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Uterine arteriovenous malformation (AVM) is a rare cause of vaginal bleeding and miscarriage. We report two cases of uterine AVMs in patients with a history of complex congenital heart disease, an association that has not been previously described. Both patients were treated by selective uterine artery embolization, a minimally invasive therapy that has revolutionized the management of uterine AVMs, thus offering an alternative to conventional hysterectomy. [ABSTRACT FROM AUTHOR]

To study the absorption of levodopa and interaction with the extracerebral dopamine antagonist domperidone, 15 patients with idiopathic Parkinson's disease were given levodopa 500 mg p.o., alone, and with domperidone pre-treatment. Domperidone pretreatment (10, 20, 40 mg, p.o., i.v. or i.m.) caused a mean 12% increase in peak plasma levodopa concentration, which occurred a mean of 10 min earlier than when levodopa was given alone. Parkinsonian disability scores were improved and peak clinical response occurred 16 min earlier with domperidone than without. Domperidone slightly increases the immediate bioavailability (over 4 h) and anti-parkinsonian response to a given dose of levodopa. [ABSTRACT FROM AUTHOR]

We have investigated the interaction of azapropazone with phenytoin in five healthy volunteers. From steady-state plasma phenytoin concentrations of about 17 mumol/l there was at least a two-fold increase following the introduction of azapropazone. The main mechanism of the interaction was a decrease in phenytoin clearance, attributable to competitive inhibition by azapropazone of phenytoin p-hydroxylation. Protein-binding of phenytoin in the plasma (as assessed by salivary phenytoin concentrations) was significantly reduced from 92 to 90% by azapropazone and similar changes occurred in in vitro studies of [3H]- phenytoin protein binding. [ABSTRACT FROM AUTHOR]

Industrial storage of granular material using silos is common, however, improved understanding of silo flow is needed. Various continuum models attempt to describe the velocity of dense granular flow in silos. Kinematic, and recently, stochastic models, based upon the diffusion of some quantity, perform well when there is a single orifice, and when the yield criterion is satisfied. However, if system stresses are insufficient to satisfy the yield criterion, or if there is a second orifice, these models fail to capture the entire flow behaviour. Advances in granular rheology have allowed a pressure dependent friction law to be defined which can capture the behaviour of granular silo flow including un-yielded zones, flow-rate independence of fill height, the Beverloo flow-rate, and various other phenomena. We performed silo discharge experiments in a flat bottomed planar silo with a single and two adjacent orifices, for two grain types. The velocity was measured using Particle Image Velocimetry. Results were compared to a mathematical model based on the μ(I) rheology which was shown to qualitatively capture the observed phenomena including plug-like zones where the yield criterion is not satisfied. These preliminary results strongly encourage future investigations into the effect of friction parameters and numerical boundary conditions.

This paper reviews the current knowledge of leishmaniasis epidemiology in Venezuela, Colombia, Ecuador, Peru, and Bolivia. In all 5 countries leishmaniasis is endemic in both the Andean highlands and the Amazon basin. The sandfly vectors belong to subgenera Helcocyrtomyia, Nyssomiya, Lutzomyia, and Psychodopygus, and the Verrucarum group. Most human infections are caused by Leishmania in the Viannia subgenus. Human Leishmania infections cause cutaneous lesions, with a minority of L. (Viannia) infections leading to mucocutaneous leishmaniasis. Visceral leishmaniasis and diffuse cutaneous leishmaniasis are both rare. In each country a significant proportion of Leishmania transmission is in or around houses, often close to coffee or cacao plantations. Reservoir hosts for domestic transmission cycles are uncertain. The paper first addresses the burden of disease caused by leishmaniasis, focusing on both incidence rates and on the variability in symptoms. Such information should provide a rational basis for prioritizing control resources, and for selecting therapy regimes. Secondly, we describe the variation in transmission ecology, outlining those variables which might affect the prevention strategies. Finally, we look at the current control strategies and review the recent studies on control.

