Proper characterization of molecular chiroptical properties is vital for organic chemistry and drug development. Nonetheless, narrow spectral ranges and the necessity for specialized equipment often limit traditional methods such as optical rotatory dispersion and electronic circular dichroism. Here, we introduce Mueller matrix polarimetry (MMP) as a more versatile tool for chiroptical analysis, capable of simultaneously capturing circular dichroism and optical rotatory dispersion spectra across ultraviolet to near-infrared wavelengths in a single measurement. We applied MMP to chiral metal complexes of Al, Mn, and Co, commonly used as catalysts in asymmetric syntheses. Using a robust experimental methodology, MMP distinguished enantiomeric forms and provided reliable chiroptical information by leveraging the inherent relationship between circular dichroism and optical rotatory dispersion. We interpreted our findings on the basis of density functional theory simulations, compared them to traditional electronic circular dichroism and absorption spectroscopies, and performed the Kramers-Kronig analysis. The combined approach of chiroptical MMP and ab-initio, for example, reveals delicate near-infrared chiroptical spectra of a neutral cobalt metal complex. Although MMP is more commonly used for solid state, the developed experimental protocol significantly expands its capabilities to solutions. It allows measurements without the need for both enantiomers and offers new insights into molecular chirality with potential applications across traditional and interdisciplinary branches of science and industry.

Thalidomide is an infamous drug used initially as a sedative until it was tragically discovered it has highly teratogenic properties. Despite this it is now being used to successfully treat a range of clinical conditions including erythema nodosum leprosum (ENL) and multiple myeloma (MM). Cereblon (CRBN), a ubiquitin ligase, is a binding target of thalidomide for both its therapeutic and teratogenic activities and forms part of an CRL4-E3 ubiquitin ligase complex with the proteins Damaged DNA Binding protein 1 (DDB1) and Cullin-4A (CUL4A). This complex mediates degradation of the zinc-finger transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), to mediate thalidomide's anti-myeloma response. To better understand the importance of CRBN and its binding partners for thalidomide teratogenesis here we analysed the expression patterns of CRBN and some of its known E3 complex binding partners in wildtype and thalidomide-treated chicken and zebrafish embryos. CRBN and DDB1 are expressed in many tissues throughout development including those that are thalidomide-sensitive while CUL4A and targets of the CRL4-CRBN E3 Ligase Complex IKZF1 and IKZF3 are expressed at different timepoints and in fewer tissues in the body than CRBN. Furthermore, IKZF3 is expressed in tissues of the eye that CRBN is not. However, although we observed rapid changes to the chicken yolk-sac membrane vasculature following thalidomide exposure, we did not detect CRL4-CRBN E3 Ligase Complex expression in the yolk-sac membrane vessels. Furthermore, we did not detect any changes in CRBN, DDB1, CUL4, IKZF1 and IKZF3 expression following thalidomide exposure in chicken and zebrafish embryos. These findings demonstrate that the anti-angiogenic activities of thalidomide may occur independent of CRBN and that thalidomide does not regulate CRL4-CRBN E3 Ligase Complex gene expression at the mRNA level.

Molecular chirality is a key concept in chemistry with implications for the origin of life and the manufacturing of pharmaceuticals. Previous simulations of a chiral molecular model with an energetic bias toward homochiral interactions show a spontaneous symmetry-breaking transition from a supercritical racemic liquid into a subcritical liquid enriched in one of the two enantiomers. Here, we employ molecular dynamics simulations in order to test the possible existence of this phenomenon in hydrogen peroxide, the smallest chiral molecule. For this purpose, we study the fluid phase of this substance between 100 and 1500 K, and from 100 kPa to 1 GPa. We find a glass transition and we suggest that hydrogen bonds play a central role in such behavior. We also test the possibility of observing chiral symmetry breaking by performing both constant temperature and cooling simulations at multiple pressures, and we do not observe the phenomenon. An analysis of the structure of the liquid shows negligible differences between homochiral and heterochiral interactions, supporting the difficulty in observing chiral symmetry breaking. If hydrogen peroxide manifests spontaneous chiral symmetry breaking, it likely takes place significantly below room temperature and is hidden by other phenomena, such as the glass transition or crystallization. More broadly, our results, and recent experimental observations, suggest that greater molecular complexity is needed for spontaneous chiral symmetry breaking in the liquid phase to occur.

Studies of (S)-thalidomide were conducted on zebrafish embryos subjected to electroporation processes using a square wave pulse generator. The results showed that the electroporation increases the absorption of (S)-thalidomide through the chorion into the growing embryos, which was confirmed by increased thalidomide levels in the embryo bodies at different hours post-treatments using differential pulse voltammetry and controlled-growth mercury drop electrode techniques. (S)-thalidomide administered by electroporation produced structural body deformations in zebrafish embryos as showed by scanning electron microscopy studies. Detailed transmission electron microscopy analysis evidenced multiple deposits of the outer layer and translucencies in the chorion structure, which was also pronounced on the mitochondrial membranes. The results confirmed the spontaneous conversion of the (S)-thalidomide enantiomer to the (R)-enantiomer in embryos exposed to the (S)-thalidomide only and subjected to electroporation pulses. The electroporation was found as a promising method to increase the uptake of (S)-thalidomide in the developmental studies on early zebrafish embryos growing in the chorion.

Toxicity is a critical hurdle in drug development, often causing the late-stage failure of promising compounds. Existing computational prediction models often focus on single-organ toxicity. However, avoiding toxicity of an organ, such as reducing gastrointestinal side effects, may inadvertently lead to toxicity in another organ, as seen in the real case of rofecoxib, which was withdrawn due to increased cardiovascular risks. Thus, simultaneous prediction of multi-organ toxicity is a desirable but challenging task. The main challenges are (1) the variability of substructures that contribute to toxicity of different organs, (2) insufficient power of molecular representations in diverse perspectives, and (3) explainability of prediction results especially in terms of substructures or potential toxicophores. To address these challenges with multiple strategies, we developed FATE-Tox, a novel multi-view deep learning framework for multi-organ toxicity prediction. For variability of substructures, we used three fragmentation methods such as BRICS, Bemis-Murcko scaffolds, and RDKit Functional Groups to formulate fragment-level graphs so that diverse substructures can be used to identify toxicity for different organs. For insufficient power of molecular representations, we used molecular representations in both 2D and 3D perspectives. For explainability, our fragment attention transformer identifies potential 3D toxicophores using attention coefficients. Scientific contribution: Our framework achieved significant improvements in prediction performance, with up to 3.01% gains over prior baseline methods on toxicity benchmark datasets from MoleculeNet (BBBP, SIDER, ClinTox) and TDC (DILI, Skin Reaction, Carcinogens, and hERG), while the multi-task learning approach further enhanced performance by up to 1.44% compared to the single-task learning framework that had already surpassed these baselines. Additionally, attention visualization aligning with literature contributes to greater transparency in predictive modeling. Our approach has the potential to provide scientists and clinicians with a more interpretable and clinically meaningful tool to assess systemic toxicity, ultimately supporting safer and more informed drug development processes.

