Factors affecting response variables with emphasis on drug release and loading for optimization of liposomes.

Drug delivery through Liposomes has shown tremendous potential in terms of the therapeutic application of nanoparticles. There are several drug-loaded liposomal formulations approved for clinical use that help mitigate harmful effects of life-threatening diseases. Developments in the field of liposomal formulations and drug delivery have made it possible for clinicians and researchers to find therapeutic solutions for complicated medical conditions. A key aspect in the development of drug-loaded liposomes is a careful review of optimization techniques to improve the overall formulation stability and efficacy. Optimization studies help in improving/modulating the various properties of drug-loaded liposomes and are vital for the development of this class of delivery systems. A comprehensive overview of the various process variables and factors involved in the optimization of drug-loaded liposomes is presented in this review. The influence of different independent variables on drug release and loading properties with the application of a statistical experimental design is also explained in this article.

Periodically, liposomes have shown tremendous potential as drug carriers as they are multifunctional nanoparticles with a unique ability to deliver drugs and other therapeutic moieties to target sites in the body. The use of statistical experimental designs and optimization models to develop drug-loaded liposomes is considered the most effective step in formulation development. A careful consideration of various factors and variables in optimizing liposome formulations has been specifically described in this review article. Thorough understanding of different factors that affect drug loading and release in liposomes provides deeper insights in achieving a stable, efficacious drug formulation. There are several new aspects and concepts which need to be explored as part of formulation development and optimization of drug-loaded liposomes and this article hopes to shed light on some important aspects in this scientific journey.

Mechanistic prediction and validation of Brevilin A Therapeutic effects in Lung Cancer.

BACKGROUND: Traditional Chinese medicine (TCM) has been found widespread application in neoplasm treatment, yielding promising therapeutic candidates. Previous studies have revealed the anti-cancer properties of Brevilin A, a naturally occurring sesquiterpene lactone derived from Centipeda minima (L.) A.Br. (C. minima), a TCM herb, specifically against lung cancer. However, the underlying mechanisms of its effects remain elusive. This study employs network pharmacology and experimental analyses to unravel the molecular mechanisms of Brevilin A in lung cancer. METHODS: The Batman-TCM, Swiss Target Prediction, Pharmmapper, SuperPred, and BindingDB databases were screened to identify Brevilin A targets. Lung cancer-related targets were sourced from GEO, Genecards, OMIM, TTD, and Drugbank databases. Utilizing Cytoscape software, a protein-protein interaction (PPI) network was established. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene set enrichment analysis (GSEA), and gene-pathway correlation analysis were conducted using R software. To validate network pharmacology results, molecular docking, molecular dynamics simulations, and in vitro experiments were performed. RESULTS: We identified 599 Brevilin A-associated targets and 3864 lung cancer-related targets, with 155 overlapping genes considered as candidate targets for Brevilin A against lung cancer. The PPI network highlighted STAT3, TNF, HIF1A, PTEN, ESR1, and MTOR as potential therapeutic targets. GO and KEGG analyses revealed 2893 enriched GO terms and 157 enriched KEGG pathways, including the PI3K-Akt signaling pathway, FoxO signaling pathway, and HIF-1 signaling pathway. GSEA demonstrated a close association between hub genes and lung cancer. Gene-pathway correlation analysis indicated significant associations between hub genes and the cellular response to hypoxia pathway. Molecular docking and dynamics simulations confirmed Brevilin A's interaction with PTEN and HIF1A, respectively. In vitro experiments demonstrated Brevilin A-induced dose- and time-dependent cell death in A549 cells. Notably, Brevilin A treatment significantly reduced HIF-1α mRNA expression while increasing PTEN mRNA levels. CONCLUSIONS: This study demonstrates that Brevilin A exerts anti-cancer effects in treating lung cancer through a multi-target and multi-pathway manner, with the HIF pathway potentially being involved. These results lay a theoretical foundation for the prospective clinical application of Brevilin A.

Gray matter atrophy in a 6-OHDA-induced model of Parkinson's disease.