Background: Participant non-response is a source of bias in all research, especially in randomised controlled trials. Participants followed up remotely can have high non-response rates. Four such trials have been conducted of a cover letter with content informed by behaviour change theory to overcome hypothesised barriers to responding to a mailed questionnaire. Pooled results to date have suggested further research to be worthwhile. We conducted an embedded randomised study within a trial of such cover letters in the hope that we would improve response rates to our postal quality of life questionnaires., Methods: One hundred forty-eight participants in the CODIFI2 diabetic foot ulcer sampling trial were randomised 1:1 to receive one of two different cover letters at follow-up timepoints: either a standard cover letter accompanying their postal follow-up questionnaires or to an 'enhanced' (theory-informed) cover letter. Questionnaires were mailed at 39, 52 and (for some participants) 104 weeks post randomisation. Outcome measures were response to mailing at each timepoint. Analysis was restricted to those for whom a questionnaire and letter was issued. Owing to limited recruitment, a reduced analysis plan, comprising solely observed response rates and 95% confidence intervals for difference in response rates was followed. Post hoc, we added our week 52 results to an already-published meta-analysis., Results: Sixty-seven out of 74 enhanced cover letter group (Enhanced) and 67/74 standard cover letter group (Standard) participants who had not already died or withdrawn were sent their first mailing at 39 weeks. The 39-week response rates were 47/67 (70.1%) and 39/67 (58.2%) for Enhanced and Standard participants, respectively. At week 52, the response rates were 45/64 (70.3%) and 35/63 (55.6%) for Enhanced and Standard participants, respectively. At week 104, the response rates were 24/33 (72.7%) and 19/33 (57.6%) for the Enhanced and Standard participants, respectively. Adding our week 52 results to a published meta-analysis increased the pooled estimate of differences in response rates to 0.04 (- 0.01 to 0.09) favouring enhanced letters., Conclusion: While this embedded randomised controlled trial observed greater response rates at all times among those randomised to the enhanced letter, the reduced sample size meant that these results are imprecise., Trial Registration: ISRCTN registry ISRCTN74929588. Registered on 5 March 2019., Competing Interests: Declarations Ethics approval and consent to participate All participants in CODIFI2 gave written informed consent to take part in the trial and all of its sub-studies, including this SWAT. The study was submitted for and received favourable ethical approval from West of Scotland REC 3 (Ref 18/WS/0235). Consent for publication This publication does not include individual participant data in any form, and so no specific consent for publication is required. Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

Aim: Recovery after surgery for colorectal cancer is a complex process, involving numerous physiological, emotional, social and economic challenges. Good information is a key factor for enabling patients to recover well, but there is a paucity of evidence to guide how this should be done. A new information intervention (Recover Together) comprising a booklet, an online video and an inpatient goal board has been developed. This study explores its feasibility, as well as the feasibility of key study methods, during its first use in the United Kingdom National Health Service (NHS)., Methods: This is a mixed methods, multi-centre, feasibility study of a complex intervention. A total of 105 participants undergoing oncological colorectal surgery will be recruited across three to four study sites in the UK. Participants will receive each component of the Recover Together intervention at defined timepoints before and during hospital admission. A series of patient-centred outcome instruments will be administered in hospital and during follow-up at 30 days and 6 months. Outcomes of feasibility will comprise the time taken to establish the intervention at participating sites, assessments of intervention fidelity and acceptability, as well as return rates of key clinical outcome instruments. The mixed methods design will comprise interviews and focus groups with patients and health professionals, non-participant observation in ward areas and clinics, user-specific video analytics and daily photographs of the goal boards., Discussion: The findings of this study will provide a feasibility assessment of the Recover Together intervention when used for the first time in NHS practice. If shown to be feasible, this will guide the development of a future definitive study to explore the clinical and cost effectiveness of the Recover Together intervention to improve recovery after surgery., Clinical Trials Registration: ISRCTN62430915., (© 2024 The Author(s). Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Objective: Ultrasound in combination with microbubbles can enhance accumulation and improve the distribution of various therapeutic agents in tumor tissue, leading to improved efficacy. Understanding the impact of treatment on the tumor microenvironment, concurrently with how microenvironment attributes affect treatment outcome, will be important for selecting appropriate patient cohorts in future clinical trials. The main aim of this work was to investigate the influence of ultrasound and microbubbles on the functional vasculature of cancer tissue., Methods: Four different tumor models in mice (bone, pancreatic, breast and colon cancer) were characterized with respect to vascular parameters using contrast-enhanced ultrasound imaging. The effect of treatment with microbubbles and ultrasound was then investigated using immunohistochemistry and confocal microscopy, quantifying the total amount of vasculature and fraction of functional vessels. Two different microbubbles were used, the clinical contrast agent SonoVue and the large bubbles generated by Acoustic Cluster Therapy (ACT), tailored for therapeutic purposes., Results: The colon cancer model displayed slower flow but a higher vascular volume than the other models. The pancreatic model showed the fastest flow but also the lowest vascular volume. Ultrasound and SonoVue transiently reduced the amount of functional vasculature in breast and colon tumors immediately after treatment. No reduction was observed for ACT, likely due to shorter ultrasound pulses and lower pressures applied., Conclusion: Variation between tumor models due to tissue characteristics emphasizes the importance of evaluating treatment suitability in the specific tissue of interest, as altered perfusion could have a large impact on drug delivery and therapeutic outcome., Competing Interests: Conflict of interest M.M. is employed by EXACT Therapeutics AS and is a co-inventor of several patents related to ACT technology. The other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Ultrasound-triggered