Safety and Feasibility of Photodynamic Therapy for Percutaneous Image-guided Abdominopelvic Abscess Drainage: Phase 1 Trial.

Background Standard-of-care abscess management includes image-guided percutaneous drainage and antibiotics; however, cure rates vary, and concern for antibiotic-resistant bacteria is growing. Photodynamic therapy (PDT), which uses light-activated dyes to generate cytotoxic reactive oxygen species, could complement the standard of care by sterilizing the abscess at the time of drainage. Purpose To evaluate safety and feasibility of PDT with methylene blue (hereafter, MB-PDT) at the time of percutaneous abscess drainage. Materials and Methods This prospective, open-label, dose-escalation, first-in-humans, registered phase 1 clinical study of MB-PDT included participants who underwent percutaneous abdominal or pelvic abscess drainage with CT or US guidance from January 2015 to March 2020 and September 2022 to September 2023. Following drainage, MB-PDT was performed with laser illumination at a fluence rate of 20 mW/cm2, with fluence groups of 6, 12, 18, 24, 30, and 36 J/cm2 (n = 3 each). The primary outcome was safety, indicated by absence of fat embolism, MB escape, abscess wall damage, and need for surgery to remove optical fibers. Preliminary efficacy end points included the time to drainage catheter removal, drainage catheter output volume, and clinical symptom and fever duration. Relationships between fluence and outcomes were analyzed with Spearman correlation and linear regression analyses, and ordinary one-way analysis of variance was used for group comparisons. Results MB-PDT was safe and feasible in all 18 participants (mean age, 60.1 years ± 18.3 [SD]; 10 female), with no negative safety outcomes observed for any participant. No study-related adverse events were encountered, and the procedure did not increase reported pain (P = .1). Clinical symptom and fever duration was shorter in participants receiving higher fluences (30 and 36 J/cm2 vs 6 J/cm2) (P = .03). The presence of antibiotic-resistant bacteria was not predictive of clinical symptom and fever duration (ß = 0.13, P = .37). Conclusion MB-PDT was a safe and feasible adjunct to image-guided percutaneous abscess drainage. Clinical measures indicated a dose-dependent response to PDT. ClinicalTrials.gov registration no.: NCT02240498 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Johnston and Goldberg in this issue.

Polymer-Based Nanoparticles with Probucol and Lithocholic Acid: A Novel Therapeutic Approach for Oxidative Stress-Induced Retinopathies.

Oxidative stress is pivotal in retinal disease progression, causing dysfunction in various retinal components. An effective antioxidant, such as probucol (PB), is vital to counteract oxidative stress and emerges as a potential candidate for treating retinal degeneration. However, the challenges associated with delivering lipophilic drugs such as PB to the posterior segment of the eye, specifically targeting photoreceptor cells, necessitate innovative solutions. This study uses formulation-based spray dry encapsulation technology to develop polymer-based PB-lithocholic acid (LCA) nanoparticles and assesses their efficacy in the 661W photoreceptor-like cell line. Incorporating LCA enhances nanoparticles' biological efficacy without compromising PB stability. In vitro studies demonstrate that PB-LCA nanoparticles prevent reactive oxygen species (ROS)-induced oxidative stress by improving cellular viability through the nuclear erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. These findings propose PB-LCA nanoparticles as a promising therapeutic strategy for oxidative stress-induced retinopathies.

Racial and Ethnic Disparities in Excess All-Cause Mortality in the First Year of the COVID-19 Pandemic.