INTRODUCTION: Magnetic resonance imaging (MRI) based brain morphometric changes in unilateral 6-hydroxydopamine (6-OHDA) induced Parkinson's disease (PD) model can be elucidated using volume-based morphometry (VBM), study of alterations in gray matter volume and Machine Learning (ML) based analyses. METHODS: We investigated gray matter atrophy in 6-OHDA induced PD model as compared to sham control using statistical and ML based analysis. VBM and atlas-based volumetric analysis was carried out at regional level. Support vector machine (SVM)-based algorithms wherein (a) features (volume) extracted from each of the 150 brain regions (b) statistically significant features (only) and (c) volumes of each cluster identified after application of VBM (VBM_Vol) were used for training the decision model. The lesion of the 6-OHDA model was validated by estimating the net contralateral rotational behaviour by the injection of apomorphine drug and motor impairment was assessed by rotarod and open field test. RESULTS AND DISCUSSION: In PD, gray matter volume (GMV) atrophy was noted in bilateral cortical and subcortical brain regions, especially in the internal capsule, substantia nigra, midbrain, primary motor cortex and basal ganglia-thalamocortical circuits in comparison with sham control. Behavioural results revealed an impairment in motor performance. SVM analysis showed 100% classification accuracy, sensitivity and specificity at both 3 and 7 weeks using VBM_Vol. CONCLUSION: Unilateral 6-OHDA induced GMV changes in both hemispheres at 7th week may be associated with progression of the disease in the PD model. SVM based approaches provide an increased classification accuracy to elucidate GMV atrophy.

IL-23p19 in osteoarthritic pain and disease.

OBJECTIVE: We have previously reported that the interleukin-23 p19 subunit (IL-23p19) is required for experimental inflammatory arthritic pain-like behaviour and disease. Even though inflammation is often a characteristic feature of osteoarthritis (OA), IL-23 is not usually considered as a therapeutic target in OA. We began to explore the role of IL-23p19 in OA pain and disease utilizing mouse models of OA and patient samples. DESIGN: The role of IL-23p19 in two mouse models of OA, namely collagenase-induced OA and monosodium iodoacetate-induced OA, was investigated using gene-deficient male mice. Pain-like behaviour and arthritis were assessed by relative static weight distribution and histology, respectively. In knee synovial tissues from a small cohort of human OA patients, a correlation analysis was performed between IL-23A gene expression and Oxford knee score (OKS), a validated Patient Reported Outcome Measure. RESULTS: We present evidence that i) IL-23p19 is required for the development of pain-like behaviour and optimal disease, including cartilage damage and osteophyte formation, in two experimental OA models and ii) IL-23A gene expression in OA knee synovial tissues correlates with a lower OKS (r=-0.742, p=0.0057). CONCLUSIONS: The findings support the possible targeting of IL-23 as a treatment for OA pain and disease progression.

Suffering makes you weaker: Limited evolutionary adaptation in competitively inferior populations.

Interspecific competition can hinder populations from evolutionarily adapting to abiotic environments, particularly by reducing population size and niche space; and feedback may arise between competitive ability and evolutionary adaptation. Here we studied populations of two model bacterial species, Escherichia coli and Pseudomonas fluorescens, that evolved in monocultures and cocultures for approximately 2400 generations at three temperatures. The two species showed a reversal in competitive dominance in cocultures along the temperature gradient. Populations from cocultures where they had been competitively dominant showed the same magnitude of fitness gain as those in monocultures. However, competitively inferior populations in cocultures showed limited abiotic adaptation compared with those in monocultures. The inferior populations in cocultures were also more likely to evolve weaker interspecific competitive ability, or go extinct. The possible competitive ability-adaptation feedback may have crucial consequences for population persistence.

Induced Moderate Hypothermia in Aortic Rupture With Retroperitoneal Bleeding: A Randomized Porcine Study.

OBJECTIVE: Induced hypothermia improves outcome in aortic arch surgery, neonatal neurointensive care, and transplant surgery for example. In contrast, spontaneous hypothermia has been associated with worse outcomes in patients suffering from hemorrhagic shock, mostly explained by its adverse effects on the coagulation system. We investigated if induced hypothermia would impair short-term survival in experimental aortic rupture with retroperitoneal bleeding. METHODS: Anesthetized pigs were randomized into 2 groups: hypothermia by peritoneal lavage of ice-cold Ringer's acetate and external cooling (n = 10) and normothermia (n = 10). Aortic rupture with retroperitoneal bleeding was induced by endovascular means creating a 6 mm hole in the retroperitoneal portion of abdominal aorta. Survival (primary outcome), hemodynamics, and arterial blood gases including lactate were collected and analyzed up to 180 min after aortic rupture. RESULTS: The body temperature (mean ± standard deviation) in the hypothermic group was 31.5 ± 1.0 °C and 38.7 ± 0.4 °C in the normothermic group at the time for aortic rupture. Survival up to 180 min after the retroperitoneal bleeding was significantly higher in the hypothermic compared with the normothermic group (P = 0.023). CONCLUSIONS: Induced hypothermia did not impair survival in this experimental retroperitoneal aortic bleeding model in anesthetized pigs. This finding may indicate a minor role for the coagulation system in this type of bleeding.