bubble-mediated local drug delivery has shown potential to increase therapeutic efficacy and reduce systemic side effects, by loading drugs into the microbubble shell and triggering delivery of the payload on demand using ultrasound. Understanding the behavior of the microbubbles in response to ultrasound is crucial for efficient and controlled release., Methods: In this work, the response of microbubbles with a coating consisting of poly(2-ethyl-butyl cyanoacrylate) (PEBCA) nanoparticles and denatured casein was characterized. High-speed recordings were taken of single microbubbles, in both bright field and fluorescence., Results: The nanoparticle-loaded microbubbles show resonance behavior, but with a large variation in response, revealing a substantial interbubble variation in mechanical shell properties. The probability of shell rupture and the probability of nanoparticle release were found to strongly depend on microbubble size, and the most effective size was inversely proportional to the driving frequency. The probabilities of both rupture and release increased with increasing driving pressure amplitude. Rupture of the microbubble shell occurred after fewer cycles of ultrasound as the driving pressure amplitude or driving frequency was increased., Conclusion: The results highlight the importance of careful selection of the driving frequency, driving pressure amplitude and duration of ultrasound to achieve the most efficient ultrasound-triggered shell rupture and nanoparticle release of protein-and-nanoparticle-stabilized microbubbles., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Focused ultrasound has experimentally been found to enhance the diffusion of nanoparticles; our aim with this work is to study this effect closer using both experiments and non-equilibrium molecular dynamics. Measurements from single particle tracking of 40 nm polystyrene nanoparticles in an agarose hydrogel with and without focused ultrasound are presented and compared with a previous experimental study using 100 nm polystyrene nanoparticles. In both cases, we observed an increase in the mean square displacement during focused ultrasound treatment. We developed a coarse-grained non-equilibrium molecular dynamics model with an implicit solvent to investigate the increase in the mean square displacement and its frequency and amplitude dependencies. This model consists of polymer fibers and two sizes of nanoparticles, and the effect of the focused ultrasound was modeled as an external oscillating force field. A comparison between the simulation and experimental results shows similar mean square displacement trends, suggesting that the particle velocity is a significant contributor to the observed ultrasound-enhanced mean square displacement. The resulting diffusion coefficients from the model are compared to the diffusion equation for a two-time continuous time random walk. The model is found to have the same frequency dependency. At lower particle velocity amplitude values, the model has a quadratic relation with the particle velocity amplitude as described by the two-time continuous time random walk derived diffusion equation, but at higher amplitudes, the model deviates, and its diffusion coefficient reaches the non-hindered diffusion coefficient. This observation suggests that at higher ultrasound intensities in hydrogels, the non-hindered diffusion coefficient can be used., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Optimising drug delivery to tumours remains an obstacle to effective cancer treatment. A prerequisite for successful chemotherapy is that the drugs reach all tumour cells. The vascular network of tumours, extravasation across the capillary wall and penetration throughout the extracellular matrix limit the delivery of drugs. Ultrasound combined with microbubbles has been shown to improve the therapeutic response in preclinical and clinical studies. Most studies apply microbubbles designed as ultrasound contrast agents. Acoustic Cluster Therapy (ACT ® ) is a novel approach based on ultrasound-activated microbubbles, which have a diameter 5-10 times larger than regular contrast agent microbubbles. An advantage of using such large microbubbles is that they are in contact with a larger part of the capillary wall, and the oscillating microbubbles exert more effective biomechanical effects on the vessel wall. In accordance with this, ACT ® has shown promising therapeutic results in combination with various drugs and drug-loaded nanoparticles. Knowledge of the mechanism and behaviour of drugs and microbubbles is needed to optimise ACT ® . Real-time intravital microscopy (IVM) is a useful tool for such studies. This paper presents the experimental setup design for visualising ACT ® microbubbles within the vasculature of tumours implanted in dorsal window (DW) chambers. It presents ultrasound setups, the integration and alignment of the ultrasound field with the optical system in live animal experiments, and the methodologies for visualisation and analysing the recordings. Dextran was used as a fluorescent marker to visualise the blood vessels and to trace drug extravasation and penetration into the extracellular matrix. The results reveal that the experimental setup successfully recorded the kinetics of extravasation and penetration distances into the extracellular matrix, offering a deeper understanding of ACT's mechanisms and potential in localised drug delivery.

Pancreatic ductal adenocarcinoma (PDAC) remains a challenging malignancy, mainly due to its resistance to chemotherapy and its complex tumour microenvironment characterised by stromal desmoplasia. There is a need for new strategies to improve the delivery of drugs and therapeutic response. Relevant preclinical tumour models are needed to test potential treatments. This paper compared orthotopic and subcutaneous PDAC tumour models and their suitability for drug delivery studies. A novel aspect was the broad range of tumour properties that were studied, including tumour growth, histopathology, functional vasculature, perfusion, immune cell infiltration, biomechanical characteristics, and especially the extensive analysis of the structure and the orientation of the collagen fibres in the two tumour models. The study unveiled new insights into how these factors impact the uptake of a fluorescent model drug, the macromolecule called 800CW. While the orthotopic model offered a more clinically relevant microenvironment, the subcutaneous model offered advantages for drug delivery studies, primarily due to its reproducibility, and it was characterised by a more efficient drug uptake facilitated by its collagen organisation and well-perfused vasculature. The tumour uptake seemed to be influenced mainly by the structural organisation and the alignment of the collagen fibres and perfusion. Recognising the diverse characteristics of these models and their multifaceted impacts on drug delivery is crucial for designing clinically relevant experiments and improving our understanding of pancreatic cancer biology.