Research on the COVID-19 pandemic in the United States has consistently found disproportionately high mortality among ethnoracial minorities, but reports differ with respect to the magnitude of mortality disparities and reach different conclusions regarding which groups were most impacted. We suggest that these variations stem from differences in the temporal scope of the mortality data used and difficulties inherent in measuring race and ethnicity. To circumvent these issues, we link Social Security Administration death records for 2010 through 2021 to decennial census and American Community Survey race and ethnicity responses. We use these linked data to estimate excess all-cause mortality for age-, sex-, race-, and ethnicity-specific subgroups and examine ethnoracial variation in excess mortality across states and over the course of the pandemic's first year. Results show that non-Hispanic American Indians and Alaska Natives experienced the highest excess mortality of any ethnoracial group in the first year of the pandemic, followed by Hispanics and non-Hispanic Blacks. Spatiotemporal and age-specific ethnoracial disparities suggest that the socioeconomic determinants driving health disparities prior to the pandemic were amplified and expressed in new ways in the pandemic's first year to disproportionately concentrate excess mortality among racial and ethnic minorities.

Failure of senolytic treatment to prevent cognitive decline in a female rodent model of aging.

There are sex differences in vulnerability and resilience to the stressors of aging and subsequent age-related cognitive decline. Cellular senescence occurs as a response to damaging or stress-inducing stimuli. The response includes a state of irreversible growth arrest, the development of a senescence-associated secretory phenotype, and the release of pro-inflammatory cytokines associated with aging and age-related diseases. Senolytics are compounds designed to eliminate senescent cells. Our recent work indicates that senolytic treatment preserves cognitive function in aging male F344 rats. The current study examined the effect of senolytic treatment on cognitive function in aging female rats. Female F344 rats (12 months) were treated with dasatinib (1.2 mg/kg) + quercetin (12 mg/kg) or ABT-263 (12 mg/kg) or vehicle for 7 months. Examination of the estrus cycle indicated that females had undergone estropause during treatment. Senolytic treatment may have increased sex differences in behavioral stress responsivity, particularly for the initial training on the cued version of the watermaze. However, pre-training on the cue task reduced stress responsivity for subsequent spatial training and all groups learned the spatial discrimination. In contrast to preserved memory observed in senolytic-treated males, all older females exhibited impaired episodic memory relative to young (6-month) females. We suggest that the senolytic treatment may not have been able to compensate for the loss of estradiol, which can act on aging mechanisms for anxiety and memory independent of cellular senescence.

Senolytic treatment alleviates doxorubicin-induced chemobrain.

Doxorubicin (Dox), a widely used treatment for cancer, can result in chemotherapy-induced cognitive impairments (chemobrain). Chemobrain is associated with inflammation and oxidative stress similar to aging. As such, Dox treatment has also been used as a model of aging. However, it is unclear if Dox induces brain changes similar to that observed during aging since Dox does not readily enter the brain. Rather, the mechanism for chemobrain likely involves the induction of peripheral cellular senescence and the release of senescence-associated secretory phenotype (SASP) factors and these SASP factors can enter the brain to disrupt cognition. We examined the effect of Dox on peripheral and brain markers of aging and cognition. In addition, we employed the senolytic, ABT-263, which also has limited access to the brain. The results indicate that plasma SASP factors enter the brain, activating microglia, increasing oxidative stress, and altering gene transcription. In turn, the synaptic function required for memory was reduced in response to altered redox signaling. ABT-263 prevented or limited most of the Dox-induced effects. The results emphasize a link between cognitive decline and the release of SASP factors from peripheral senescent cells and indicate some differences as well as similarities between advanced age and Dox treatment.

Full genome sequence analysis of African swine fever virus isolates from Cameroon.