Pin1 maintains the effector program of pathogenic Th17 cells in autoimmune neuroinflammation.

Th17 cells mediated immune response is the basis of a variety of autoimmune diseases, including multiple sclerosis and its mouse model of immune aspects, experimental autoimmune encephalomyelitis (EAE). The gene network that drives both the development of Th17 and the expression of its effector program is dependent on the transcription factor RORγt. In this report, we showed that Peptidylprolyl Cis/Trans Isomerase, NIMA-Interacting 1 (Pin1) formed a complex with RORγt, and enhanced its transactivation activity, thus sustained the expression of the effector genes as well as RORγt in the EAE-pathogenic Th17 cells. We first found out that PIN1 was highly expressed in the samples from patients of multiple sclerosis, and the expression of Pin1 by the infiltrating lymphocytes in the central nerve system of EAE mice was elevated as well. An array of experiments with transgenic mouse models, cellular and molecular assays was included in the study to elucidate the role of Pin1 in the pathology of EAE. It turned out that Pin1 promoted the activation and maintained the effector program of EAE-pathogenic Th17 cells in the inflammation foci, but had little effect on the priming of Th17 cells in the draining lymph nodes. Mechanistically, Pin1 stabilized the phosphorylation of STAT3 induced by proinflammatory stimuli, and interacted with STAT3 in the nucleus of Th17 cells, which resulted in the increased expression of Rorc. Moreover, Pin1 formed a complex with RORγt, and enhanced the transactivation of RORγt to the +11 kb enhancer of Rorc, which enforced and maintained the expression of both Rorc and the effector program of pathogenic Th17 cells in EAE. Finally, the inhibition of Pin1, by genetic knockdown or by small molecule inhibitor, deceased the population of Th17 cells and the neuroinflammation, and alleviated the symptoms of EAE. These findings suggest that Pin1 is a potential therapeutic target for MS and other autoimmune inflammatory diseases.

The perspective of the logarithmic field sprayer technology.

A logarithmic sprayer was suggested about 70 years ago, but it has not yet been seriously used in research and development, and subsequent registration of plant protection products. Logarithmic sprayers have resorted to mere demonstration experiments to show end users and others how plant protection products work. Fitting dose-response curves in field experiments, however, generates much essential information, e.g., extraction of various effective field rate levels (e.g., ED20, ED50, and ED80). One of the reasons for it rarely being used in the registration of plant protection products is that the dose-response curve regression was hitherto difficult to fit; the registration requirement solely focuses on analyses of variance. Another alleged obstacle is that the logarithmic plots have systematically, not randomly distributed field rates. This paper goes through some of the problems of how to non-randomly analyze field rates by taking autocorrelation into account to make the logarithmic sprayer palatable as registration documentation by assessing efficacy, selectivity, environmental side effects, general toxicity of plant protection products, and cost-effectiveness. The development in precision agriculture, drone technology, and automation of data capture and subsequent analysis could make the logarithmic sprayer a cost-effective alternative to numerous ANOVA experiments with very few fixed field rates to aid the precision spraying of pesticides and thus reduce unnecessary environmental side effects. © 2024 Society of Chemical Industry.

Effects of extracellular vesicles for ischemic stroke: A meta­analysis of preclinical studies.

