Examining emotion regulation and inflammation as predictors of maternal mental health after fetal anomaly diagnosis.

OBJECTIVE: Fetal anomalies occur in approximately 3% of pregnancies and receiving the diagnosis may be a potentially traumatic experience for families. The mental health of mothers receiving diagnoses and what predicts resilience or poor mental health is understudied. Emotion regulation is an important, modifiable, transdiagnostic factor of mental health, and may be protective post-diagnosis. Evaluating biomarkers of stress, including IL-6 and Allostatic Load (AL), can also serve as early indicators of risk, indicative of early intervention. This study assessed whether reappraisal, suppression, IL-6, and AL was associated with mental health outcomes and resilience in women after receiving a fetal anomaly diagnosis. METHODS: Pregnant women (N=108) presenting to a fetal concerns clinic for initial consultation completed measures of emotion regulation (i.e., reappraisal and suppression), depression, anxiety, posttraumatic stress symptoms, and resilience between 2019-2022. A blood draw was used to assess IL-6 and create composite allostatic load measure including: IL-6, blood pressure, heart rate, glucose, cortisol, and body mass index. RESULTS: Linear regressions controlling for age, gestational age, and perceived fetal diagnosis severity, demonstrated that IL-6 was negatively associated with resilience and positively associated with depression. Reappraisal was positively associated to resilience and negatively associated with depression, anxiety, and PTSD, whereas state insurance status was positively associated to anxiety and PTS symptoms. Suppression and allostatic load were not significant. CONCLUSIONS: Women experiencing fetal anomaly diagnosis represent an understudied population with unaddressed mental health needs. Reappraisal serves as not only a protective factor, but one that can be enhanced to promote maternal resilience and mental health. Furthermore, elevated IL-6 may be a critical early indicator of potential intervention needs among women who are pregnant, to mitigate negative psychological states and enhance resilience.

A clinical review of elbow ligament repairs and reconstructions in the acute and chronic settings.

Background: The ligamentous and osseous structures of the elbow joint are the major contributors to its inherent stability and damage to any of these structures can result in elbow instability. The aim of this study is to present objective and subjective outcomes following ligament repairs and/or reconstructions for acute elbow instability and chronic elbow instability. Methods: This study included patients who underwent an elbow ligament repair and/or reconstruction for acute or chronic elbow instability. We performed a comprehensive retrospective data analysis of the patient's files, followed by a clinical examination and X-ray of these patients. Results: We identified 12 acute stabilizations and 22 stabilizations for chronic instability. Patients who underwent stabilization for chronic instability had statistically significant improvements in their preoperative flexion and extension; 14.8 ± 6.4° and 5.9 ± 2.5°. Patients with chronic instability achieved better extension-flexion and pronation-supination arcs compared with their acute instability counterparts and this reached statistical significance. When the elbow pain and function scores were compared, we found stabilizations in the acute setting had better outcomes. There were two cases of postoperative instability, one in the acute instability group and one in the chronic instability group. Conclusion: This study provides evidence for elbow ligament repairs and reconstructions in both acute and chronic settings. It is an effective way of stabilizing the elbow joint in chronic instability patients, and results in an improvement in their overall range of motion. These patients achieved a greater range of motions compared with their acute instability counterparts.

A systematic review of nanocarriers for treatment of urologic cancers.

Nanocarriers (NCs) are a form of nanotechnology widely investigated in cancer treatment to improve the safety and efficacy of systemic therapies by increasing tumor specificity. Numerous clinical trials have explored the use of NCs in urologic cancers since the approval of the first NCs for cancer treatment over 20 years ago. The objective of this systematic review is to examine the effectiveness and safety of NCs in treating urological cancers. This paper summarizes the state of the field by investigating peer-reviewed, published results from 43 clinical trials involving the use of NCs in bladder, prostate, and kidney cancer patients with a focus on safety and efficacy data. Among the 43 trials, 16 were phase I, 20 phase II, and 4 phase I/II. No phase III trials have been reported. While both novel and classic NCs have been explored in urologic cancers, NCs already approved for the treatment of other cancers were more widely represented. Trials in prostate cancer and mixed trials involving both urologic and non-urologic cancer patients were the most commonly reported trials. Although NCs have demonstrable efficacy with adequate safety in non-urologic cancer patient populations, current clinical stage NC options appear to be less beneficial in the urologic cancer setting. For example, nab-paclitaxel and liposomal doxorubicin have proven ineffective in the treatment of urologic cancers despite successes in other cancers. However, several ongoing pre-clinical studies using targeted and locally applied improved NCs may eventually improve their utility.

