New approach methodologies for risk assessment using deep learning.

The advancement of technologies and the development of more efficient artificial intelligence (AI) enable the processing of large amounts of data in a very short time. Concurrently, the increase in information within biological databases, such as 3D molecular structures or networks of functional macromolecule associations, will facilitate the creation of new methods for risk assessment that can serve as alternatives to animal testing. Specifically, the predictive capabilities of AI as new approach methodologies (NAMs) are poised to revolutionise risk assessment approaches.

Determining Targets for Antiretroviral Drug Concentrations: A Causal Framework Illustrated With Pediatric Efavirenz Data From the CHAPAS-3 Trial.

Background: Determining a therapeutic window for maintaining antiretroviral drug concentrations within an appropriate range is required for identifying effective dosing regimens. The limits of this window are typically calculated using predictive models. We propose that target concentrations should instead be calculated based on counterfactual probabilities of relevant outcomes and describe a counterfactual framework for this.

Comparative genomics reveals carbohydrate enzymatic fluctuations and herbivorous adaptations in arthropods.

Background: Arthropods represent the largest and most diverse phylum on Earth, playing a pivotal role in the biosphere. One key to their evolutionary success is their ability to feed on plant material. However, their endogenous enzymatic repertoire, which contributes to plant digestion, remains largely unexplored and poorly understood.

Limited Short-Term Evolution of SARS-CoV-2 RNA-Dependent RNA Polymerase under Remdesivir Exposure in Upper Respiratory Compartments.

Background: The extent of the SARS-CoV-2 short-term evolution under Remdesivir (RDV) exposure and whether it varies across different upper respiratory compartments are not fully understood.

Methods: Patients hospitalized for COVID-19, with or without RDV therapy, were enrolled and completed up to three visits, in which they provided specimens from four respiratory compartments. Near full-length genome SARS-CoV-2 sequences were obtained from viral RNA, standard lineage and variant assignments were performed, and viral mutations in the RNA-dependent RNA polymerase (RdRp) region-the RDV target gene-were detected and compared between participants with and without RDV, across the four compartments, within participants across visits, and versus a larger sequence dataset.

Causal Inference for Continuous Multiple Time Point Interventions.

There are limited options to estimate the treatment effects of variables which are continuous and measured at multiple time points, particularly if the true dose-response curve should be estimated as closely as possible. However, these situations may be of relevance: in pharmacology, one may be interested in how outcomes of people living with-and treated for-HIV, such as viral failure, would vary for time-varying interventions such as different drug concentration trajectories. A challenge for doing causal inference with continuous interventions is that the positivity assumption is typically violated.

Effectiveness of a novel experimental herbal toothpaste against bacterial consortium associated with dental caries.

Background: To evaluate the effectiveness of an experimental toothpaste based on Juss. essential oil against a bacterial consortium associated with dental caries.

Material And Methods: The antibacterial activity of the essential oil was evaluated by the disk diffusion and microdilution tests against , and .

In vitro, ex vivo, instrumental and clinical evaluation of a topical cream on the signs of periorbital ageing.

Objective: Periorbital skin ageing signs are multidimensional, highly visible and a concern for many. We evaluated the potential efficacy of an eye cream to diminish these signs.

Methods: Biological markers associated with ageing, barrier function and homeostasis were analysed in vitro to determine the effects of topically applied eye cream, compared to those of a placebo using human skin tissue models and/or explants.

Liver and cardiovascular outcomes in lean non-alcoholic fatty liver disease: an updated systematic review and meta-analysis of about 1 million individuals.

Background And Aims: Non-alcoholic fatty liver disease (NAFLD) is present in lean people. However, the magnitude of the prognostic hepatic and cardiovascular risk in these patients compared to non-lean counterparts remains unclear. We aimed to investigate this topic, and to explore whether these risks change based on factors related to NAFLD severity.

Studying Continuous, Time-varying, and/or Complex Exposures Using Longitudinal Modified Treatment Policies.

This tutorial discusses a methodology for causal inference using longitudinal modified treatment policies. This method facilitates the mathematical formalization, identification, and estimation of many novel parameters and mathematically generalizes many commonly used parameters, such as the average treatment effect. Longitudinal modified treatment policies apply to a wide variety of exposures, including binary, multivariate, and continuous, and can accommodate time-varying treatments and confounders, competing risks, loss to follow-up, as well as survival, binary, or continuous outcomes.

Pain Management Treatments and Opioid Use Disorder Risk in Medicaid Patients.

Introduction: People with chronic pain are at increased risk of opioid misuse. Less is known about the unique risk conferred by each pain management treatment, as treatments are typically implemented together, confounding their independent effects. This study estimated the extent to which pain management treatments were associated with risk of opioid use disorder (OUD) for those with chronic pain, controlling for baseline demographic and clinical confounding variables and holding other pain management treatments at their observed levels.