Pulsed focused ultrasound (FUS) in combination with microbubbles has been shown to improve delivery and penetration of nanoparticles in tumors. To understand the mechanisms behind this treatment, it is important to evaluate the contribution of FUS without microbubbles on increased nanoparticle penetration and transport in the tumor extracellular matrix (ECM). A composite agarose hydrogel was made to model the porous structure, the acoustic attenuation and the hydraulic conductivity of the tumor ECM. Single-particle tracking was used as a novel method to monitor nanoparticle dynamics in the hydrogel during FUS exposure. FUS exposure at 1 MHz and 1 MPa was performed to detect any increase in nanoparticle diffusion or particle streaming at acoustic parameters relevant for FUS in combination with microbubbles. Results were compared to a model of acoustic streaming. The nanoparticles displayed anomalous diffusion in the hydrogel, and FUS with a duty cycle of 20% increased the nanoparticle diffusion coefficient by 23%. No increase in diffusion was found for lower duty cycles. FUS displaced the hydrogel itself at duty cycles above 10%; however, acoustic streaming was found to be negligible. In conclusion, pulsed FUS alone cannot explain the enhanced penetration of nanoparticles seen when using FUS and microbubbles for nanoparticle delivery, but it could be used as a tool to enhance diffusion of particles in the tumor ECM.

Objective: Pre-clinical trials have obtained promising results that focused ultrasound (FUS) combined with microbubbles (MBs) increases tumor uptake and the therapeutic effect of drugs. The aims of the study described here were to investigate whether FUS and MBs could improve the effect of chemotherapy in patients with liver metastases from colorectal cancer and to investigate the safety and feasibility of using FUS + MBs., Methods: We included 17 patients with liver metastases from colorectal cancer, selected two lesions in each patient's liver and randomized the lesions for, respectively, treatment with FUS + MBs or control. After chemotherapy (FOLFIRI or FOLFOXIRI), the lesions were treated with FUS (frequency = 1.67 MHz, mechanical index = 0.5, pulse repetition frequency = 0.33 Hz, 33 oscillations, duty cycle = 0.2%-0.4% and MBs (SonoVue) for 35 min). Nine boluses of MBs were injected intravenously at 3.5 min intervals. Patients were scheduled for four cycles of treatment. Changes in the size of metastases were determined from computed tomography images., Results: Treatment with FUS + MBs is safe at the settings used. There was considerable variation in treatment response between lesions and mixed response between lesions receiving only chemotherapy. There is a tendency toward larger-volume reduction in lesions treated with FUS + MBs compared with control lesions, but a mixed response to chemotherapy and lesion heterogeneity make it difficult to interpret the results., Conclusion: The combination of FUS and MBs is a safe, feasible and available strategy for improving the effect of chemotherapy in cancer patients. Therapeutic effect was not demonstrated in this trial. Multicenter trials with standardized protocols should be performed., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Many organisms live in fragmented populations, which has profound consequences on the dynamics of associated parasites. Metapopulation theory offers a canonical framework for predicting the effects of fragmentation on spatiotemporal host–parasite dynamics. However, empirical studies of parasites in classical metapopulations remain rare, particularly for vector-borne parasites. Here, we quantify spatiotemporal patterns and possible drivers of infection probability for several ectoparasites (fleas, Ixodes trianguliceps and Ixodes ricinus ) and vector-borne microparasites ( Babesia microti , Bartonella spp., Hepatozoon spp.) in a classically functioning metapopulation of water vole hosts. Results suggest that the relative importance of vector or host dynamics on microparasite infection probabilities is related to parasite life-histories. Bartonella , a microparasite with a fast life-history, was positively associated with both host and vector abundances at several spatial and temporal scales. In contrast, B. microti , a tick-borne parasite with a slow life-history, was only associated with vector dynamics. Further, we provide evidence that life-history shaped parasite dynamics, including occupancy and colonization rates, in the metapopulation. Lastly, our findings were consistent with the hypothesis that landscape connectivity was determined by distance-based dispersal of the focal hosts. We provide essential empirical evidence that contributes to the development of a comprehensive theory of metapopulation processes of vector-borne parasites.