Provider-reported experiences, barriers, and perspectives on genetic testing as part of autism diagnosis.

Several professional organizations recommend conducting genetic testing as part of the autism diagnosis process, as it can provide additional information and benefits for autistic people and their families. However, there is disagreement among autism communities about whether genetic testing reflects autistic people's best interests. In practice, rates of clinical genetic testing for autism are much lower than diagnoses, creating a large gap between clinical guidelines and real clinical encounters. To investigate one potential source of this gap, we interviewed 14 healthcare providers about the autism diagnostic process and their actions related to autism genetic testing. We recruited a sample of primarily Ph.D. level-psychologists and analyzed our qualitative data using a five-step framework analysis method. Participants generally had positive or mixed views of genetic testing in autism. They described their current experiences of implementation of genetic testing, including that they did not often find it changed their clinical practice. Only some providers recommended it to everyone receiving an autism diagnosis. They also listed factors which discourage families from getting testing, including high costs, families feeling overwhelmed, other support needs taking priority, and ethical implications. Notably, providers highlighted a trend of referring patients to research genetic testing rather than clinical testing, which may provide a cheaper and easier alternative but is not likely to return results to participants. Finally, participants felt they needed more training in genetics and listed specific topics of uncertainty. Our research highlights a need to further educate clinicians in the uses and limitations of genetic testing for autism and suggests content areas of focus for genetics educators.

Symptomatic perianeursymal cyst development 20 years after endovascular treatment of a ruptured giant aneurysm: Case report and updated review.

Perianeurysmal cysts are a rare and poorly understood finding in patients both with treated and untreated aneurysms. While the prior literature suggests that a minority of perianeurysmal cysts develop 1-4 years following endovascular aneurysm treatment, this updated review demonstrates that nearly half of perianeurysmal cysts were diagnosed following aneurysm coiling, with the other half diagnosed concurrently with an associated aneurysm prior to treatment. 64% of perianeurysmal cysts were surgically decompressed, with a 39% rate of recurrence requiring re-operation. We report a case of a 71-year-old woman who presented with vertigo and nausea and was found to have a 3.4 cm perianeurysmal cyst 20 years after initial endovascular coiling of a ruptured giant ophthalmic aneurysm. The cyst was treated with endoscopic fenestration followed by open fenestration upon recurrence. The case represents the longest latency from initial aneurysm treatment to cyst diagnosis reported in the literature and indicates that the diagnosis of perianeurysmal cyst should remain on the differential even decades after treatment. Based on a case discussion and updated literature review, this report highlights proposed etiologies of development and management strategies for a challenging lesion.

Endoscopic endonasal approach for olfactory groove meningioma resection: Strategies and outcomes in a retrospective case series.

OBJECTIVE: Though the endoscopic endonasal approach (EEA) is a widely accepted treatment for skull base tumors, the specific use of EEA for olfactory groove meningiomas (OGMs) is debated, with variable outcomes reported in the literature. We review the surgical results of OGM resections for one surgeon including the operative approach, surgical nuances, and outcomes, with a focus on factors relating to patient selection which favor EEA over transcranial approaches. METHODS: We retrospectively reviewed thirteen cases of endoscopic endonasal resection of olfactory groove meningiomas. Patient characteristics, clinical characteristics, surgical outcomes, and complications were analyzed. Extent of resection was determined based on volumetric analysis of pre- and postoperative MRI. RESULTS: Anatomic characteristics that render a tumor difficult to access fully are lateral extension beyond the mid-orbit and anterior extension to the falx. Simpson Grade I resection was achieved in 11/13 (84.6 %) cases. Mean pre-operative tumor volume was 8.99 cm3 (range 2.19-16.79 cm3), and 92 % of tumors were WHO grade I. We demonstrate 2 cases of smell preservation, possible with small unilateral tumors and tumors that are confined to either the anterior or posterior portion of the cribriform plate. The post-operative CSF leak rate was 7.7 %, without prophylactic lumbar CSF drainage. The mortality rate was 7.7 % (n = 1) after infectious complications following CSF leak. CONCLUSIONS: Endoscopic endonasal resection of olfactory groove meningiomas is an effective and safe operative method with outcomes and complication rates comparable to transcranial approaches. Key considerations include careful patient selection and familiarity with technical nuances of endoscopic endonasal approach for this specific tumor type.

Overcoming brain-derived therapeutic resistance in HER2+ breast cancer brain metastasis.