African swine fever (ASF) is a devastating disease of domestic pigs that has spread across the globe since its introduction into Georgia in 2007. The etiological agent is a large double-stranded DNA virus with a genome of 170 to 180 kb in length depending on the isolate. Much of the differences in genome length between isolates are due to variations in the copy number of five different multigene families that are encoded in repetitive regions that are towards the termini of the covalently closed ends of the genome. Molecular epidemiology of African swine fever virus (ASFV) is primarily based on Sanger sequencing of a few conserved and variable regions, but due to the stability of the dsDNA genome changes in the variable regions occur relatively slowly. Observations in Europe and Asia have shown that changes in other genetic loci can occur and that this could be useful in molecular tracking. ASFV has been circulating in Western Africa for at least forty years. It is therefore reasonable to assume that changes may have accumulated in regions of the genome other than the standard targets over the years. At present only one full genome sequence is available for an isolate from Western Africa, that of a highly virulent isolate collected from Benin during an outbreak in 1997. In Cameroon, ASFV was first reported in 1981 and outbreaks have been reported to the present day and is considered endemic. Here we report three full genome sequences from Cameroon isolates of 1982, 1994 and 2018 outbreaks and identify novel single nucleotide polymorphisms and insertion-deletions that may prove useful for molecular epidemiology studies in Western Africa and beyond.

Probucol-bile acid based nanoparticles protect auditory cells from oxidative stress: an in vitro study.

Aim: Excessive free radicals contribute to oxidative stress and mitochondrial dysfunction in sensorineural hearing loss (SNHL). The antioxidant probucol holds promise, but its limited bioavailability and inner ear barriers hinder effective SNHL treatment. Methodology: We addressed this by developing probucol-loaded nanoparticles with polymers and lithocholic acid and tested them on House Ear Institute-Organ of Corti cells. Results: Probucol-based nanoparticles effectively reduced oxidative stress-induced apoptosis, enhanced cellular viability, improved probucol uptake and promoted mitochondrial function. Additionally, they demonstrated the capacity to reduce reactive oxygen species through the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway. Conclusion: This innovative nanoparticle system holds the potential to prevent oxidative stress-related hearing impairment, providing an effective solution for SNHL.

Hearing loss affects millions of people worldwide, and its prevalence is expected to double by 2050. Current treatments have limitations, pushing researchers to explore new options. Oxidative stress is a key player in hearing loss and is known to damage inner ear hair cells. While antioxidants, known for their protective effects, hold promise, delivering them effectively to the inner ear is challenging. Scientists have been testing nanoparticles loaded with the antioxidant probucol to fight hearing loss. In this study, these particles protected inner ear cells in cell studies, offering potential hope for preventing hearing problems. This research is a significant step toward finding better treatments for hearing loss.

Probucol-Ursodeoxycholic Acid Otic Formulations: Stability and In Vitro Assessments for Hearing Loss Treatment.

Targeted drug delivery is an ongoing aspect of scientific research that is expanding through the design of micro- and nanoparticles. In this paper, we focus on spray dried microparticles as carriers for a repurposed lipophilic antioxidant (probucol). We characterise the microparticles and quantify probucol prior to assessing cytotoxicity on both control and cisplatin treated hair cells (known as House Ear Institute-Organ of Corti 1; HEI-OC1). The addition of water-soluble polymers to 2% ß-cyclodextrin resulted in a stable probucol formulation. Ursodeoxycholic acid (UDCA) used as formulation excipient increases probucol miscibility and microparticle drug content. Formulation characterisations reveals spray drying results in spherical UDCA-drug microparticles with a mean size distribution of ∼5-12 µm. Probucol microparticles show stable short-term storage conditions accounting for only ∼10% loss over seven days. By mimicking cell culture conditions, both UDCA-probucol (67%) and probucol only (82%) microparticles show drug release in the initial two hours. Furthermore, probucol formulations with or without UDCA preserve cell viability and reduce cisplatin-induced oxidative stress. Mitochondrial bioenergetics results in lower basal respiration and non-mitochondrial respiration, with higher maximal respiration, spare capacity, ATP production and proton leak within cisplatin challenged UDCA-probucol groups. Overall, we present a facile method for incorporating lipophilic antioxidant carriers in polymer-based particles that are tolerated by HEI-OC1 cells and show stable drug release, sufficient in reducing cisplatin-induced reactive oxygen species accumulation.

Biotechnological Effects of Advanced Smart-Bile Acid Cyclodextrin-Based Nanogels for Ear Delivery and Treatment of Hearing Loss.