Learning optimal dynamic treatment regimes from longitudinal data.

Investigators often report estimates of the average treatment effect (ATE). While the ATE summarizes the effect of a treatment on average, it does not provide any information about the effect of treatment within any individual. A treatment strategy that uses an individual's information to tailor treatment to maximize benefit is known as an optimal dynamic treatment rule (ODTR).

Causal Inference for Social Network Data.

We describe semiparametric estimation and inference for causal effects using observational data from a single social network. Our asymptotic results are the first to allow for dependence of each observation on a growing number of other units as sample size increases. In addition, while previous methods have implicitly permitted only one of two possible sources of dependence among social network observations, we allow for both dependence due to transmission of information across network ties and for dependence due to latent similarities among nodes sharing ties.

Contrasting defence mechanisms against spider mite infestation in cyanogenic and non-cyanogenic legumes.

Understanding the complex interactions between plants and herbivores is essential for improving crop resistance. Aiming to expand the role of cyanogenesis in plant defence, we investigated the response of the cyanogenic Phaseolus lunatus (lima bean) and the non-cyanogenic Phaseolus vulgaris (common bean) to Tetranychus urticae (spider mite) infestation. Despite mite infesting both legumes, leaf damage infringed by this feeder was reduced in lima bean.

Plant Cyanogenic-Derived Metabolites and Herbivore Counter-Defences.

The release of cyanide from cyanogenic precursors is the central core of the plant defences based on the cyanogenesis process. Although cyanide is formed as a coproduct of some metabolic routes, its production is mostly due to the degradation of cyanohydrins originating from cyanogenic glycosides in cyanogenic plants and the 4-OH-ICN route in Brassicaceae. Cyanohydrins are then hydrolysed in a reversible reaction generating cyanide, being both, cyanohydrins and cyanide, toxic compounds with potential defensive properties against pests and pathogens.

Synthesis of PEGylated amphiphilic block copolymers with pendant linoleic moieties by combining ring-opening polymerization and click chemistry.

This study focused on synthesizing and characterizing PEGylated amphiphilic block copolymers with pendant linoleic acid (Lin) moieties as an alternative to enhance their potential in drug delivery applications. The synthesis involved a two-step process, starting with ring-opening polymerization of ε-caprolactone (CL) and propargylated cyclic carbonate (MCP) to obtain PEG-b-P(CL-co-MCP) copolymers, which were subsequently modified via click chemistry. Various reaction conditions were explored to improve the yield and efficiency of the click chemistry step.

Spider mite herbivory induces an ABA-driven stomatal defense.

Arthropod herbivory poses a serious threat to crop yield, prompting plants to employ intricate defense mechanisms against pest feeding. The generalist pest 2-spotted spider mite (Tetranychus urticae) inflicts rapid damage and remains challenging due to its broad target range. In this study, we explored the Arabidopsis (Arabidopsis thaliana) response to T.

Host response during unresolved urinary tract infection alters female mammary tissue homeostasis through collagen deposition and TIMP1.

Exposure to pathogens throughout a lifetime influences immunity and organ function. Here, we explore how the systemic host-response to bacterial urinary tract infection (UTI) induces tissue-specific alterations to the mammary gland. Utilizing a combination of histological tissue analysis, single cell transcriptomics, and flow cytometry, we identify that mammary tissue from UTI-bearing mice displays collagen deposition, enlarged ductal structures, ductal hyperplasia with atypical epithelial transcriptomes and altered immune composition.

Practical causal mediation analysis: extending nonparametric estimators to accommodate multiple mediators and multiple intermediate confounders.

Mediation analysis is appealing for its ability to improve understanding of the mechanistic drivers of causal effects, but real-world data complexities challenge its successful implementation, including (i) the existence of post-exposure variables that also affect mediators and outcomes (thus, confounding the mediator-outcome relationship), that may also be (ii) multivariate, and (iii) the existence of multivariate mediators. All three challenges are present in the mediation analysis we consider here, where our goal is to estimate the indirect effects of receiving a Section 8 housing voucher as a young child on the risk of developing a psychiatric mood disorder in adolescence that operate through mediators related to neighborhood poverty, the school environment, and instability of the neighborhood and school environments, considered together and separately. Interventional direct and indirect effects (IDE/IIE) accommodate post-exposure variables that confound the mediator-outcome relationship, but currently, no readily implementable nonparametric estimator for IDE/IIE exists that allows for both multivariate mediators and multivariate post-exposure intermediate confounders.

Results of a Novel Long-Term Method for Laparoscopic Skills Online Training.

Ensuring patient safety in minimally invasive surgery (MIS) within the field of pediatric surgery requires systematic and extensive practice. Many groups have proposed mastery learning programs encompassing a range of training methods. However, short courses often have a narrow focus on specific objectives, limiting opportunities for sustained training.