Objective: The blood-brain barrier (BBB) is an obstacle for cerebral drug delivery. Controlled permeabilization of the barrier by external stimuli can facilitate the delivery of drugs to the brain. Acoustic Cluster Therapy (ACT®) is a promising strategy for transiently and locally increasing the permeability of the BBB to macromolecules and nanoparticles. However, the mechanism underlying the induced permeability change and subsequent enhanced accumulation of co-injected molecules requires further elucidation., Methods: In this study, the behavior of ACT® bubbles in microcapillaries in the murine brain was observed using real-time intravital multiphoton microscopy. For this purpose, cranial windows aligned with a ring transducer centered around an objective were mounted to the skull of mice. Dextrans labeled with 2 MDa fluorescein isothiocyanate (FITC) were injected to delineate the blood vessels and to visualize extravasation., Discussion: Activated ACT® bubbles were observed to alter the blood flow, inducing transient and local increases in the fluorescence intensity of 2 MDa FITC-dextran and subsequent extravasation in the form of vascular outpouchings. The observations indicate that ACT® induced a transient vascular leakage without causing substantial damage to the vessels in the brain., Conclusion: The study gave novel insights into the mechanism underlying ACT®-induced enhanced BBB permeability which will be important considering treatment optimization for a safe and efficient clinical translation of ACT®., Competing Interests: Conflict of interest E.B.O, S.K., S.H.T., S.S., C.d.L.D. and M.O. declare no competing interests. M.M. is employed by EXACT Therapeutics AS, an ultrasound and microbubble-enhanced therapy company. Employment started after this study was conducted. This work has been used as a patent example., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Currently available cytotoxic treatments have limited effect on pancreatic ductal adenocarcinoma (PDAC) because desmoplastic stroma limits drug delivery. Efforts have been made to overcome these barriers by drug targeting the tumor microenvironment. Results so far are promising, but without clinical impact. Our aim was to investigate whether ultrasound and microbubbles could improve the uptake and therapeutic response of conventional chemotherapy., Methods: Orthotopic pancreatic tumors growing in mice were treated with commercially available FOLFIRINOX (fluorouracil, irinotecan, oxaliplatin and calcium folinate) and SonoVue microbubbles combined with focused ultrasound. Tumor uptake of platinum (Pt) was measured by inductively coupled plasma mass spectroscopy (ICP-MS), and tumor volumes were measured by ultrasound imaging., Discussion: Uptake of Pt, the active ingredient of oxaliplatin, was significantly increased after ultrasound treatment of orthotopic PDAC tumors. Multiple injections with FOLFIRONOX increased the amount of Pt in tumors. However, the enhanced accumulation did not improve therapeutic response. Increased uptake of Pt confirms that ultrasound and microbubbles have potential in clinical practice with existing drugs., Conclusion: The lack of therapeutic response, despite increased uptake in tumor tissue, emphasizes the importance of studying how to overcome stromal barriers., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Colorectal and ovarian cancers frequently develop peritoneal metastases with few treatment options. Intraperitoneal chemotherapy has shown promising therapeutic effects, but is limited by rapid drug clearance and systemic toxicity. We therefore encapsulated the cabazitaxel taxane in poly(alkyl cyanoacrylate) (PACA) nanoparticles (NPs), designed to improve intraperitoneal delivery. Toxicity of free and encapsulated cabazitaxel was investigated in rats by monitoring clinical signs, organ weight and blood hematological and biochemical parameters. Pharmacokinetics, biodistribution and treatment response were evaluated in mice. Biodistribution was investigated by measuring both cabazitaxel and the 2-ethylbutanol NP degradation product. Drug encapsulation was shown to increase intraperitoneal drug retention, leading to prolonged intraperitoneal drug residence time and higher drug concentrations in peritoneal tumors. As a result, encapsulation of cabazitaxel improved the treatment response in two in vivo models bearing intraperitoneal tumors. Together, these observations indicate a strong therapeutic potential of NP-based cabazitaxel encapsulation as a novel treatment for peritoneal metastases., Competing Interests: Conflict of interest YM has patent #WO 2019/185685 pending to SINTEF TTO. YM, KF and KGF have patent #WO 2020/192950 and patent #US 16/366596 pending to SINTEF TTO., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Early detection of amyloid-β (Aβ) aggregates is a critical step to improve the treatment of Alzheimer's disease (AD) because neuronal damage by the Aβ aggregates occurs before clinical symptoms are apparent. We have previously shown that luminescent conjugated oligothiophenes (LCOs), which are highly specific towards protein aggregates of Aβ, can be used to fluorescently label amyloid plaque in living rodents., Objective: We hypothesize that the LCO can be used to target gadolinium to the amyloid plaque and hence make the plaque detectable by T1-weighted magnetic resonance imaging (MRI)., Methods: A novel LCO-gadolinium construct was synthesized to selectively bind to Aβ plaques and give contrast in conventional T1-weighted MR images after intravenous injection in Tg-APPSwe mice., Results: We found that mice with high plaque-burden could be identified using the LCO-Gd constructs by conventional MRI., Conclusion: Our study shows that MR imaging of amyloid plaques is challenging but feasible, and hence contrast-mediated MR imaging could be a valuable tool for early AD detection.

Alginate hydrogels have been broadly investigated for use in medical applications due to their biocompatibility and the possibility to encapsulate cells, proteins, and drugs. In the treatment of peritoneal metastasis, rapid drug clearance from the peritoneal cavity is a major challenge. Aiming to delay drug absorption and reduce toxic side effects, cabazitaxel (CAB)-loaded poly(alkyl cyanoacrylate) (PACA) nanoparticles were encapsulated in alginate microspheres. The PACAlg alginate microspheres were synthesized by electrostatic droplet generation and the physicochemical properties, stability, drug release kinetics, and mesothelial cytotoxicity were analyzed before biodistribution and therapeutic efficacy were studied in mice. The 450 µm microspheres were stable at in vivo conditions for at least 21 days after intraperitoneal implantation in mice, and distributed evenly throughout the peritoneal cavity without aggregation or adhesion. The nanoparticles were stably retained in the alginate microspheres, and nanoparticle toxicity to mesothelial cells was reduced, while the therapeutic efficacy of free CAB was maintained or improved in vivo. Altogether, this work presents the alginate encapsulation of drug-loaded nanoparticles as a promising novel strategy for the treatment of peritoneal metastasis that can improve the therapeutic ratio between toxicity and therapeutic efficacy.