Ischemic stroke is a common occurrence worldwide, posing a severe threat to human health and leading to negative financial impacts. Currently available treatments still have numerous limitations. As research progresses, extracellular vesicles are being found to have therapeutic potential in ischemic stroke. In the present study, the literature on extracellular vesicle therapy in animal studies of ischemic stroke was screened by searching databases, including PubMed, Embase, Medline, Web of Science and the Cochrane Library. The main outcomes of the present study were the neurological function score, apoptotic rate and infarct volumes. The secondary outcomes were pro-inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß and IL-6. The study quality was assessed using the CAMARADES Checklist. Subgroup analyses were performed to evaluate factors influencing extracellular vesicle therapy. Review Man3ager5.3 was used for data analysis. A total of 20 relevant articles were included in the present meta-analysis. The comprehensive analysis revealed that extracellular vesicles exerted a significant beneficial effect on neurobehavioral function, reducing the infarct volume and decreasing the apoptotic rate. Moreover, extracellular vesicles were found to promote nerve recovery by inhibiting pro-inflammatory factors (TNF-α, IL-1ß and IL-6). On the whole, the present meta-analysis examined the combined effects of extracellular vesicles on nerve function, infarct volume, apoptosis and inflammation, which provides a foundation for the clinical study of extracellular vesicles.

Histopathological evaluation of the lungs in experimental autoimmune encephalomyelitis.

IMPORTANCE: Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis characterized by inflammation within the central nervous system. However, inflammation in non-neuronal tissues, including the lungs, has not been fully evaluated. OBJECTIVE: This study evaluated the inflammatory response in lungs of EAE mice by immunohistochemistry and histochemistry. METHODS: Eight adult C57BL/6 mice were injected with myelin oligodendrocyte glycoprotein35-55 to induce the EAE. Lungs and spinal cords were sampled from the experimental mice at the time of sacrifice and used for the western blotting, histochemistry, and immunohistochemistry. RESULTS: Histopathological examination revealed inflammatory lesions in the lungs of EAE mice, characterized by infiltration of myeloperoxidase (MPO)- and galectin-3-positive cells, as determined by immunohistochemistry. Increased numbers of collagen fibers in the lungs of EAE mice were confirmed by histopathological analysis. Western blotting revealed significantly elevated level of osteopontin (OPN), cluster of differentiation 44 (CD44), MPO and galectin-3 in the lungs of EAE mice compared with normal controls (p < 0.05). Immunohistochemical analysis revealed both OPN and CD44 in ionized calcium-binding adapter molecule 1-positive macrophages within the lungs of EAE mice. CONCLUSIONS AND RELEVANCE: Taken together, these findings suggest that the increased OPN level in lungs of EAE mice led to inflammation; concurrent increases in proinflammatory factors (OPN and galectin-3) caused pulmonary impairment.

Intraperitoneal injection of mesenchymal stem cells-conditioned media (MSCS-CM) treated monocyte can potentially alleviate motor defects in experimental autoimmune encephalomyelitis female mice; An original experimental study.

INTRODUCTION: Multiple sclerosis (MS), as a destructive pathology of myelin in central nervous system (CNS), causes physical and mental complications. Experimental autoimmune encephalomyelitis (EAE) is laboratory model of MS widely used for CNS-associated inflammatory researches. Cell therapy using macrophage M2 (MPM2) is a cell type with anti-inflammatory characteristics for all inflammatory-based neuropathies. This experimental study investigated the probable therapeutic anti-inflammatory effects of intraperitoneal (IP) injection of MPM2 on alleviation of motor defect in EAE-affected animals. MATERIALS AND METHODS: 24 C57/BL6 female mice were divided into four groups of EAE, EAE + Dexa, EAE + PBS, and EAE + MP2. EAE was induced through deep cervical injection of spinal homogenate of guinea pigs. MPM2 cells were harvested from bone marrow and injected (106cells/ml) in three days of 10, 13 and 16 post-immunizations (p.i). Clinical score (CS), anti-inflammatory cytokines (IL-4, IL-10), pro-inflammatory gene expression (TNF-α, IL-1ß) and histopathological investigations (HE, Nissl and Luxol Fast Blue) were considered. Data were analyzed using SPSS software (v.19) and p < 0.05 was considered significant level. RESULTS: During EAE induction, the mean animal weight was decreased (p < 0.05); besides, following MPM2 injection, the weight gain was applied (p < 0.05) in EAE + MPM2 groups than control. Increased (p < 0.05) levels of CS was found during EAE induction in days 17-28 in EAE animals; besides, CS was decreased (p < 0.05) in EAE + MPM2 group than EAE animals. Also, in days 25-28 of experiment, the CS was decreased (p < 0.05) in EAE + MPM2 than EAE + Dexa. Histopathological assessments revealed low density of cell nuclei in corpus callosum, microscopically. LFB staining also showed considerable decrease in white matter density of corpus callosum in EAE group. Acceleration of white matter density was found in EAE + MPM2 group following cell therapy procedure. Genes expression of TNF-α, IL-1ß along with IL-4 and IL-10 were decreased (p < 0.05) in EAE + MPM2 group. CONCLUSION: IP injection of MPM2 to EAE-affected female mice can potentially reduce the CNS inflammation, neuronal death and myelin destruction. MPM2 cell therapy can improve animal motor defects.