Teratogens play a crucial role in the development of birth defects, making effective screening vital for prevention and management. This study aimed to develop an optimized zebrafish embryo-based platform for teratogenicity screening and further evaluate its findings with established clinical and animal data. Zebrafish embryos [6-8 h post-fertilization (hpf)] were exposed to 19 different test solutions, including nine known teratogens and ten non-teratogens, in 96-well plates, and mortality and morphological abnormalities were assessed at 48, 72, and 96 hpf. The half-lethal concentration (LC50) and half-effective concentration (EC50) were calculated from the counts of dead and abnormal embryos, respectively. The teratogenicity index (TI), defined as LC50/EC50, was used to classify the chemicals. Of the tested compounds, eight were identified as teratogenic, nine as non-teratogenic, and two outliers due to solubility constraints in this assessment. Notably, extending the exposure duration to 96 hpf provided a more accurate assessment of teratogenicity compared to shorter exposures. Eight teratogenic substances exhibited a TI greater than 3, while (-)-thalidomide did not yield a definitive TI due to low solubility. Among the non-teratogenic chemicals, nine had a TI below 3, with ajmaline also lacking a precise TI due to solubility constraints. These findings suggest that using a 6-8 hpf to 96 hpf exposure window and establishing a TI threshold of 3 can facilitate reliable teratogenicity risk assessment. Furthermore, the phenotypes observed in zebrafish embryos were consistent with typical teratogenic malformations documented in clinical and animal studies. This study demonstrates that the refined zebrafish embryo teratogenicity testing method coupled with the TI, can be an effective tool for assessing teratogenic risk.

More than 90 million women in the United States have given birth. Randomized controlled trials (RCTs) of medications almost always exclude pregnant participants.

To quantify the health effects of excluding pregnant participants from RCTs.

Decision analytic framework applied to case studies of thalidomide, COVID-19 vaccines, and dolutegravir.

Varied.

Pregnant people and their children.

The authors modeled the ex post facto health effects of RCTs, comparing projected health effects of medication uptake had an RCT been conducted versus historically observed outcomes. They also modeled the a priori health effects that could have been anticipated in trial planning. They converted health effect estimates to monetary value using standard benchmarks.

Across case studies, health benefits from conducting RCTs during pregnancy were projected to far exceed expected adverse effects (AEs) from RCTs. For example, had thalidomide been tested in a completed RCT with 200 treated participants, about 33 children would have experienced severe AEs, whereas knowledge from the RCT would have prevented 8000 thalidomide-related birth defects, 99.6% of all thalidomide-related birth defects from 1956 to 1962. Likewise, if RCTs for COVID-19 vaccines had included pregnant participants and if posttrial pregnant uptake were conservatively assumed to mirror that of age- and state-matched nonpregnant women, a projected 20% of COVID-19-related maternal deaths and stillbirths (8% of all maternal deaths and 1% of all stillbirths) in the United States would have been prevented from March to November 2021. Across case studies, the a priori value of RCT data would have exceeded the approximately $100 million cost of phase 1 to 3 RCTs.

Parameter uncertainty.

Systematic inclusion in RCTs could benefit both pregnant people and their children by both speeding AE detection and increasing uptake of beneficial medications.

None.

Sustainable toxicology is vital for living species and the environment because it guarantees the safety, efficacy, and regulatory compliance of drugs, treatments, vaccines, and chemicals in living organisms and the environment. Conventional toxicological methods often lack sustainability as they are costly, time-consuming, and sometimes inaccurate. It means delays in producing new drugs, vaccines, and treatments and understanding the adverse effects of the chemicals on the environment. To address these challenges, the healthcare sector must leverage the power of the Generative-AI (GenAI) paradigm. This paper aims to help understand how the healthcare field can be revolutionized in multiple ways by using GenAI to facilitate sustainable toxicological developments. This paper first reviews the present literature and identifies the possible classes of GenAI that can be applied to toxicology. A generalized and holistic visualization of various toxicological processes powered by GenAI is presented in tandem. The paper discussed toxicological risk assessment and management, spotlighting how global agencies and organizations are forming policies to standardize and regulate AI-related development, such as GenAI, in these fields. The paper identifies and discusses the advantages and challenges of GenAI in toxicology. Further, the paper outlines how GenAI empowers Conversational-AI, which will be critical for highly tailored toxicological solutions. This review will help to develop a comprehensive understanding of the impacts and future potential of GenAI in the field of toxicology. The knowledge gained can be applied to create sustainable GenAI applications for various problems in toxicology, ultimately benefiting our societies and the environment.

Chiral structures assembled from colloids are of great interest for applications in metamaterials and micromachines. However, similar to their molecular counterparts, these assemblies often result in racemic mixtures. Achieving homochirality by breaking the symmetry remains a significant challenge. Here, we report an approach to obtain single-handed clusters from colloidal dimers using orthogonal electric and magnetic fields. Applying an alternating-current electric field perpendicular to the substrate generates a mixture of chiral clusters with both handedness. However, symmetry is broken by superimposing a planar rotating magnetic field, favoring one chirality over the other. The cluster's chirality can be precisely controlled in situ by adjusting the magnetic field's direction and strength, as well as the electric field frequency. Remarkably, this method also induces uniform chirality in initially achiral clusters when exposed solely to the electric field. Both experimental and numerical analyses reveal that the stability of specific handedness depends on the competition between forces and torques generated by the magnetic field, electric field, and electrohydrodynamic flow. Furthermore, we propose a strategy for producing colloidal clusters with uniform sizes and single-handedness through dynamic tuning of the electric and magnetic fields. This work not only demonstrates the potential of integrating external fields but also provides a viable way to create reconfigurable chiral colloidal structures.

Testing for developmental toxicity is an integral part of chemical regulations. The applied tests are laborious and costly and require a large number of vertebrate test animals. To reduce animal numbers and associated costs, the zebrafish embryo was proposed as an alternative model. In this study, we investigated the potential of transcriptome analysis in the zebrafish embryo model to support the identification of potential biomarkers for key events in developmental toxicity, using the inhibition of angiogenesis as a proof of principle. Therefore, the effects on the zebrafish transcriptome after exposure to the tyrosine kinase inhibitors, sorafenib (1.3 µM and 2.4 µM) and SU4312 (1 µM, 2 µM, and 5 µM), and the putative vascular disruptor compound rotenone (25 nM and 50 nM) were analyzed. An early (2 hpf-hours post fertilization) and a late (24 hpf) exposure start with a time resolved transcriptome analysis was performed to compare the specificity and sensitivity of the responses with respect to anti-angiogenesis. We also showed that toxicodynamic responses were related to the course of the internal concentrations. To identify differentially expressed genes (DEGs) the time series data were compared by applying generalized additive models (GAMs). We observed mainly unspecific developmental toxicity in the early exposure scenario, while a specific repression of vascular related genes was only partially observed. In contrast, differential expression of vascular-related genes could be identified clearly in the late exposure scenario. Rotenone did not show angiogenesis-specific response on a transcriptomic level, indicating that the observed mild phenotype of angiogenesis inhibition may represent a secondary effect.

Proximal Femoral Focal Deficiency (PFFD) is the most proximal manifestation of a syndrome involving Congenitally Shortened lower Limbs (CSL), which also affects the fibula and midline metatarsals. This pattern of congenital human long bone deficiencies corresponds, in a time dependent manner, to the failed ingrowth pathways of new blood vessels of the growing embryonic limb. The distal femoral condyles are, in contrast, served by an alternative vascular supply from around the knee joint, and so remain resistant to the CSL deficiency.

We hypothesize that embryonic vascular dysgenesis causes PFFD, as well as the cardinal features of the Femoral, Fibular and midline Metatarsal deficiencies (FFM) syndrome.