Brain metastasis of HER2+ breast cancer occurs in about 50% of all women with metastatic HER2+ breast cancer and confers poor prognosis for patients. Despite effective HER2-targeted treatments of peripheral HER2+ breast cancer with Trastuzumab +/-HER2 inhibitors, limited brain permeability renders these treatments inefficient for HER2+ breast cancer brain metastasis (BCBM). The scarcity of suitable patient-derived in-vivo models for HER2+ BCBM has compromised the study of molecular mechanisms that promote growth and therapeutic resistance in brain metastasis. We have generated and characterized new HER2+ BCBM cells (BCBM94) isolated from a patient HER2+ brain metastasis. Repeated hematogenic xenografting of BCBM94 consistently generated BCBM in mice. The clinically used receptor tyrosine kinase inhibitor (RTKi) Lapatinib blocked phosphorylation of all ErbB1-4 receptors and induced the intrinsic apoptosis pathway in BCBM94. Neuregulin-1 (NRG1), a ligand for ErbB3 and ErbB4 that is abundantly expressed in the brain, was able to rescue Lapatinib-induced apoptosis and clonogenic ability in BCBM94 and in HER2+ BT474. ErbB3 was essential to mediate the NRG1-induced survival pathway that involved PI3K-AKT signalling and the phosphorylation of BAD at serine 136 to prevent apoptosis. High throughput RTKi screening identified the brain penetrable Poziotinib as highly potent compound to reduce cell viability in HER2+ BCBM in the presence of NRG1. Successful in-vivo ablation of BCBM94- and BT474-derived HER2+ brain tumors was achieved upon two weeks of treatment with Poziotinib. MRI revealed BCBM remission upon poziotinib, but not with Lapatinib treatment. In conclusion, we have established a new patient-derived HER2+ BCBM in-vivo model and identified Poziotinib as highly efficacious RTKi with excellent brain penetrability that abrogated HER2+ BCBM brain tumors in our mouse models.

An Orally Efficacious Thyrotropin Receptor Ligand Inhibits Growth and Metastatic Activity of Thyroid Cancers.

CONTEXT: Thyroid-stimulating hormone (or thyrotropin) receptor (TSHR) could be a selective target for small molecule ligands to treat thyroid cancer (TC). OBJECTIVE: We report a novel, orally efficacious ligand for TSHR that exhibits proliferation inhibitory activity against human TC in vitro and in vivo, and inhibition of metastasis in vivo. METHODS: A35 (NCATS-SM4420; NCGC00241808) was selected from a sublibrary of >200 TSHR ligands. Cell proliferation assays including BrdU incorporation and WST-1, along with molecular docking studies were done. In vivo activity of A35 was assessed in TC cell-derived xenograft (CDX) models with immunocompromised (NSG) mice. Formalin-fixed, paraffin-embedded sections of tumor and lung tissues were observed for the extent of cell death and metastasis. RESULTS: A35 was shown to stimulate cAMP production in some cell types by activating TSHR but not in TC cells, MDA-T32, and MDA-T85. A35 inhibited proliferation of MDA-T32 and MDA-T85 in vitro and in vivo, and pulmonary metastasis of MDA-T85F1 in mice. In vitro, A35 inhibition of proliferation was reduced by a selective TSHR antagonist. Inhibition of CDX tumor growth without decreases in mouse weights and liver function showed A35 to be efficacious without apparent toxicity. Lastly, A35 reduced levels of Ki67 in the tumors and metastatic markers in lung tissues. CONCLUSION: We conclude that A35 is a TSHR-selective inhibitor of TC cell proliferation and metastasis, and suggest that A35 may be a promising lead drug candidate for the treatment of differentiated TC in humans.

Unlocking the Potential of Clustering and Classification Approaches: Navigating Supervised and Unsupervised Chemical Similarity.

