practice, the experimenter is often responsible for the data analysis and therefore relies on statistical software, often without being aware of the software default settings and how they can impact the outputs of data analysis.

Molecular and Functional Characterization of Different BrainSphere Models for Use in Neurotoxicity Testing on Microelectrode Arrays.

The currently accepted methods for neurotoxicity (NT) testing rely on animal studies. However, high costs and low testing throughput hinder their application for large numbers of chemicals. To overcome these limitations, in vitro methods are currently being developed based on human-induced pluripotent stem cells (hiPSC) that allow higher testing throughput at lower costs.

A human iPSC-based in vitro neural network formation assay to investigate neurodevelopmental toxicity of pesticides.

Proper brain development is based on the orchestration of key neurodevelopmental processes (KNDP), including the for­mation and function of neural networks. If at least one KNDP is affected by a chemical, an adverse outcome is expected. To enable a higher testing throughput than the guideline animal experiments, a developmental neurotoxicity (DNT) in vitro testing battery (DNT IVB) comprising a variety of assays that model several KNDPs was set up.

[Treatment of the contracted first Commissure of the Hand: Literature Overview and own Experiences].

The freely movable thumb is of central importance for the function of the human hand. This mobility is necessarily linked to an undisturbed function of the commissure between the thumb and the index finger or, if the index finger is missing, the middle finger. A significant contracture of the first commissure, caused by whatever genesis, inevitably results in a significant loss of function up to almost complete inability to use.

Clinical adoptive regulatory T Cell therapy: State of the art, challenges, and prospective.

Rejection of solid organ transplant and graft host disease (GvHD) continue to be challenging in post transplantation management. The introduction of calcineurin inhibitors dramatically improved recipients' short-term prognosis. However, long-term clinical outlook remains poor, moreover, the lifelong dependency on these toxic drugs leads to chronic deterioration of graft function, in particular the renal function, infections and malignancies.

Tranexamic Acid Use in Breast Surgery: A Systematic Review and Meta-Analysis.

Background: The perioperative use of tranexamic acid (TXA) has become popular among plastic surgeons for a variety of surgical procedures. The aim of this study was to perform a systematic review and meta-analysis on the results reported in the literature regarding the effect of perioperative systemic TXA administration in breast surgery.

Methods: The PubMed, MEDLINE, Embase, CENTRAL, and CINAHL databases were searched for both randomized clinical trials and observational studies.