Arteriography of CSL with PFFD reveals diminution or failed formation of the Femoral Artery (FA), which corresponds to downstream skeletal reductions. It may also reveal preservation of the primitive Axial Artery (AA) of the embryonic limb. The combination of missing and retained primitive vessels inform the time, place, and nature of the etiologic vascular events. This suggests that PFFD is the visible expression of a normally prefigured cartilaginous scaffold of the femur, which develops in conformity with the available pattern of blood vessels present. The teratogen thalidomide, known to affect the forming embryonic vasculature, also produces PFFD indistinguishable from the naturally occurring entity.

The entire spectrum of PFFD, including phocomelia, fibular, and metatarsal dystrophisms, should thus be regarded as downstream skeletal results of embryonic arterial dysgeneses.

Knowledge of unintended effects of drugs is critical in assessing the risk of treatment and in drug repurposing. Although numerous existing studies predict drug-side effect presence, only four of them predict the frequency of the side effects. Unfortunately, current prediction methods 1) do not utilize drug targets, 2) do not predict well for unseen drugs, and 3) do not use multiple heterogeneous drug features. We propose a novel deep learning-based drug-side effect frequency prediction model. Our model utilized heterogeneous features such as target protein information as well as molecular graph, fingerprints, and chemical similarity to create drug embeddings simultaneously. Furthermore, the model represents drugs and side effects into a common vector space, learning the dual representation vectors of drugs and side effects, respectively. We also extended the predictive power of our model to compensate for the drugs without clear target proteins using the Adaboost method. We achieved state-of-the-art performance over the existing methods in predicting side effect frequencies, especially for unseen drugs. Ablation studies show that our model effectively combines and utilizes heterogeneous features of drugs. Moreover, we observed that, when the target information given, drugs with explicit targets resulted in better prediction than the drugs without explicit targets.

In recent years, targeted protein degradation (TPD) strategies leveraging the autophagy-lysosomal pathway (ALP) have transcended the limitations of conventional drug molecules, emerging as a highly promising approach for selectively eliminating disease-related proteins via the cell's intrinsic degradation machinery. These TPD methods, such as autophagosome-tethering compounds (ATTEC), autophagy-targeting chimera (AUTAC), AUTOphagy-TArgeting chimera (AUTOTAC), and chaperone-mediated autophagy (CMA) targeting chimera, exhibit efficacy in degrading misfolded protein aggregates associated with neurodegenerative disorders. Moreover, the excessive accumulation of misfolded proteins or protein complexes in the placenta has been identified as a significant contributor to preeclampsia (PE). Given the lack of effective treatments for PE, the application of autophagy-mediated TPD technology presents a novel therapeutic avenue. This review draws parallels between misfolded protein aggregates in neurodegenerative diseases and placenta-derived PE, integrating a substantial number of full-text studies. By harnessing TPD technologies grounded in the ALP, these autophagic degraders offer a pioneering approach for targeted therapy in PE by dismantling potential targets. Presently, there is limited exploration of ALP technology for identifying target proteins in the placenta. Nonetheless, we have proposed several potential target proteins, laying the groundwork for future therapeutic endeavors.

Including lactating women in clinical trials is imperative to generate relevant drug exposure and safety data needed to advise on clinical use of drugs in this understudied population. Recent changes in perspectives, regulatory guidance, and international networks which outline pragmatic approaches for advancing the conduct of clinical lactation studies are discussed. Case studies demonstrating successful application of modeling and simulation to complement clinical lactation data for enhanced knowledge of infant drug exposure are presented.

Unilateral amelia, a rare congenital anomaly characterized by the absence of one limb, is often accompanied by severe malformations in other systems. Although the survival of affected infants beyond the neonatal period is rare, some cases have been documented with varying outcomes. This case report discusses a newborn with unilateral amelia and multiple congenital anomalies.

A 41-week gestation stillbirth from Palestine was delivered after a normal pregnancy, except for prenatal ultrasound findings of absent left upper limb, severe lower limb deformities, preaxial polydactyly, syndactyly, dextrocardia, and asymmetric hydrocephalus. Postnatal examination revealed additional craniofacial anomalies, gastrointestinal malformations, and respiratory abnormalities. Despite the severe deformities, the infant survived beyond 2 months.

Unilateral amelia is often associated with other congenital malformations, indicating complex embryological disruptions. The combination of limb deficiency with visceral abnormalities complicates management and prognosis. While stillbirths and early neonatal deaths are common, this case's survival beyond 2 months is a notable exception. This report contributes valuable insight into the prognosis of such rare congenital conditions.

This case emphasizes the rarity of unilateral amelia with multiple congenital defects and underscores the importance of comprehensive prenatal evaluation and genetic counseling. The patient's extended survival provides new perspectives on the management and outcomes of infants with such complex anomalies.

Ovarian cancer (OC) is the most lethal gynecological malignancy and a major global health concern, often diagnosed at advanced stages with poor survival rates. Despite advancements in treatment, resistance to standard chemotherapy remains a critical challenge with limited treatment options available. In recent years, the role of metabolic reprogramming in OC has emerged as a key factor driving tumor progression, therapy resistance, and poor clinical outcomes.

This review explores the intricate connections between metabolic syndrome, enhanced glycolysis, and altered lipid metabolism within OC cells, which fuel the aggressive nature of the disease. We discuss how metabolic pathways are rewired in OC to support uncontrolled cell proliferation, survival under hypoxic conditions, and evasion of cell death mechanisms, positioning metabolic alterations as central to disease progression. The review also highlights the potential of repurposed metabolic-targeting drugs, such as metformin and statins, which have shown promise in preclinical studies for their ability to disrupt these altered metabolic pathways.

Drug repurposing offers a promising strategy to overcome chemoresistance and improve patient outcomes. Future research should focus on unraveling the complex metabolic networks in OC to develop innovative, targeted therapies that can enhance treatment efficacy and patient survival.

Enantioseparation and enantiorecognition are crucial in the pharmaceutical analysis of chiral substances, impacting safety, efficacy, and regulatory compliance. Enantioseparation refers to the process of separating enantiomers from a mixture, typically achieved through chromatography techniques like HPLC and SFC. In contrast, enantiorecognition involves the identification of enantiomers based on their interaction with a chiral selector without the need for separation. Recent advancements in these techniques have significantly improved enantioseparation efficiency and resolution. Chiral stationary phases (CSPs) have evolved, offering better selectivity, including hybrid organic-inorganic materials and miniaturization. The use of green solvents has also reduced environmental impact. Non-chromatographic methods, such as circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy, enable enantiorecognition through interactions with polarized light or chiral solvents. However, these methods face challenges, including high costs, limited solvent compatibility, and shorter operational lifespans compared with chromatographic techniques. Recent developments in solvent-tolerant hybrid CSPs aim to address these limitations. This review highlights these innovations, focusing on their relevance to the pharmaceutical industry, pollution control, and quality assurance, and emphasizes the growing importance of these techniques in the production and regulation of chiral drugs.

Several adverse drug reactions (ADRs) go unreported within a healthcare setting despite the risks they cause. We therefore decided to conduct this study in order to recognize the obstacles that hinder the healthcare professionals (HCPs) in a tertiary care hospital in Kattankulathur, Tamil Nadu from reporting ADRs and what strategies ought to be implemented.

We carried out a cross-sectional study among the HCPs such as doctors, pharmacists and nurses within our institution. A pre-validated questionnaire was used to collect data on the socio-demographics, barriers and facilitators in reporting ADR. A 2 weeks timeline was given to the HCPs to fill the questionnaire forms. Out of the 107 forms distributed, we received 80 of them that were duly filled. Data was analyzed using IBM SPSS version 26.