Inner ear delivery requires safe and effective drug delivery vehicles incorporating high-viscosity formulations with permeation enhancers. This study designs novel thermoresponsive-smart polymer-bile acid and cyclodextrin-based nanogels for inner ear delivery. Nanogels are examined for their rheological and physical properties. The biocompatibility studies will be assessed on auditory and macrophage cell lines by investigating the impact of nanogels on cellular viability, mitochondrial respiration, glycolysis, intracellular oxidative stress, inflammatory profile, and macrophage polarization. Novel ther nanogels based on bile acid and beta-cyclodextrin show preserved porous nanogels' inner structure, exhibit non-Newtonian, shear-thinning fluid behavior, have fast gelation at 37 °C and minimal albumin adsorption on the surface. The nanogels have minimal impact on cellular viability, mitochondrial respiration, glycolysis, intracellular oxidative stress, and inflammatory profile of the auditory cell line House Ear Institute-Organ of Corti 1 after 24 h incubation. Nanogel exposure of 24 h to macrophage cell line RAW264.7 leads to decreased viability, mitochondrial dysfunction, and increased intracellular ROS and inflammatory cytokines. However, polarization changes from M2 anti-inflammatory to M1 pro-inflammatory macrophages are minimal, and inflammatory products of RAW264.7 macrophages do not overly disrupt the survivability of HEI-OC1 cells. Based on these results, thermoresponsive bile acid and cyclodextrin nanogels can be potential drug delivery vehicles for inner ear drug delivery.

Polymer-Based Nanoparticles for Inner Ear Targeted Trans Differentiation Gene Therapy.

Hearing loss is a significant disability that often goes under recognised, largely due to poor identification, prevention, and treatment. Steps are being made to amend these pitfalls in the investigation of hearing loss, however, the development of a cure to reverse advanced forms remains distant. This review details some current advances in the treatment of hearing loss, with a particular focus on genetic-based nanotechnology and how it may provide a useful avenue for further research. This review presents a broad background on the pathophysiology of hearing loss and some current interventions. We also highlight some potential genes that may be useful in the amelioration of hearing loss. Pathways of cellular differentiation from stem or supporting cell to functional hair cell are covered in detail, as this mechanism represents a key means of regenerating these cell types. Overall, we believe that polymer-based nanotechnology coupled with novel excipients represents a useful area of further research in the treatment of hearing loss, although further studies in this area are required.

Bile Acid Application in Cell-Targeting for Molecular Receptors in Relation to Hearing: A Comprehensive Review.

Bile acids play important roles in the human body, and changes in their pool can be used as markers for various liver pathologies. In addition to their functional effects in modulating inflammatory responses and cellular survivability, the unconjugated or conjugated, secondary, or primary nature of bile acids accounts for their various ligand effects. The common hydrophilic bile acids have been used successfully as local treatment to resolve drug-induced cell damage or to ameliorate hearing loss. From various literature references, bile acids show concentration and tissue-dependent effects. Some hydrophobic bile acids act as ligands modulating vitamin D receptors, muscarinic receptors, and calcium-activated potassium channels, important proteins in the inner ear system. Currently, there are limited resources investigating the therapeutic effects of bile acid on hearing loss and little to no information on detecting bile acids in the remote ear system, let alone baseline bile acid levels and their prevalence in healthy and disease conditions. This review presents both hydrophilic and hydrophobic human bile acids and their tissue-specific effects in modulating cellular integrity, thus considering the possible effects and extended therapeutic applicability of bile acids to the inner ear tissue.

The effect of deoxycholic acid-based hydrogels on hepatic, muscle and pancreatic beta cells.

