Investigation of Sonication Parameters for Large-Volume Focused Ultrasound-Mediated Blood-Brain Barrier Permeability Enhancement Using a Clinical-Prototype Hemispherical Phased Array.

Background/Objectives: Focused ultrasound (FUS) and microbubble (MB) exposure is a promising technique for targeted drug delivery to the brain; however, refinement of protocols suitable for large-volume treatments in a clinical setting remains underexplored. Methods: Here, the impacts of various sonication parameters on blood-brain barrier (BBB) permeability enhancement and tissue damage were explored in rabbits using a clinical-prototype hemispherical phased array developed in-house, with real-time 3D MB cavitation imaging for exposure calibration. Initial experiments revealed that continuous manual agitation of MBs during infusion resulted in greater gadolinium (Gd) extravasation compared to gravity drip infusion. Subsequent experiments used low-dose MB infusion with continuous agitation and a low burst repetition frequency (0.2 Hz) to mimic conditions amenable to long-duration clinical treatments. Results: Key sonication parameters-target level (proportional to peak negative pressure), number of bursts, and burst length-significantly affected BBB permeability enhancement, with all parameters displaying a positive relationship with relative Gd contrast enhancement (p < 0.01). Even at high levels of BBB permeability enhancement, tissue damage was minimal, with low occurrences of hypointensities on T2*-weighted MRI. When accounting for relative Gd contrast enhancement, burst length had a significant impact on red blood cell extravasation detected in histological sections, with 1 ms bursts producing significantly greater levels compared to 10 ms bursts (p = 0.03), potentially due to the higher pressure levels required to generate equal levels of BBB permeability enhancement. Additionally, albumin and IgG extravasation correlated strongly with relative Gd contrast enhancement across sonication parameters, suggesting that protein extravasation can be predicted from non-invasive imaging. Conclusions: These findings contribute to the development of safer and more effective clinical protocols for FUS + MB exposure, potentially improving the efficacy of the approach.

A Transmit-Receive Phased Array for Microbubble-Mediated Focused Ultrasound Brain Therapy in Small Animals.

Focused ultrasound (FUS) combined with circulating microbubbles (MBs) can be employed for non-invasive, localized agent delivery across the blood-brain barrier (BBB). Previous work has demonstrated the feasibility of clinical-scale transmit-receive phased arrays for performing transcranial therapies under MB imaging feedback. OBJECTIVE: This study aimed to design, construct, and evaluate a dual-mode phased array for MB-mediated FUS brain therapy in small animals. METHODS: A 256-element sparse hemispherical array (100 mm diameter) was fabricated by installing 128 PZT cylinder transmitters (f0 = 1.16 MHz) and 128 broadband PVDF receivers within a 3D-printed scaffold. RESULTS: The transmit array's focal size at the geometric focus was 0.8 mm × 0.8 mm × 1.7 mm, with a 31 mm/27 mm (lateral/axial) steering range. The receive array's point spread function was 0.6 mm × 0.6 mm × 1.5 mm (1.16 MHz source) at the geometric focus, and sources were localized up to 30 mm/16 mm (lateral/axial) from geometric focus. The array was able to spatially map MB cloud activity in 3D throughout a vessel-mimicking phantom at sub-, ultra-, and second-harmonic frequencies. Preliminary in-vivo work demonstrated its ability to induce localized BBB permeability changes under 3D sub-harmonic MB imaging feedback in a mouse model. CONCLUSION: Small form factor transmit-receive phased arrays enable acoustic imaging-controlled FUS and MB-mediated brain therapies with high targeting precision required for rodent studies. SIGNIFICANCE: Dual-mode phased arrays dedicated for small animal use will facilitate high-throughput studies of FUS-mediated BBB permeability enhancement to explore novel therapeutic strategies for future clinical application.

Transducer module apodization to reduce bone heating during focused ultrasound uterine fibroid ablation with phased arrays: A numerical study.