Out of the 80 HCPs, only 22 of them had reported any ADRs in their career. 52% of our HCPs reported the lack of understanding of ADR reporting mechanism as their main hindrance. Additionally, 25 (31%) of the HCPs stated that reporting ADRs is time consuming. 18 (22%) of them reported a fear of legal liability. 13 (16%) of them stated that the reporting from is complicated and 29 (36%) stated a lack of motivation as the reason for not reporting ADR. Majority of our HCPs 76 (95%) recommended the need for continuous medical education and training as the best strategy to improve ADR reporting.

Barriers such as time constraints, workload pressures and competing priorities often hinder HCPs from dedicating adequate attention to ADR reporting. The inclusion of topics related to ADR reporting in the curriculum (i.e. clinical pharmacology) and increased awareness from the ADR monitoring centre were seen to be significant facilitators to enhance ADR reporting among health care practitioners.

The research of chiral separation technology is of great significance for understanding the origin of life and promoting the application of chiral molecules. Herein, anionic chiral pillar[6]arene and cationic pillar[6]arene were designed and synthesized, and a chiral pillar[6]arene membrane was constructed by layer-by-layer assembly through electrostatic interactions. The transport rates of l-Ala and d-Ala in this channel were 14.33 and 1.86 μM cm-2 h-1, respectively, and the transport rate of l-Ala was 7.7 times that of d-Ala. In the transport experiment of Ala racemate, the ee value of l-Ala in the permeate after a single separation was 62%, indicating that this channel has a certain chiral separation ability. The effects of the assembly method, the number of chiral layers, and the driving force on the separation effect were further studied, and the selective transport mechanism was explored through the host-guest interaction at the molecular level and theoretical simulation. This strategy provides a new template for expanding the application of chiral pillar[n]arenes in the field of membrane separation.

Degrons are short amino acid sequences that can facilitate the degradation of protein substrates. They can be classified as either ubiquitin-dependent or -independent based on their interactions with the ubiquitin proteasome system (UPS). These amino acid sequences are often found in exposed regions of proteins serving as either a tethering point for an interaction with an E3 ligase or initiating signaling for the direct degradation of the protein. Recent advancements in the protein degradation field have shown the therapeutic potential of both classes of degrons through leveraging their degradative effects to engage specific protein targets. This review explores what targeted protein degradation applications degrons can be used in and how they have inspired new degrader technology to target a wide variety of protein substrates.

In the past decade, significant advances have been made in the field of chiral separation, which is crucial for biological and pharmaceutical applications. Enantioselective membranes have emerged as a promising platform for efficient chiral separation due to their unique properties such as large surface area, tunable pore size, and high selectivity. These membranes are particularly effective in separating enantiomers because of their ability to facilitate selective interactions between the membrane material and chiral molecules. This article provides a comprehensive review of the recent progress in enantioselective membranes for chiral separation. Key topics discussed include various membrane fabrication methods, functionalization approaches, and the characterization of membrane properties, specifically in the context of applications like drug delivery, biomolecule separation, and pharmaceutical analysis. Furthermore, the review addresses the current challenges, potential solutions, and future prospects in this rapidly evolving field, highlighting the direction for upcoming research.

Medication use is increasing to treat both pre-existing and pregnancy-related medical conditions or complications. This study aims to investigate factors associated with multiple medication use during pregnancy, as well as any increased risk of pregnancy complications for women taking multiple medications.

A retrospective analysis of routinely collected medical records of singleton pregnant women was conducted in Southeast Melbourne, Australia, between 2016 and 2021. Self-reported medication use was recorded as part of routine medical care, starting from the first antenatal booking appointment and continuing for every subsequent antenatal appointment until birth. Multimorbidity was defined as having two or more medical conditions. Logistic regression was used to assess factors influencing multiple medication use (defined as taking two or more non-supplemental medications at any stage of pregnancy) and associations with pregnancy complications.

Of 48,502 participants, 34.9% used one medication, while 11.7% used multiple medications. Women of older age (30-34, 35-39, and ≥  40 years), higher body mass index (25.0-29.9 kg/m2 and ≥  30 kg/m2), born in Australasia and Oceania, higher socioeconomic status, and multimorbidity were more likely to use multiple medications during pregnancy. Women taking multiple medications had a higher risk of preterm and caesarean deliveries, fetal death, and neonatal admissions to intensive care. Sensitivity analyses exploring different morbidity categories produced no changes to findings.

Medication use during pregnancy is prevalent, with many pregnant mothers taking multiple medications. Given the rising maternal age, body mass index, and morbidities in pregnancy, the use of medications during pregnancy is increasing. Such use correlates with an increased chance of adverse pregnancy outcomes. In the context of limited trials on the safety and efficacy of medications in pregnancy, timely harnessing of the information available within routine medical records for post-marketing surveillance is important.

This Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) systematic review synthesized effects of background levels of per- and polyfluorylalkyl substance (PFAS) levels on reproductive health outcomes in the general public: fertility, preterm birth, miscarriage, ovarian health, menstruation, menopause, sperm health, and in utero fetal growth. The inclusion criteria included original research (or primary) studies, human subjects, and investigation of outcomes of interest following non-occupational exposures. It drew from four databases (Web of Science, PubMed, Embase and Health and Environmental Research Online (HERO)) using a standardized search string for all studies published between 1 January 2017 and 13 April 2022. Risk of bias was assessed by two independent reviewers. Data were extracted and reviewed by multiple reviewers. Each study was summarized under its outcome in terms of methodology and results and placed in context, with recommendations for future research. Of 1712 records identified, 30 were eligible, with a total of 27,901 participants (33 datasets, as three studies included multiple outcomes). There was no effect of background levels of PFAS on fertility. There were weakly to moderately increased odds of preterm birth with higher perfluorooctane sulfonic acid (PFOS) levels; the same for miscarriage with perfluorooctanoic acid (PFOA) levels. There was limited yet suggestive evidence for a link between PFAS and early menopause and primary ovarian insufficiency; menstrual cycle characteristics were inconsistent. PFAS moderately increased odds of PCOS- and endometriosis-related infertility, respectively. Sperm motility and DNA health were moderately impaired by multiple PFAS. Fetal growth findings were inconsistent. This review may be used to inform forthcoming drinking water standards and policy initiatives regarding PFAS compounds and drinking water. Future reviews would benefit from more recent studies. Larger studies in these areas are warranted. Future studies should plan large cohorts and open access data availability to capture small effects and serve the public. Funding: Great Lakes Water Authority (Detroit, MI), the Erb Family Foundation through Healthy Urban Waters at Wayne State University (Detroit, MI), and Wayne State University CLEAR Superfund Research (NIH P42ES030991).

Pharmacogenomics (PGx) investigates how genomes control enzyme expression. Developmental pharmacology (DP) describes the temporal sequence of enzymes impacting absorption, distribution, metabolism, and excretion (ADME) of food and drugs.

US and European Union (EU) legislation facilitate and/or enforce pediatric studies for all new drugs, called overall 'pediatric drug development' (PDD). DP and PDD look at patients' chronological age, but oscillate between legal and physiological meanings of the term 'child.' Children's bodies become mature with puberty.

Decades after first DP observations in babies, PGx offers a better understanding of the variability of safety and efficacy of drugs, of the process of aging, and of shifting enzyme patterns across aging. We should rethink and revise outdated interpretations of ADME changes in minors. The Declaration of Helsinki forbids pointless studies that some pediatric researchers and regulatory agencies, more so the EMA than the FDA, demand pointless pediatric studies is regrettable. Medicine needs to differentiate between legal and physiological meanings of the term 'child' and should use objective measures of maturity.