Quercetin regulates dendritic cell activation by targeting STAT4 in the treatment of experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a class of autoimmune diseases mainly caused by the immune system attacking the myelin sheath of the axons in the nervous system. Although the pathogenesis of MS is complex, studies have shown that dendritic cells (DCs) play a vital role in the pathogenesis of MS. Quercetin (QU) has a unique advantage in clinical application, especially for treating autoimmune diseases. However, the mechanism of QU in the treatment of experimental autoimmune encephalomyelitis (EAE) remains unclear. In this study, we explore the potential role of QU in EAE. Finally, we find that QU has anti-inflammatory activities and neural protective effects in EAE. The experimental results suggest that the cellular basis for QU's function is to inhibit the activation of DCs while modulating the Th17 cell differentiation in the co-culture system. Further, QU may target STAT4 to inhibit its activation in DCs. This work will be of great significance for the future development and utilization of QU.

ExGenet, Integrating Design of Experiments and Response Surface Methodology for Cancer Gene Detection in Gene Regulatory Networks.

Objective: Network analysis techniques often require tuning hyperparameters for optimal performance. For instance, the independent cascade model necessitates determining the probability of diffusion. Despite its importance, a consensus on effective parameter adjustment remains elusive. Methods: In this study, we propose a novel approach utilizing experimental design methodologies, specifically 2-Factorial Analysis for Screening, and Response Surface Methodology (RSM) for parameter adjustment. We apply this methodology to the task of detecting cancer driver genes in colorectal cancer. Result: Through experimental validation of colorectal cancer data, we demonstrate the effectiveness of our proposed methodology. Compared with existing methods, our approach offers several advantages, including reduced computational overhead, systematic parameter selection grounded in statistical theory, and improved performance in detecting cancer driver genes. Conclusion: This study presents a significant advancement in the field of network analysis by providing a practical and systematic approach to hyperparameter tuning. By optimizing parameter settings, our methodology offers promising implications for critical biomedical applications such as cancer driver gene detection.

More Satisfaction, Less Equality: Distributive Effects of Transparent Needs in a Laboratory Experiment.

Societies are confronted with the dilemma that need satisfaction requires transparent individual needs. We study the effect of information about others' needs on the distribution of a joint endowment in a three-player network exchange game in a laboratory experiment. Need levels are exogenously given and either transparent (known to all three network members) or opaque (only known to the players themselves). The three players negotiate in dyads until two players agree on a distribution. We expect that the transparency of need thresholds raises need satisfaction but lowers equality. The results suggest that the members of the dyad who agree on the distribution can satisfy their own need thresholds even when information about thresholds is opaque. The effect of transparency on the remaining network member is antithetical: while transparency increases the rate of need satisfaction, it decreases the average share of allocations when needs are low. In the opaque condition, allocated shares are larger, but need satisfaction is lower. This reveals the ambivalent distributive effects of transparent need thresholds: Transparency helps those with the highest need thresholds, but it can hurt those with lower need thresholds, and it barely affects the ones with the most influence on the decision. Supplementary Information: The online version contains supplementary material available at 10.1007/s11211-024-00434-0.

Experimental design considerations and statistical analyses in preclinical tumor growth inhibition studies.

Animal models are used in cancer pre-clinical research to identify drug targets, select compound candidates for clinical trials, determine optimal drug dosages, identify biomarkers, and ensure compound safety. This tutorial aims to provide an overview of study design and data analysis from animal studies, focusing on tumor growth inhibition (TGI) studies used for prioritization of anticancer compounds. Some of the experimental design aspects discussed here include the selection of the appropriate biological models, the choice of endpoints to be used for the assessment of anticancer activity (tumor volumes, tumor growth rates, events, or categorical endpoints), considerations on measurement errors and potential biases related to this type of study, sample size estimation, and discussions on missing data handling. The tutorial also reviews the statistical analyses employed in TGI studies, considering both continuous endpoints collected at single time-point and continuous endpoints collected longitudinally over multiple time-points. Additionally, time-to-event analysis is discussed for studies focusing on event occurrences such as animal deaths or tumor size reaching a certain threshold. Furthermore, for TGI studies involving categorical endpoints, statistical methodology is outlined to compare outcomes among treatment groups effectively. Lastly, this tutorial also discusses analysis for assessing drug combination synergy in TGI studies, which involves combining treatments to enhance overall treatment efficacy. The tutorial also includes R sample scripts to help users to perform relevant data analysis of this topic.