Acoustic Cluster Therapy (ACT®) is a platform for improving drug delivery and has had promising pre-clinical results. A clinical trial is ongoing. ACT® is based on microclusters of microbubbles-microdroplets that, when sonicated, form a large ACT® bubble. The aim of this study was to obtain new knowledge on the dynamic formation and oscillations of ACT® bubbles by ultrafast optical imaging in a microchannel. The high-speed recordings revealed the microbubble-microdroplet fusion, and the gas in the microbubble acted as a vaporization seed for the microdroplet. Subsequently, the bubble grew by gas diffusion from the surrounding medium and became a large ACT® bubble with a diameter of 5-50 μm. A second ultrasound exposure at lower frequency caused the ACT® bubble to oscillate. The recorded oscillations were compared with simulations using the modified Rayleigh-Plesset equation. A term accounting for the physical boundary imposed by the microchannel wall was included. The recorded oscillation amplitudes were approximately 1-2 µm, hence similar to oscillations of smaller contrast agent microbubbles. These findings, together with our previously reported promising pre-clinical therapeutic results, suggest that these oscillations covering a large part of the vessel wall because of the large bubble volume can substantially improve therapeutic outcome., Competing Interests: Declaration of Competing Interest A.H. is CEO of EXACT Therapeutics. The other authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Ultrasound focused toward tumors in the presence of circulating microbubbles improves the delivery of drug-loaded nanoparticles and therapeutic outcomes; however, the efficacy varies among the different properties and conditions of the tumors. Therefore, there is a need to optimize the ultrasound parameters and determine the properties of the tumor tissue important for the successful delivery of nanoparticles. Here, we propose a mesoscopic model considering the presence of entropic forces to explain the ultrasound-enhanced transport of nanoparticles across the capillary wall and through the interstitium of tumors. The nanoparticles move through channels of variable shape whose irregularities can be assimilated to barriers of entropic nature that the nanoparticles must overcome to reach their targets. The model assumes that focused ultrasound and circulating microbubbles cause the capillary wall to oscillate, thereby changing the width of transcapillary and interstitial channels. Our analysis provides values for the penetration distances of nanoparticles into the interstitium that are in agreement with experimental results. We found that the penetration increased significantly with increasing acoustic intensity as well as tissue elasticity, which means softer and more deformable tissue (Young modulus lower than 50 kPa), whereas porosity of the tissue and pulse repetition frequency of the ultrasound had less impact on the penetration length. We also considered that nanoparticles can be absorbed into cells and to extracellular matrix constituents, finding that the penetration length is increased when there is a low absorbance coefficient of the nanoparticles compared with their diffusion coefficient (close to 0.2). The model can be used to predict which tumor types, in terms of elasticity, will successfully deliver nanoparticles into the interstitium. It can also be used to predict the penetration distance into the interstitium of nanoparticles with various sizes and the ultrasound intensity needed for the efficient distribution of the nanoparticles., (Copyright © 2021 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Successful delivery of drugs and nanomedicine to tumors requires a functional vascular network, extravasation across the capillary wall, penetration through the extracellular matrix, and cellular uptake. Nanomedicine has many merits, but penetration deep into the tumor interstitium remains a challenge. Failure of cancer treatment can be caused by insufficient delivery of the therapeutic agents. After intravenous administration, nanomedicines are often found in off-target organs and the tumor extracellular matrix close to the capillary wall. With circulating microbubbles, ultrasound exposure focused toward the tumor shows great promise in improving the delivery of therapeutic agents. In this review, we address the impact of focused ultrasound and microbubbles to overcome barriers for drug delivery such as perfusion, extravasation, and transport through the extracellular matrix. Furthermore, we discuss the induction of an immune response with ultrasound and delivery of immunotherapeutics. The review discusses mainly preclinical results and ends with a summary of ongoing clinical trials., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Delivery of drugs and nanomedicines to tumors is often heterogeneous and insufficient and, thus, of limited efficacy. Microbubbles in combination with ultrasound have been found to improve delivery to tumors, enhancing accumulation and penetration. We used a subcutaneous prostate cancer xenograft model in mice to investigate the effect of free and nanoparticle-encapsulated cabazitaxel in combination with ultrasound and microbubbles with a lipid shell or a shell of nanoparticles. Sonopermeation reduced tumor growth and prolonged survival (26%-100%), whether the free drug was co-injected with lipid-shelled microbubbles or the nanoformulation was co-injected with lipid-shelled or nanoparticle-shelled microbubbles. Coherently with the improved therapeutic response, we found enhanced uptake of nanoparticles directly after ultrasound treatment that lasted several weeks (2.3 × -15.8 × increase). Neither cavitation dose nor total accumulation of nanoparticles could explain the variation within treatment groups, emphasizing the need for a better understanding of the tumor biology and mechanisms involved in ultrasound-mediated treatment., Competing Interests: Conflict of interest disclosure S.S., Y.M., E.S., A.