The so-called undruggable space is an exciting area of potential growth for drug development. Undruggable proteins are defined as those unable to be targeted via conventional small molecule drugs. New modalities are being developed to potentially target these proteins. Targeted protein degradation (TPD) is one such new modality, which over the last two decades has moved from academia to industry. TPD makes use of the endogenous degradation machinery present in all cells, in which E3 ubiquitin ligases mark proteins for degradation via ubiquitin attachment. This session explored the challenges and perspectives of using protein degraders as novel therapeutic agents. The session began with a general introduction to the modality, followed by considerations in evaluating their on- and off-target toxicities including data from an IQ Consortium working group survey. Unique absorption, distribution, metabolism, and excretion (ADME) properties of degrader molecules were presented in relation to their effect on drug development and nonclinical safety assessment. The role of transgenic models in evaluating hemotoxicity associated with cereblon-based therapies was then discussed. A case study to derisk dose-limiting thrombocytopenia was also presented. Finally, a regulatory perspective on the challenges of having toxicity associated with protein degraders was presented.

Off-label use of medicinal products has become an important part of mainstream and legitimate medical practice worldwide. This practice is common in oncology, obstetrics, paediatrics, and in the management of infectious diseases (notably HIV), and inflammatory conditions as well as in rare and/or orphan diseases. However, the off-label use of medicines recently-raised many clinical and legal difficulties, not only among medical practitioners but also among pharmacists and other healthcare professionals.

This paper, therefore, highlights the advantages (such as cost saving for both the patient and the country/insurance that is paying for the medication) and disadvantages (insufficient evidence available) of the use of medicines to treat specific conditions or indications for which they are currently not registered.

Off-label drug use can be likened to a double-edged sword, offering valuable opportunities for medical practitioners while carrying potential risks. When the scientific basis for off-label use is unclear, it may place patients at risk of unapproved experimentation, unforeseen health hazards, and ineffective treatments. Hence, there is a pressing need in South Africa for clear regulatory guidelines on off-label drug use. Additionally, the timely review and approval of new indications for medicines, backed by robust scientific evidence, are essential. This would reduce the significant burden and inherent risks faced by medical practitioners when using medicines off-label to provide compassionate care.

Traumatic carotid artery pseudoaneurysms (PSAs) represent a vascular anomaly with potential for serious complications, including stroke. Traditional treatments involve endovascular stenting, which may not be ideally suited to otherwise healthy vessels that have the potential to remodel. Given the limitations of smaller animal models in replicating human vasculature and the need for improved treatment modalities, this study introduces a novel swine model for the creation and evaluation of carotid PSAs.

The PSAs were created from bovine dura and anastomosed in an end-to-side fashion to bilateral carotid arteries. The PSAs were radiologically followed up post-operatively and were harvested at 3 and 10 days for histological analysis.

Pseudoaneurysms were successfully created in both animals without intra-operative or immediate post-operative complications. Radiological analysis showed well-perfused PSAs with intra-aneurysmal turbulence, hemodynamically mimicking human carotid artery PSAs. There was no evidence of thrombus or arterial stenosis. Histological examinations revealed thrombus maturation and tight anastomosis of the PSA sac with the native artery.

This PSA swine model offers a replicable, cost-effective, and easily implemented tool with the potential to advance carotid PSA management and educational efforts in vascular surgery.

The model presented in this methodology paper allows for a standardized PSA animal model allowing for the standardization of a clinical entity which is frequently heterogenenous in morphology. This can allow for the development of new therapies or provide a ground truth for computer modelling for further in silico study.

Clozapine is an antipsychotic which was approved in 1989 for treatment-resistant schizophrenia in the United States (US). There were few randomized trials before its approval and potentially lethal clozapine adverse drug reactions (ADRs), such as agranulocytosis and myocarditis were identified by pharmacovigilance. VigiBase, the WHO global database, is a cornerstone of international pharmacovigilance efforts for ADR identification during post-marketing surveillance. This systematic review of the literature explores additional contributions to the knowledge of clozapine ADRs from recent VigiBase studies.

Using the terms "clozapine AND VigiBase" we conducted an article search in PubMed on September 5, 2024. Of the 29 articles, 11 were excluded and 18 described in the Results section.

All clozapine ADRs were described in two VigiBase studies. One on pregnancy indicated no increased risk with clozapine compared with other antipsychotics; the other reported 191,557 clozapine ADRs, including 22,956 fatal outcomes through January 15, 2023, and paid attention to the reporting style of the top 4 reporting countries (the US, the United Kingdom, Canada and Australia). Infections were described in three VigiBase studies where clozapine treatment was associated with infections, respiratory aspiration, and pneumonia. Rapid titration can lead to localized clozapine-induced inflammations including myocarditis, pericarditis or pancreatitis, or generalized inflammations such as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. Clozapine-induced inflammation was described in four VigiBase studies, two focused on all ages (myocarditis and DRESS) and two on youth (myocarditis and another on pericarditis and pancreatitis). Other specific ADRs were described in nine VigiBase studies (hematological malignancies, rhabdomyolysis, sialorrhea, seizures, diabetes mellitus, drug-induced parkinsonism, withdrawal symptoms, and suicidal behaviors).

The spectrum of respiratory aspiration - aspiration pneumonia - pneumonia and other infections are significant causes of fatal outcomes in clozapine-treated patients. Clozapine had anti-suicidal effects versus other antipsychotics across all VigiBase labels of suicidal behavior.

Background: About 80% of pregnant women use at least one medication during their pregnancy period. Many drugs that are not allowed to be used during pregnancy (from FDA Pregnancy Categories D and X) were used. Irrational use of these drugs during pregnancy may result in different birth defects, as explained by thalidomide and diethylstilbestrol's tragedy. Knowledge of drug utilization and associated factors that affect the pattern is important to enhance rational prescribing. But information about prescription patterns and associated factors among pregnant women is scarce in the Debre Tabor area and generally in Ethiopia. Objective: This study was aimed at assessing drug prescription patterns, potential teratogenicity, and associated factors among pregnant women attending the antenatal care unit at Debre Tabor Comprehensive Specialized Hospital, Debre Tabor, Northwest Ethiopia. Methods: A retrospective cross-sectional study design was performed on 359 pregnant women attending antenatal care units from June 01, 2022, to August 30, 2022, in the hospital. Necessary data were obtained through a questionnaire by reviewing the medical charts of the women. Analysis of the data was performed using SPSS Version 23. The association of the independent variables to medication use was assessed using multivariate logistic regression. A p value of less than 0.05 was considered significant. Results: Most of the study participants (325/359) were married (90.5%). From a total of 359 participants, 350 (97.5%) were prescribed with drugs. About 64% (385/602) of the prescribed medications were iron and vitamins. The most commonly prescribed medications are iron and folic acid combination (340/602, 56.5%), albendazole (48/602, 8%), mebendazole (37/602, 6.1%), omeprazole (33/602, 5.5%), followed by amoxicillin (32/602, 5.3%). The majority (79.3%) of the drugs were from FDA Pregnancy Categories A and B. Prescribed drug utilization was more probable in women who first visited the facility at their second (AOR = 2.91, 95% CI [1.12-6.64]) and third trimesters (AOR = 4.32, 95% CI [1.37-6.81]), had chronic illness (AOR = 7.54, 95% CI [2.34-14.68]), and live in rural areas (AOR = 2.47, 95% CI [1.56-8.43]). Conclusion: The study revealed that the prescription pattern in the hospital is in line with the WHO reference. Age, gravidity, number of ANC visits, first visit to the facility, presence of chronic illness, educational status, and residency were significantly associated with prescription drug use in pregnant mothers. But still, some pregnant women received drugs that may have teratogenicity risk (FDA Category C).