The impact of a reproductive health voucher in Uganda using a quasi-experimental matching design.

This study assesses the impact of a voucher project that targeted vulnerable and poor pregnant women in Uganda. Highly subsidised vouchers gave access to a package of safe delivery services consisting of four antenatal visits, safe delivery, one postnatal visit, the treatment and management of selected pregnancy-related medical conditions and complications, and emergency transport. Vouchers were sold during the project's operational period from 2016 to 2019. This study covers 8 out of 25 project-benefiting districts in Uganda and a total of 1,881 pregnancies, including both beneficiary and non-beneficiary mothers. Using a matching design, the results show a positive effect on the survival of new-born babies. The difference in the survival rate between the control group and the treatment group is 5.4% points, indicating that the voucher project reduced infant mortality by more than 65 per cent.

An improved method of local coloring in vertical-slot fishways to enhance the fish migration effect of grass carp.

Vertical-slot fishway (VSF) has been used in many water conservancy projects to restore the river connectivity. A high-quality fishway project should facilitate fish to discovering the exit and passing through, avoiding to long stay in the fishway and delay the migration. Current research on fishway engineering has not yielded an expected passing ratio of fish migration, and it is therefore of great significance to further study the assisting effect of VSF in fish migration. To begin with, we preliminarily determined the attractive and repelling colors of grass carps based on their swimming behavior in a static water pool configured with local colors. Combined with the migration route of the grass carp in a VSF pool without local coloring, four local coloring cases were designed. Based on the camera results of the four experimental local coloring cases, a comparative analysis was conducted with the blank control group frame by frame. This was followed by the statistics of the number of successfully migrated grass carps and their total completion time. On that basis, the assisting effect of VSF in fish migration under the four cases was evaluated in terms of the reduction rate of migration route length, the reduction rate of completion time, and the improvement rate of passing ratio. The research outcomes indicated that green and blue act as attractive colors while yellow and red serve as repelling colors for grass carp. Adding colors to the training wall and dividing wall in the VSF pool, the migration route of grass carp was appropriately adjusted, alongside a shortened completion time and an improved passing ratio. Of the four local coloring cases, the recommended case showed a significant effect on migration route, with more concentrated moving trajectories and shortened route length. Typically, the migration route length decreased by 26%, and the frequency of fish long staying at the junction between the training wall and dividing wall was markedly reduced, as well as the frequency of fish swimming along the water flow from upstream to downstream. The completion time was shortened by 26%, and the passing ratio was enhanced by 44%. The approach of combining local coloring with fish behavior and fishway hydraulics in the pool surpassed the method that optimizes the fishway design only from the fishway hydraulics. The improved method greatly shortened the migration route length, reduced the completion time, and significantly improved the passing ratio of fish passage objects in the VSF. The present research mainly focuses on using model experiments to evaluate the local coloring cases. In the future studies, we will configure local colors to the sidewalls of on-site fishways using environmentally friendly paint or colored organic glass panels. With the monitoring results of the completion time and passing ratio of fish passage objects, the recommended case can be further verified and optimized, thereby providing a more reasonable and feasible local coloring case for assisting fish migration in the VSF project.

Numerical studies on shortening the duration of HIFU ablation therapy and their experimental validation.