Å., C.D., R.H. and S.B. are co-inventors of a patent describing the nanoparticle-stabilized microbubbles (US20200023073 A1)., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The blood-brain barrier (BBB) is a major obstacle to treating several brain disorders. Focused ultrasound (FUS) in combination with intravascular microbubbles increases BBB permeability by opening tight junctions, creating endothelial cell openings, improving endocytosis and increasing transcytosis. Here we investigated whether combining FUS and microbubbles with transferrin receptor-targeting liposomes would result in enhanced delivery to the brain of post-natal rats compared with liposomes lacking the BBB-targeting moiety. For all animals, increased BBB permeability was observed after FUS treatment. A 40% increase in accumulation of transferrin receptor-targeting liposomes was observed in the FUS-treated hemisphere, whereas the isotype immunoglobulin G liposomes showed no increased accumulation. Confocal laser scanning microscopy of brain sections revealed that both types of liposomes were mainly observed in endothelial cells in the FUS-treated hemisphere. The results demonstrate that FUS and microbubble treatment combined with BBB-targeting liposomes could be a promising approach to enhance drug delivery to the brain., Competing Interests: Conflict of interest disclosure The authors declare no competing interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Chemotherapy and radiotherapy have drastically improved cancer survival, but they can result in significant short- and long-term cardiovascular complications, most commonly heart failure from chemotherapy, whilst radiotherapy increases the risk of premature coronary artery disease (CAD), valve, and pericardial diseases. Cardiac computed tomography (CT) with calcium scoring has a role in screening asymptomatic patients for premature CAD, cardiac CT angiography (CTCA) allows the identification of significant CAD, also in the acute settings where concerns exist towards invasive angiography. CTCA integrates the diagnostic work-up and guides surgical/percutaneous management of valvular heart diseases and allows the assessment of pericardial conditions, including detection of effusion and pericardial calcification. It is a widely available and fast imaging modality that allows a one-step evaluation of CAD, myocardial, valvular, and pericardial disease. This review aims to provide an update on its current use and accompanying evidence-base for cardiac CT in the management of cardio-oncology patients., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Ultrasound (US) in combination with microbubbles (MB) has had promising results in improving delivery of chemotherapeutic agents. However, most studies are done in immunodeficient mice with xenografted tumors. We used two phenotypes of the spontaneous transgenic adenocarcinoma of the mouse prostate (TRAMP) model to evaluate if US + MB could enhance the therapeutic efficacy of cabazitaxel (Cab). Cab was either injected intravenously as free drug or encapsulated into nanoparticles. In both cases, Cab transiently reduced tumor and prostate volume in the TRAMP model. No additional therapeutic efficacy was observed combining Cab with US + MB, except for one tumor. Additionally, histology grading and immunostaining of Ki67 did not reveal differences between treatment groups. Mass spectrometry revealed that nanoparticle encapsulation of Cab increased the circulation time and enhanced the accumulation in liver and spleen compared with free Cab. The therapeutic results in this spontaneous, clinically relevant tumor model differ from the improved therapeutic response observed in xenografts combining US + MB and chemotherapy., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Understanding the electronic energy landscape in metal halide perovskites is essential for further improvements in their promising performance in thin-film photovoltaics. Here, we uncover the presence of above-bandgap oscillatory features in the absorption spectra of formamidinium lead triiodide thin films. We attribute these discrete features to intrinsically occurring quantum confinement effects, for which the related energies change with temperature according to the inverse square of the intrinsic lattice parameter, and with peak index in a quadratic manner. By determining the threshold film thickness at which the amplitude of the peaks is appreciably decreased, and through ab initio simulations of the absorption features, we estimate the length scale of confinement to be 10-20 nm. Such absorption peaks present a new and intriguing quantum electronic phenomenon in a nominally bulk semiconductor, offering intrinsic nanoscale optoelectronic properties without necessitating cumbersome additional processing steps.