BACKGROUND: The field of toxicology has witnessed substantial advancements in recent years, particularly with the adoption of new approach methodologies (NAMs) to understand and predict chemical toxicity. Class-based methods such as clustering and classification are key to NAMs development and application, aiding the understanding of hazard and risk concerns associated with groups of chemicals without additional laboratory work. Advances in computational chemistry, data generation and availability, and machine learning algorithms represent important opportunities for continued improvement of these techniques to optimize their utility for specific regulatory and research purposes. However, due to their intricacy, deep understanding and careful selection are imperative to align the adequate methods with their intended applications. OBJECTIVES: This commentary aims to deepen the understanding of class-based approaches by elucidating the pivotal role of chemical similarity (structural and biological) in clustering and classification approaches (CCAs). It addresses the dichotomy between general end point-agnostic similarity, often entailing unsupervised analysis, and end point-specific similarity necessitating supervised learning. The goal is to highlight the nuances of these approaches, their applications, and common misuses. DISCUSSION: Understanding similarity is pivotal in toxicological research involving CCAs. The effectiveness of these approaches depends on the right definition and measure of similarity, which varies based on context and objectives of the study. This choice is influenced by how chemical structures are represented and the respective labels indicating biological activity, if applicable. The distinction between unsupervised clustering and supervised classification methods is vital, requiring the use of end point-agnostic vs. end point-specific similarity definition. Separate use or combination of these methods requires careful consideration to prevent bias and ensure relevance for the goal of the study. Unsupervised methods use end point-agnostic similarity measures to uncover general structural patterns and relationships, aiding hypothesis generation and facilitating exploration of datasets without the need for predefined labels or explicit guidance. Conversely, supervised techniques demand end point-specific similarity to group chemicals into predefined classes or to train classification models, allowing accurate predictions for new chemicals. Misuse can arise when unsupervised methods are applied to end point-specific contexts, like analog selection in read-across, leading to erroneous conclusions. This commentary provides insights into the significance of similarity and its role in supervised classification and unsupervised clustering approaches. https://doi.org/10.1289/EHP14001.

Prophylactic treatment with the c-Abl inhibitor, neurotinib, diminishes neuronal damage and the convulsive state in pilocarpine-induced mice.

The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows that inhibiting c-Abl tyrosine kinase prevents apoptosis, reduces dendritic spine loss, and maintains N-methyl-d-aspartate (NMDA) receptor subunit 2B (NR2B) phosphorylated in in vitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promotes c-Abl phosphorylation, and disrupting c-Abl activity leads to fewer seizures, increases latency toward SE, and improved animal survival. Currently, clinically used c-Abl inhibitors are non-selective and have poor brain penetration. The allosteric c-Abl inhibitor, neurotinib, used here has favorable potency, selectivity, pharmacokinetics, and vastly improved brain penetration. Neurotinib-administered mice have fewer seizures and improved survival following pilocarpine-SE induction. Our findings reveal c-Abl kinase activation as a key factor in ictogenesis and highlight the impact of its inhibition in preventing the insurgence of epileptic-like seizures in rodents and humans.

Development and validation of PAMPA-BBB QSAR model to predict brain penetration potential of novel drug candidates.

Efficiently circumventing the blood-brain barrier (BBB) poses a major hurdle in the development of drugs that target the central nervous system. Although there are several methods to determine BBB permeability of small molecules, the Parallel Artificial Membrane Permeability Assay (PAMPA) is one of the most common assays in drug discovery due to its robust and high-throughput nature. Drug discovery is a long and costly venture, thus, any advances to streamline this process are beneficial. In this study, ∼2,000 compounds from over 60 NCATS projects were screened in the PAMPA-BBB assay to develop a quantitative structure-activity relationship model to predict BBB permeability of small molecules. After analyzing both state-of-the-art and latest machine learning methods, we found that random forest based on RDKit descriptors as additional features provided the best training balanced accuracy (0.70 ± 0.015) and a message-passing variant of graph convolutional neural network that uses RDKit descriptors provided the highest balanced accuracy (0.72) on a prospective validation set. Finally, we correlated in vitro PAMPA-BBB data with in vivo brain permeation data in rodents to observe a categorical correlation of 77%, suggesting that models developed using data from PAMPA-BBB can forecast in vivo brain permeability. Given that majority of prior research has relied on in vitro or in vivo data for assessing BBB permeability, our model, developed using the largest PAMPA-BBB dataset to date, offers an orthogonal means to estimate BBB permeability of small molecules. We deposited a subset of our data into PubChem bioassay database (AID: 1845228) and deployed the best performing model on the NCATS Open Data ADME portal (https://opendata.ncats.nih.gov/adme/). These initiatives were undertaken with the aim of providing valuable resources for the drug discovery community.

Efficacy of class III antiarrhythmics and magnesium combination therapy for atrial fibrillation / Eficacia del tratamiento de combinación de anti-arrítmicos clase III y magnesio para la fibrilación auricular