Aim: The aim of this study is to test the biocompatibility of hydrogels with polysaccharides and bile acids on three murine cell lines. Materials & methods: Novel hydrogels containing poloxamer 407, polysaccharides (starch, pectin, acacia, carboxymethyl and methyl 2-hydroxyethyl cellulose) and deoxycholic acid were prepared using cold method, sterilized and used in biological assays to determine effects on hepatic, muscle, and pancreatic beta cells. Results and conclusion: Hydrogels with deoxycholic acid had tissue-depending effects on cellular survival and bioenergetics, resulting in the best cellular viability and bioenergetics within pancreatic beta cells. Further research is needed as proposed hydrogels may be beneficial for cell delivery systems of pancreatic beta cells.

In this study, we made gels using different materials, including five types of sugar and an acid found in bile. We investigated whether these gels would harm cells and their respiration. Muscle cells responded poorly to gels, as gels harmed their natural processes. Liver cells responded slightly better to gels, but gels still harmed them a lot. Cells found in the pancreas were not especially affected by gels, and these gels may be good candidates for further research with pancreatic cells. The gels could potentially be used to deliver drugs to the cells.

Probucol-bile acid nanoparticles: a novel approach and promising solution to prevent cellular oxidative stress in sensorineural hearing loss.

The use of antioxidants could thus prove an effective medication to prevent or facilitate recovery from oxidative stress-induced sensorineural hearing loss (SNHL). One promising strategy to prevent SNHL is developing probucol (PB)-based nanoparticles using encapsulation technology and administering them to the inner ear via the established intratympanic route. The preclinical, clinical and epidemiological studies support that PB is a proven antioxidant that could effectively prevent oxidative stress in different study models. Such findings suggest its applicability in preventing oxidative stress within the inner ear and its associated neural cells. However, several hurdles, such as overcoming the blood-labyrinth barrier, ensuring sustained release, minimising systemic side effects and optimising targeted delivery in the intricate inner ear structures, must be overcome to efficiently deliver PB to the inner ear. This review explores the background and pathogenesis of hearing loss, the potential of PB in treating oxidative stress and its cellular mechanisms, and the obstacles linked to inner ear drug delivery for effectively introducing PB to the inner ear.

Proton beam therapy and dentofacial development in paediatric cancer patients: A scoping review.

Purpose: It is known that radiation to dentofacial structures during childhood can lead to developmental disturbances. However, this appears to be a relatively subordinated research subject. For this reason, this review aims to establish the current evidence base on the effect of PBT on dentofacial development in paediatric patients treated for cancer in the head and neck region. Materials and methods: A comprehensive search was undertaken to identify both published and unpublished studies or reports. A single reviewer completed initial screening of abstracts; 2 independent reviewers completed secondary screening and data extraction. A narrative synthesis was then conducted. Results: 82 records were screened in total, resulting in 11 included articles. These articles varied in terms of study design and reporting quality. Owing to both poor study reporting and limited patient numbers, it is not possible to determine the effect of cancer diagnosis, chronological age at treatment, radiation dose or treatment modality on the incidence of facial deformation or dental development anomalies. Conclusion: Disturbances in dentofacial development are an under-reported toxicity in paediatric cancer survivors treated with PBT to the head and neck. There is a need for more research on dentofacial toxicity reporting, focused on the impact of treatment age, radiation dose, concurrent therapies, and the subsequent impact on quality of life.

Novel polysaccharides-bile acid-cyclodextrin gel systems and effects on cellular viability and bioenergetic parameters.

Aim: The novel hydrogel systems made from sodium alginate, pectin, beta-cyclodextrin and deoxycholic acid (DCA) were proposed as potential drug-delivery matrices. Materials & methods: To ensure biocompatibility, rheological parameters were examined and hydrogels' effects on bioenergetic parameters and cellular viability on murine hepatic, and muscle and pancreatic beta cells. Results & conclusion: All hydrogels show non-Newtonian, shear thinning behavior. Cells displayed various oxygen-dependent viability patterns, with the bile acid overall adversely affecting their biological activities. All cells performed best under normoxia, with pancreatic beta cells displaying the most profound oxygen-dependent viability behavior. The cells tolerated the addition of a moderate concentration of beta-cyclodextrin to the polymer matrix.