COVID-19 pandemic is caused by the SARS-CoV-2 virus, whose internalization and infection are mediated by the angiotensin-converting enzyme 2 (ACE2). The identification of novel approaches to tackle this step is instrumental for the development of therapies for the management of COVID-19 and other diseases with a similar mechanism of infection. Thalidomide, a drug sadly known for its teratogenic effects, has potent immunomodulatory and anti-inflammatory properties. Treatment with this drug has been shown to improve the immune functions of COVID-19 patients and proposed for the management of COVID-19 in clinical practice through drug repositioning. Here, we investigated the molecular details linking thalidomide to ACE2 and COVID-19, showing that in conditions mimicking SARS-CoV-2-associated cytokine storm, the transcription factor ΔNp63α and ACE2 are stabilized, and IL-8 production is increased. In such conditions, we found p63 to bind to and regulate the expression of the ACE2 gene. We previously showed that ΔNp63α is degraded upon thalidomide treatment and now found that treatment with this drug-or with its analogue lenalidomide-downregulates ACE2 in a p63-dependent manner. Finally, we found that thalidomide treatment reduces in vitro infection by pseudo-SARS-CoV-2, a baculovirus pseudotyped with the SARS-CoV-2 spike protein. Overall, we propose the dual effect of thalidomide in reducing SARS-CoV-2 viral re-entry and inflammation through p63 degradation to weaken SARS-CoV-2 entry into host cells and mitigate lung inflammation, making it a valuable option in clinical management of COVID-19. KEY MESSAGES: Thalidomide treatment results in p63-dependent ACE2 downregulation. ACE2 is a p63 transcriptional target. Thalidomide reduces the "cytokine storm" associated to COVID-19. Thalidomide prevents viral re-entry of SARS-CoV-2 by p63-dependent ACE2 downregulation. Thalidomide is a modulator of SARS-CoV-2 or other ACE2-dependent infections. ACE2 is modulated by a pharmacological substance.

The global pharmaceutical industry has a long history of prioritizing profits over public health through widespread practices such as price gouging, deceptive marketing, and fraud. A prominent example of this issue is the mislabeling and mass-marketing of OxyContin by Purdue Pharmaceuticals (Purdue) that catalyzed the opioid crises in and beyond the United States.

Guided by Actor-Network Theory, this case study employs Visual Network Analysis to map the actors-networks involved in responding to the harms caused by Purdue. Data was generated from peer-reviewed and grey literature published between 2007 and 2022 (n = 40) and imported into Gephi visualization software where centrality metrics were applied.

A total of 39 actors and 99 relationships were visualized based on the relational thinking that actors who are heavily interconnected with others are rendered important. Centrality measures identified the socio-technical centrality of Purdue in influencing the response to the harms it caused. Purdue exerted influence through various avenues, most prominently through the creation and cooptation of pain advocacy groups, their close ties with United States elected officials, and through embedding pro-opioid messaging in international guidance documents. In doing so, Purdue was able to extend the reach and impact of their opioid promotion, while simultaneously limiting the capacity of regulatory bodies to pursue accountability and implement policies to mitigate opioid-related harms.

This study advances understandings of the complex interplay between transnational pharmaceutical companies, global health systems, regulatory bodies, and public health. In doing so, we underscore the need for stronger regulation and increased transparency surrounding the interactions between pharma, patient groups, governments, and international organizations to better address and prevent future harms.

Systematic under-representation of pregnant women and gender diverse pregnant people in clinical research has prevented them from benefitting fairly from biomedical advances. The resulting lack of pharmacological safety and efficacy data leads to medicine discontinuation, sub-optimal dosing, and reliance on repurposed therapies. We identify four roadblocks to fair inclusion. First, investment and research are inhibited by protectionist attitudes among research gatekeepers who view pregnancy as a vulnerable state. Second, exclusion ignores human-specific biological variations affecting medication absorption and impacts on the pregnant body. Third, pregnant populations in low-and middle-income countries face a double disadvantage due to gender and location, despite bearing a disproportionate maternal mortality burden. Fourth, perspectives and experiences of pregnant populations are undervalued in clinical intervention design. We propose five actions to optimize fair inclusion: fostering reciprocal partnerships, prioritizing multi-disciplinary research, awareness-raising of the need for pharmaceutical innovation, conducting regulatory analyses, and promoting responsible inclusion over presumptive exclusion.

Congenital anomalies of the external ear can have a significant impact on a child's development and quality of life. While genetic factors play a crucial role in the etiology of these anomalies, environmental factors such as drug exposure during pregnancy may also contribute to their occurrence. This study aims to investigate the association between drug exposure and congenital anomalies of the external ear using data from an adverse drug reaction report database. Using OpenVigil 2.1, we queried the FAERS database to retrieve adverse event reports from the first quarter of 2004 to the first quarter of 2024. To identify relevant cases, we used Medical Dictionary for Regulatory Activities terms focusing on congenital anomalies of the external ear. Drug generic names were sourced from the DrugBank database. To assess safety signals and rank drugs by their signal strength, we conducted a disproportionality analysis, generating reporting odds ratios (ROR) and proportional reporting ratios (PRR). A total of 20,754,281 AE reports were identified in the FAERS database from Q1 2004 to Q1 2024, of which 1763 were related to congenital anomalies of the external ear. Valproic acid (122 cases) was associated with the most cases, followed by mycophenolate mofetil (105 cases) and lamotrigine (65 cases). According to the disproportionality analysis, the top five drugs with the highest ROR and PRR were primidone (ROR: 397.05, 95% CI 147.21, 1070.9; PRR: 388.71, 95% CI 145.89, 1035.7), valproic acid (ROR: 239.46, 95% CI 123.75, 463.37; PRR: 236.42, 95% CI 123.82, 451.43), tapazole (ROR: 198.35, 95% CI 63.49, 619.67; PRR: 196.25, 95% CI 62.97, 611.67), nevirapine (ROR: 138.24, 95% CI 82.9, 230.51; PRR: 137.23, 95% CI 82.44, 228.44), and sebivo (ROR: 117.1, 95% CI 48.51, 282.67; PRR: 116.37, 95% CI 48.17, 281.12). This study identified several drugs significantly associated with congenital anomalies of the external ear in the FAERS database using disproportionality analysis. The findings can help healthcare professionals better recognize and manage drug-induced congenital anomalies of the external ear, particularly when prescribing high-risk medications. Further research is needed to elucidate the mechanisms underlying these associations and develop strategies for preventing and mitigating drug-induced congenital anomalies of the external ear.

To examine patterns in the dispensing of category X medications (Therapeutic Goods Administration categorisation system for prescribing medicines in pregnancy) to women aged 15-49 years in Australia during 2008-2021, and patterns of concurrent use of hormonal long-acting reversible contraception (LARC) and other hormonal contraception.

Retrospective cohort study; analysis of 10% random sample of national Pharmaceutical Benefits Scheme dispensing data.

Women aged 15-49 years dispensed category X medications, Australia, 1 January 2013 - 31 December 2021.