Atrial fibrillation is a common cardiac arrhythmia, and has been a significant financial burden. Class III antiarrhythmics such as dofetilide, ibutilide, and amiodarone are indicated for rhythm control. Magnesium may possess intrinsic antiarrhythmic properties, and may potentially increase the efficacy of class III antiarrhythmics when used concomitantly. Objective: The purpose of this article is to review the literature on the efficacy of magnesium in addition to Class III antiarrhythmics, specifically amidarone, ibutilide, and dofetilide for the cardioversion of atrial fibrillation. Methods: Databases Pubmed and CINAHL are utilized along with the search terms amiodarone, dofetilide, ibutlide, magnesium, atrial fibrillation, conversion, rhythm control, and cardioversion. Results: One study on dofetilide and 5 studies on ibutilide were identified. No studies were found on amiodarone. Patients with atrial fibrillation who received dofetilide and magnesium had higher rates of successful cardioversion as compared to those who only received dofetilide. Conversion rates were similar between the 2 treatment groups for patients with atrial flutter. As for ibutilide, 4 studies have shown that the addition of magnesium significantly increases conversion rates for patients with atrial fibrillation or typical atrial flutter. Conversion rates were similar for patients with atypical atrial flutter. One study showed that addition of magnesium did not improve efficacy of ibutilide. Higher doses of magnesium (4 g) were associated with improved outcomes. Adverse effects of magnesium were mild and included flushing, tingling, and dizziness. Patients who received magnesium had shorter corrected QT intervals and smaller increase in corrected QT interval from baseline. Compare to previous studies, studies included in this review had higher conversion rates for dofetilide and ibutilide as well as dofetilide and magnesium or ibutilide and magnesium combination therapies. However, only 2 ibutilide studies and 1 dofetilide study reported baseline characteristics such as left atrial size, history of heart failure, and duration of atrial fibrillation, which are significant predictors of successful cardioversion. Therefore, differences in baseline demographics may have influenced the results. Conclusion: Magnesium may be used as adjunct for dofetilide and ibutilide due to potential improved efficacy and minimal toxicity. Dose ranging studies should be conducted in the future to establish the optimal dose and duration of therapy as well as the optimal serum magnesium concentration in order for the clinician to manage and monitor patients appropriately (AU)

La fibrilación auricular es una arritmia cardiaca frecuente, y se ha identificado como una carga financiera significativa. Los anti-arrítmicos clase III como la dofetilida, ibutilida y amiodarona están indicados para el control del ritmo. El magnesio posee propiedades intrínsecas anti-arrítmicas y potencialmente puede aumentar la eficacia de los anti-arrítimicos de clase III cuando se usa concomitantemente. Objetivo: El objetivo de este artículo es revisar la literatura sobre la eficacia del magnesio adicionado a los anti-arrítmicos de clase III, específicamente amiodarona, ibutilida y dofetilida para la cardioversión de la fibrilación auricular. Métodos: Se utilizaron las bases de datos Pubmed y CINAHL con los términos de busca amiodarona, dofetilida, ibutilida, magnesio, fibrilación auricular, conversión, control del ritmo y cardioversión. Resultados: Se identificaron 1 estudio de dofetilida y 5 estudios de ibutilida. No se encontraron estudios con amiodarona. Los pacientes con fibrilación auricular que habían recibido dofetilida y magnesio tenían tasas más altas de cardioversión con éxito comparados con los que habían recibido sólo dofetilida. Las tasas de conversión fueron similares entre los dos grupos de tratamientos para pacientes con aleteo auricular. Para la ibutilida, los 4 estudios mostraron que la adición de magnesio aumenta significativamente las tasas de conversión para pacientes con fibrilación auricular o aleteo auricular típico. Las tasas de conversión fueron similares para pacientes con aleteo auricular atípico. Un estudio mostró que la adición de magnesio no mejoraba la eficacia de la ibutilida. Dosis altas de magnesio (4 g) se asociaron a mejores resultados. Los efectos adversos del magnesio fueron suaves e incluyeron enrojecimiento, hormigueo y mareo. Los pacientes que recibieron magnesio tuvieron intervalos QT corregidos más cortos y menores incrementos del intervalo QT corregido. Comparado con estudios previos, los estudios incluidos en esta revisión tenían tasas de conversión más altas para dofetilida e ibutilida, así como para tratamientos de combinación de dofetilida y magnesio o ibutilida y magnesio. Sin embargo, sólo 2 estudios de ibutilida y 1 de dofetilida comunicaron las características basales tales como tamaño auricular izquierdo, historia de fallo cardiaco, y duración de la fibrilación auricular, que son predictores significativos de éxito en la cardioversión. Por tanto, las diferencias en la demografía inicial pueden haber influenciado en los resultados. Conclusión: El magnesio puede utilizarse como coadyuvante de dofetilida e ibutilida debido al potencial de mejorar la eficacia y su mínima toxicidad. En el futuro deberían realizarse estudios de rango de dosis para establecer la dosis óptima y la duración del tratamiento, así como la óptima concentración sérica de magnesio para que los clínicos manejen y monitoricen a los pacientes apropiadamente (AU)