High Intensity Focused Ultrasound (HIFU) is used in clinical practice for thermal ablation of malignant and benign solid tumors located in various organs. One of the reason limiting the wider use of this technology is the long treatment time resulting from i.a. the large difference between the size of the focal volume of the heating beam and the size of the tumor. Therefore, the treatment of large tumors requires scanning their volume with a sequence of single heating beams, the focus of which is moved in the focal plane along a specific trajectory with specific time and distance interval between sonications. To avoid an undesirable increase in the temperature of healthy tissues surrounding the tumor during scanning, the acoustic power and exposure time of each HIFU beam as well as the time intervals between sonications should be selected in such a way as to cover the entire volume of the tumor with necrosis as quickly as possible. This would reduce the costs of treatment. The aim of this study was to quantitatively evaluate the hypothesis that selecting the average acoustic power and exposure time for each individual heating beam, as well as the temporal intervals between sonications, can significantly shorten treatment time. Using 3D numerical simulations, the dependence of the duration of treatment of a tumor with a diameter of 5 mm or 9 mm (requiring multiple exposure to the HIFU beam) on the sonication parameters (acoustic power, exposure time) of each single beam capable of delivering the threshold thermal dose (CEM43 = 240 min) to the treated tissue volume was examined. The treatment duration was determined as the sum of exposure times to individual beams and time intervals between sonications. The tumor was located inside the ex vivo tissue sample at a depth of 12.6 mm. The thickness of the water layer between the HIFU transducer and the tissue was 50 mm. The sonication and scanning parameters selected using the developed algorithm shortened the duration of the ablation procedure by almost 14 times for a 5-mm tumor and 20 times for a 9-mm tumor compared to the duration of the same ablation plan when a HIFU beam was used of a constant acoustic power, constant exposure time (3 s) and constant long time intervals (120 s) between sonications. Results of calculations of the location and size of the necrotic lesion formed were experimentally verified on ex vivo pork loin samples, showing good agreement between them. In this way, it was proven that the proper selection of sonication and scanning parameters for each HIFU beam allows to significantly shorten the time of HIFU therapy.

Assessing the Influence of Redlining on Intergenerational Wealth and Body Mass Index Through a Quasi-experimental Framework.

BACKGROUND: Higher levels of body mass index (BMI), particularly for those who have obesity defined as class II and III, are correlated with excess risk of all-cause mortality in the USA, and these risks disproportionately affects marginalized communities impacted by systemic racism. Redlining, a form of structural racism, is a practice by which federal agencies and banks disincentivized mortgage investments in predominantly racialized minority neighborhoods, contributing to residential segregation. The extent to which redlining contributes to current-day wealth and health inequities, including obesity, through wealth pathways or limited access to health-promoting resources, remains unclear. Our quasi-experimental study aimed to investigate the generational impacts of redlining on wealth and body mass index (BMI) outcomes. METHODS: We leveraged the Panel Study of Income Dynamics (PSID) and Home Owners' Loan Corporation (HOLC) maps to implement a geographical regression discontinuity design, where treatment assignment is randomly based on the boundary location of PSID grandparents in yellowlined vs. redlined areas and used outcome measures of wealth and mean BMI of grandchildren. To estimate our effects, we used a continuity-based approach and applied data-driven procedures to identify the most appropriate bandwidths for a valid estimation and inference. RESULTS: In our fully adjusted model, grandchildren with grandparents living in redlined areas had lower average household wealth (ß = - $35,419; 95% CIrbc - $37,423, - $7615) and a notably elevated mean BMI (ß = 7.47; 95% CIrbc - 4.00, 16.60), when compared to grandchildren whose grandparents resided in yellowlined regions. CONCLUSION: Our research supports the idea that redlining, a historical policy rooted in structural racism, is a key factor contributing to disparities in wealth accumulation and, conceivably, body mass index across racial groups.

Animal models of immune-mediated demyelinating polyneuropathies.

Immune-mediated demyelinating polyneuropathies (IMDPs) are rare disorders in which dysregulated adaptive immune responses cause peripheral nerve demyelinating inflammation and axonal injury in susceptible individuals. Despite significant advances in understanding IMDP pathogenesis guided by patient data and representative mammalian models, specific therapies are lacking. Significant knowledge gaps in IMDP pathogenesis still exist, e.g. precise antigen(s) and mechanisms that initially trigger immune system activation and identification of large population disease susceptibility factors. The initial directional cues for antigen-specific effector or autoreactive leukocyte trafficking into peripheral nerves are also unknown. An overview of current animal models, with emphasis on the experimental autoimmune neuritis and spontaneous autoimmune peripheral polyneuropathy models, is provided. Insights on the initial directional cues for peripheral nerve tissue specific autoimmunity using a novel Major Histocompatibility Complex class II conditional knockout mouse strain are also discussed, suggesting an essential research tool to study cell- and time-dependent adaptive immunity in autoimmune diseases.