Incident and prevalent dispensing of category X medications, by medication class, age group, and year; contraceptive overlap (proportions of women dispensed hormonal LARC or other hormonal contraception that overlapped the first dispensing of category X medications), by medication class.

Among 15 627 women aged 15-49 years dispensed category X medications during 2013-2021, the prevalence of dispensing increased from 4.6 in 2013 to 8.7 per 1000 women aged 15-49 years in 2021; the largest increase was for the dispensing of dermatological agents, from 3.9 to 7.9 per 1000 women aged 15-49 years. LARC overlap was inferred for 2059 women at the time of first dispensing of category X medications (13.2%); 3441 had been dispensed any type of hormonal contraception (22.1%). The proportion with LARC overlap was smallest for those dispensed dermatological agents (1806 of 14 331 women, 12.6%); for this drug class, both LARC overlap (adjusted odds ratio [aOR], 0.17; 95% confidence interval [CI], 0.14-0.20) and any hormonal contraception overlap (aOR, 0.28; 95% CI, 0.25-0.32) were less likely for those aged 15-19 years than for women aged 25-29 years.

Concurrent use of highly effective hormonal contraception at the time of first dispensing of category X medications is low in Australia, raising concerns about potential fetal harms during unintended pregnancies. Awareness of the importance of hormonal contraception and its uptake by women prescribed category X medications should be increased.

As people living with thalidomide embryopathy (TE) are now entering their seventh decade, we examine the impact of ageing and the prevalence of comorbid health conditions reported in holistic needs assessments (HNAs) by individuals with TE, compare it with an age-matched sample of the general population, and explore the relationship between comorbidities and TE pattern of impairment.

The HNA categories were mapped and compared to those of the Health Survey for England (HSE) and analysed across four impairment groups (A-D).

94% (392/415) of individuals with TE residing in the UK participated in the HNA and consented to a secondary analysis of the data. Less than 2% (5/392) reported no comorbidities; 94% reported nervous system problems; including pain, pins and needles and numbness. Individuals with TE reported a significantly greater number of health comorbidities, including musculoskeletal problems, than the age-matched HSE population.

Individuals with TE report significantly more health and well-being concerns than the general population of a similar age. Long-term monitoring is needed to ensure that support and rehabilitation services can meet their evolving needs.

The placenta plays a critical role in maternal-fetal nutrient transport and fetal protection against drugs. Creating physiological in vitro models to study these processes is crucial, but technically challenging. This study introduces an efficient cell model that mimics the human placental barrier using co-cultures of primary trophoblasts and primary human umbilical vein endothelial cells (HUVEC) on a Transwell®-based system. Monolayer formation was examined over 7 days by determining transepithelial electrical resistance (TEER), permeability of Lucifer yellow (LY) and inulin, localization of transport proteins at the trophoblast membrane (immunofluorescence), and syncytialization markers (RT-qPCR/ELISA). We analysed diffusion-based (caffeine/antipyrine) and transport-based (leucine/Rhodamine-123) processes to study the transfer of physiologically relevant compounds. The latter relies on the adequate localization and function of the amino-acid transporter LAT1 and the drug transporter P-glycoprotein (P-gp) which were studied by immunofluorescence microscopy and application of respective inhibitors (2-Amino-2-norbornanecarboxylic acid (BCH) for LAT1; cyclosporine-A for P-gp). The formation of functional monolayer(s) was confirmed by increasing TEER values, low LY transfer rates, minimal inulin leakage, and appropriate expression/release of syncytialization markers. These results were supported by microscopic monitoring of monolayer formation. LAT1 was identified on the apical and basal sides of the trophoblast monolayer, while P-gp was apically localized. Transport assays confirmed the inhibition of LAT1 by BCH, reducing both intracellular leucine levels and leucine transport to the basal compartment. Inhibiting P-gp with cyclosporine-A increased intracellular Rhodamine-123 concentrations. Our in vitro model mimics key aspects of the human placental barrier. It represents a powerful tool to study nutrient and drug transport mechanisms across the placenta, assisting in evaluating safer pregnancy therapies.

Embryofetal development (EFD) studies are performed to characterize risk of drugs in pregnant women and on embryofetal development. In line with the ICH S5(R3) guideline, these studies are generally conducted in one rodent and one non-rodent species, commonly rats and rabbits. However, the added value of conducting EFD studies in two species to risk assessment is debatable. In this study, rat and rabbit EFD studies were evaluated to analyze the added value of a second species. Information on rat and rabbit EFD studies conducted for human pharmaceuticals submitted for marketing authorization to the European Medicines Agency between 2004 and 2022 was collected from the database of the Dutch Medicines Evaluation Board, along with EFD studies conducted for known human teratogens. In total, 369 compounds were included in the database. For 55.6% of the compounds similar effects were observed in rat and rabbit EFD studies. Discordance was observed for 44.6% of compounds. Discordance could often be explained based on occurrence of maternal toxicity or the compound's mechanism of action. For other compounds, discordance was considered of limited clinical relevance due to high exposure margins or less concerning EFD toxicity. For 6.2%, discordance could not be explained and was considered clinically relevant. Furthermore, for specific therapeutic classes, concordance between rat and rabbit could vary. In conclusion, in many cases the added value of conducting EFD studies in two species is limited. These data could help identify scenarios in which (additional) EFD studies could be waived or create a weight-of-evidence model to determine the need for (additional) EFD studies.

The placenta is a transient organ that forms during pregnancy and acts as a biological barrier, mediating exchange between maternal and fetal circulation. Placental disorders, such as preeclampsia, fetal growth restriction, placenta accreta spectrum, and gestational trophoblastic disease, originate in dysfunctional placental development during pregnancy and can lead to severe complications for both the mother and fetus. Unfortunately, treatment options for these disorders are severely lacking. Challenges in designing therapeutics for use during pregnancy involve selectively delivering payloads to the placenta while protecting the fetus from potential toxic side effects. Nanomedicine holds great promise in overcoming these barriers; the versatile and modular nature of nanocarriers, including prolonged circulation times, intracellular delivery, and organ-specific targeting, can control how therapeutics interact with the placenta. In this review, nanomedicine strategies are discussed to treat and diagnose placental disorders with an emphasis on understanding the unique pathophysiology behind each of these diseases. Finally, prior study of the pathophysiologic mechanisms underlying these placental disorders has revealed novel disease targets. These targets are highlighted here to motivate the rational design of precision nanocarriers to improve therapeutic options for placental disorders.

Recurrent aphthous stomatitis (RAS) is considered as the most common oral mucosal lesion affecting up to 25% of people worldwide. Thalidomide has been reported for the treatment of RAS, but the evidence has not been systematically evaluated. We first systematically reviewed the efficacy and safety of thalidomide for the treatment of RAS.

We searched The Cochrane Library, PubMed, Scopus, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), Chinese BioMedical Literature Database (CBM), Wanfang Data, and VIP information from inception to December 2023. Randomized controlled trials (RCTs) comparing thalidomide with control for RAS were included in the analysis. The primary outcome were complete response and overall response, and the secondary outcome were recurrence interval (RI), ulcer number and size, healing time, visual analogue scale (VAS), immunological data, and adverse events. Meta-analysis was conducted using the Review Manager 5.4 software.

Twenty-one trials involving 1668 patients were included in this review. The results of our meta-analysis showed that thalidomide significantly improved the complete response rate and overall response rate, prolonged the recurrence interval, accelerated the healing process, reduced the number and size of ulcers, and lowered TNF-α levels in the treatment of RAS. However, thalidomide significantly increases adverse events.