To improve therapeutic efficacy of nanocarrier drug delivery systems, it is essential to improve their uptake and penetration in tumour tissue, enhance cellular uptake and ensure efficient drug release at the tumour site. Here we introduce a tumour targeting drug delivery system based on the ultrasound-mediated delivery of enzyme sensitive liposomes. These enzyme sensitive liposomes are coated with cleavable poly(ethylene glycol) (PEG) which will be cleaved by two members of the enzyme matrix metalloproteinase family (MMP-2 and MMP-9). Cleavage of the PEG coat can increase cellular uptake and will destabilize the liposomal membrane which can result in accelerated drug release. The main aim of the work was to study the effect of focused ultrasound and microbubbles on the delivery and therapeutic efficacy of the MMP sensitive liposome. The performance of the MMP sensitive liposome was compared to a non-MMP sensitive version and Doxil-like liposomes. In vitro, the cellular uptake and cytotoxicity of the liposomes were studied, while in vivo the effect of ultrasound and microbubbles on the tumour accumulation, biodistribution, microdistribution, and therapeutic efficacy were investigated. For all tested liposomes, ultrasound and microbubble treatment resulted in an improved tumour accumulation, increased extravasation, and increased penetration of the liposomes from blood vessels into the extracellular matrix. Surprisingly, penetration depth was independent of the ultrasound intensity used. Ultrasound-mediated delivery of free doxorubicin and the Doxil-like and MMP sensitive liposome resulted in a significant reduction in tumour volume 28 days post the first treatment and increased median survival. The MMP sensitive liposome showed better therapeutic efficacy than the non-MMP sensitive version indicating that cleaving the PEG-layer is important. However, the Doxil-like liposome outcompeted the MMP and non-MMP sensitive liposome, both with and without the use of ultrasound and microbubbles., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Young stars are surrounded by a circumstellar disk of gas and dust, within which planet formation can occur. Gravitational forces in multiple star systems can disrupt the disk. Theoretical models predict that if the disk is misaligned with the orbital plane of the stars, the disk should warp and break into precessing rings, a phenomenon known as disk tearing. We present observations of the triple-star system GW Orionis, finding evidence for disk tearing. Our images show an eccentric ring that is misaligned with the orbital planes and the outer disk. The ring casts shadows on a strongly warped intermediate region of the disk. If planets can form within the warped disk, disk tearing could provide a mechanism for forming wide-separation planets on oblique orbits., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Although the first nanomedicine was clinically approved more than two decades ago, nanoparticles' (NP) in vivo behavior is complex and the immune system's role in their application remains elusive. At present, only passive-targeting nanoformulations have been clinically approved, while more complicated active-targeting strategies typically fail to advance from the early clinical phase stage. This absence of clinical translation is, among others, due to the very limited understanding for in vivo targeting mechanisms. Dynamic in vivo phenomena such as NPs' real-time targeting kinetics and phagocytes' contribution to active NP targeting remain largely unexplored. To better understand in vivo targeting, monitoring NP accumulation and distribution at complementary levels of spatial and temporal resolution is imperative. Here, we integrate in vivo positron emission tomography/computed tomography imaging with intravital microscopy and flow cytometric analyses to study α v β 3 -integrin-targeted cyclic arginine-glycine-aspartate decorated liposomes and oil-in-water nanoemulsions in tumor mouse models. We observed that ligand-mediated accumulation in cancerous lesions is multifaceted and identified "NP hitchhiking" with phagocytes to contribute considerably to this intricate process. We anticipate that this understanding can facilitate rational improvement of nanomedicine applications and that immune cell-NP interactions can be harnessed to develop clinically viable nanomedicine-based immunotherapies.

Introduction: Acoustic cluster therapy (ACT) comprises co-administration of a formulation containing microbubble/microdroplet clusters (PS101), together with a regular medicinal drug ( e.g. , a chemotherapeutic) and local ultrasound (US) insonation of the targeted pathological tissue ( e.g. , the tumor). PS101 is confined to the vascular compartment and, when the clusters are exposed to regular diagnostic imaging US fields, the microdroplets undergo a phase-shift to produce bubbles with a median diameter of 22 µm when unconstrained by the capillary wall. In vivo these bubbles transiently lodge in the tumor's microvasculature. Low frequency ultrasound (300 kHz) at a low mechanical index (MI = 0.15) is then applied to drive oscillations of the deposited ACT bubbles to induce a range of biomechanical effects that locally enhance extravasation, distribution, and uptake of the co-administered drug, significantly increasing its therapeutic efficacy., Methods: In this study we investigated the therapeutic efficacy of ACT with liposomal doxorubicin for the treatment of triple negative breast cancer using orthotopic human tumor xenografts (MDA-MB-231-H.luc) in athymic mice (ICR-NCr-Foxn1 nu ). Doxil ® (6 mg/kg, i.v. ) was administered at days 0 and 21, each time immediately followed by three sequential ACT (20 ml/kg PS101) treatment procedures (n = 7-10). B-mode and nonlinear ultrasound images acquired during the activation phase were correlated to the therapeutic efficacy., Results: Results show that combination with ACT induces a strong increase in the therapeutic efficacy of Doxil ® , with 63% of animals in complete, stable remission at end of study, vs . 10% for Doxil ® alone (p < 0.02). A significant positive correlation (p < 0.004) was found between B-mode contrast enhancement during ACT activation and therapy response. These observations indicate that ACT may also be used as a theranostic agent and that ultrasound contrast enhancement during or before ACT treatment may be employed as a biomarker of therapeutic response during clinical use., (Copyright © 2020 Bush, Healey, Shah, Box, Kirkin, Eccles, Sontum, Kotopoulis, Kvåle, van Wamel, Davies and Bamber.)