Thalidomide has a significant benefit in the treatment of RAS. However, considering the potential side effects of thalidomide, it may be an optimal treatment option for major RAS patients or cases that do not respond to topical agents.

PROSPERO registration number: CRD42024495038.

Small-molecule drugs are effective and thus most widely used. However, their applications are limited by their reliance on active high-affinity binding sites, restricting their target options. A breakthrough approach involves molecular glues, a novel class of small-molecule compounds capable of inducing protein-protein interactions (PPIs). This opens avenues to target conventionally undruggable proteins, overcoming limitations seen in conventional small-molecule drugs. Molecular glues play a key role in targeted protein degradation (TPD) techniques, including ubiquitin-proteasome system-based approaches such as proteolysis targeting chimeras (PROTACs) and molecular glue degraders and recently emergent lysosome system-based techniques like molecular degraders of extracellular proteins through the asialoglycoprotein receptors (MoDE-As) and macroautophagy degradation targeting chimeras (MADTACs). These techniques enable an innovative targeted degradation strategy for prolonged inhibition of pathology-associated proteins. This review provides an overview of them, emphasizing the clinical potential of molecular glues and guiding the development of molecular-glue-mediated TPD techniques.

Research on embryonic development is entering into a new era. As a traditionally descriptive discipline within anatomy, embryologists have formed international consortia and digitized important histological collections for preservation and open access. Embryonic development has recently received a wider attention in context with temporo-spatial transcriptomics at single cell level. These can be expected to fuel the realization of the transdisciplinary significance of efforts to decipher embryonic development. Addressing its complexities encompasses a wealth of challenges that intersect across the domains of science, society, and politics underlining its outstanding importance as well as its inherently interdisciplinary nature. The challenges of this field are by no means confined to understanding the intricate biological mechanisms but also have humanitarian implications. To fully appreciate the mechanisms underlying human development, principles of embryogenesis have predominantly been analyzed employing animal models which allow us to broaden our view on developmental processes. As a result of recent pioneering work and technical progress centered around stem cell-based 3D approaches, we are entering into a historical new phase of learning about mammalian embryonic development. In vertebrates, a growing concern now focuses the reduction of animal experimentation. This perspective article outlines the major challenges in this amazing field that offer an enormous potential for basic biomedical sciences as well as related translational approaches if they are tackled in a multidisciplinary discourse.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is globally increasing in prevalence. The rise of ASD can be partially attributed to diagnostic expansion and advocacy efforts; however, the interplay between genetic predisposition and modern environmental exposures is likely driving a true increase in incidence. A range of evidence indicates that prenatal exposures are critical. Infection during pregnancy, gestational diabetes, and maternal obesity are established risk factors for ASD. Emerging areas of research include the effects of maternal use of selective serotonin reuptake inhibitors, antibiotics, and exposure to toxicants during pregnancy on brain development and subsequent ASD. The underlying pathways of these risk factors remain uncertain, with varying levels of evidence implicating immune dysregulation, mitochondrial dysfunction, oxidative stress, gut microbiome alterations, and hormonal disruptions. This narrative review assesses the evidence of contributing prenatal environmental factors for ASD and associated mechanisms as potential targets for novel prevention strategies.

Herein, we report the synthesis of new 4-amino-2-(piperidin-3-yl)isoindoline-1,3-diones and their biological evaluation in a series of in vitro experiments. The synthetic production of these materials was initiated upon the condensation of appropriate nitrophthalic acid derivatives with various 3-aminopiperidines; subsequent reduction provided the final products in moderate to good yields. Readily available chiral pool reagents facilitated entry into optically enriched samples, while the piperidine scaffold furnished a variety of amide and alkylated entries. In total, 16 candidates were produced, and their ensuing treatment in LPS-challenged RAW cells effected slight reductions in secreted TNF-α but provided more robust and dose-dependent declines in nitrite and IL-6 levels relative to basal amounts, all concurrent with maintenance of cellular viability across the concentration ranges screened. The secondary amine cohort including rac-6, (R)-7, and (S)-8 rendered the most pronounced dose-dependent reductions in nitrite and IL-6. When dosed at 30 μM, (R)-7 demonstrated the most compelling effects, with decreases of 32 % and 40 % for nitrite and IL-6, respectively. Notable reductions in the inflammatory markers were also observed for 19 which effected declines in TNF-α (14 %), nitrite (19 %), and IL-6 (11 %) when treated at 30 μM. Additionally, four representative compounds were further evaluated against numerous CNS receptors, channels, and transporters, with 6, 9, and 19 demonstrating varying degrees of nanomolar-to-low-micromolar binding to the σ-1 and σ-2 receptors and also to serotonin receptors 5HT2A, 5HT2B and 5HT3. In this regard, 6 displayed perhaps the most noteworthy affinities, with binding at σ-2 (Ki = 2.2uM), 5HT2B (Ki = 561 nM) and 5HT3 (Ki = 536 nM). Furthermore, no pronounced or dose-dependent Cereblon/DDB1 binding was observed for the screened representative compounds 6, 9, 18 and 19.

Teratogens encompass any agent capable of causing a birth defect or elevating the incidence of defects within the population. This category includes substances like drugs, both legal and illegal. These substances cause congenital anomalies depending on the stage of development at the time of exposure, the dose, and the exposure time associated with the embryo. The most sensitive period is the embryonic stage, when the three leaflets give rise to tissues and organs. Susceptibility to teratogenesis decreases during the fetal phase but morphological and functional disturbance of the fetus may still occur. Substance use during pregnancy and its adverse effects are a public health problem and the lay population does not have access to this information. Particularly concerning is the period within the first six weeks of pregnancy, often before a woman realizes she is pregnant. Developmental data for many substances are simply not available, which makes the problem more serious. The aim of this study is to reflect on the teratogenic effects of licit and illicit substances in humans, focusing particularly on the dose that can induce malformations and their incidence in humans.

Under regulations such as REACH, testing of novel and established compounds for their (neuro)toxic potential is a legal requirement in many countries. These are largely based on animal-, cost-, and time-intensive in vivo models, not in line with the 3 Rs' principle of animal experimentation. Thus, the development of alternative test methods has also received increasing attention in neurotoxicology. Such methods focus either on physiological alterations in brain development and neuronal pathways or on behavioral changes. An example of a behavioral developmental neurotoxicity (DNT) assay is the zebrafish (Danio rerio) embryo coiling assay, which quantifies effects of compounds on the development of spontaneous movement of zebrafish embryos. While the importance of embryo-to-embryo contact prior to hatching in response to environmental contaminants or natural threats has been documented for many other clutch-laying fish species, little is known about the relevance of intra-clutch contacts for zebrafish. Here, the model neurotoxin rotenone was used to assess the effect of grouped versus separate rearing of the embryos on the expression of the coiling behavior. Some group-reared embryos reacted with hyperactivity to the exposure, to an extent that could not be recorded effectively with the utilized software. Separately reared embryos showed reduced activity, compared with group-reared individuals when assessing. However, even the control group embryos of the separately reared cohort showed reduced activity, compared with group-reared controls. Rotenone could thus be confirmed to induce neurotoxic effects in zebrafish embryos, yet modifying one parameter in an otherwise well-established neurotoxicity assay such as the coiling assay may lead to changes in behavior influenced by the proximity between individual embryos. This indicates a complex dependence of the outcome of behavior assays on a multitude of environmental parameters.