BACKGROUND: During magnetic resonance-guided focused ultrasound (MRgFUS) surgery for uterine fibroids, ablation of fibrous tissues in proximity to the hips and spine is challenging due to heating within the bone that can cause patients to experience pain and potentially damage nerves. This far-field bone heating limits the volume of fibroid tissue that is treatable via MRgFUS. PURPOSE: To investigate transducer module apodization for improving the ratio of focal-to-bone heating ( Δ T ratio $\Delta T_{\mathrm{ratio}}$ ) when targeting fibroid tissue close to the hips and spine, to enable MRgFUS treatments closer to the bone. METHODS: Acoustic and thermal simulations were performed using 3D magnetic resonance imaging (MRI)-derived anatomies of ten patients who underwent MRgFUS ablation for uterine fibroids using a low-frequency ( 0.5 MHz $0.5 \ \text{MHz}$ ) 6144-element flat fully-populated modular phased array system (Arrayus Technologies Inc., Burlington, Canada) at our institution as part of a larger clinical trial (NCT03323905). Transducer modules ( 64 elements $64 \ \text{elements}$ per module) whose beams intersected with no-pass zones delineated within the field were identified, their output power levels were reduced by varying blocking percentage levels, and the resulting temperature field distributions were evaluated across multiple sonications near the hip and spine bones in each patient. Acoustic and thermal simulations took approximately 20 min $20 \ \text{min}$ ( 7 min $7 \ \text{min}$ ) and 1 min $1 \ \text{min}$ ( 30 s $30 \ \text{s}$ ) to run for a single near-spine (near-hip) target, respectively. RESULTS: For all simulated sonications, transducer module blocking improved Δ T ratio $\Delta T_{\mathrm{ratio}}$ compared to the no blocking case. In just over half of sonications, full module blocking maximized Δ T ratio $\Delta T_{\mathrm{ratio}}$ (increase of 82% ± $\pm$ 38% in 50% of hip targets and 49% ± $\pm$ 30% in 62% of spine targets vs. no blocking; mean ± SD), at the cost of more diffuse focusing (focal heating volumes increased by 13% ± 13% for hip targets and 39% ± 27% for spine targets) and thus requiring elevated total (hip: 6% ± 17%, spine: 37% ± 17%) and peak module-wise (hip: 65% ± 36%, spine: 101% ± 56%) acoustic power levels to achieve equivalent focal heating as the no blocking control case. In the remaining sonications, partial module blocking provided further improvements in both Δ T ratio $\Delta T_{\mathrm{ratio}}$ (increased by 29% ± 25% in the hip and 15% ± 12% in the spine) and focal heating volume (decrease of 20% ± 10% in the hip and 34% ± 17% in the spine) relative to the full blocking case. The optimal blocking percentage value was dependent on the specific patient geometry and target location of interest. Although not all individual target locations saw the benefit, element-wise phase aberration corrections improved the average Δ T ratio $\Delta T_{\mathrm{ratio}}$ compared to the no correction case (increase of 52% ± 47% in the hip, 35% ± 24% in the spine) and impacted the optimal blocking percentage value. Transducer module blocking enabled ablative treatments to be carried out closer to both hip and spine without overheating or damaging the bone (no blocking: 42 ± 1 mm $42\pm 1 \ \text{mm}$ / 17 ± 2 mm $17 \pm 2 \ \text{mm}$ , full blocking: 38 ± 1 mm $38\pm 1 \ \text{mm}$ / 8 ± 1 mm $8\pm 1 \ \text{mm}$ , optimal partial blocking: 36 ± 1 mm $36\pm 1 \ \text{mm}$ / 7 ± 1 mm $7\pm 1 \ \text{mm}$ for hip/spine). CONCLUSION: The proposed transducer apodization scheme shows promise for improving MRgFUS treatments of uterine fibroids, and may ultimately increase the effective treatment envelope of MRgFUS surgery in the body by enabling tissue ablation closer to bony structures.

Long-Term Safety and Efficacy of Focused Ultrasound Capsulotomy for Obsessive-Compulsive Disorder and Major Depressive Disorder.

BACKGROUND: Magnetic resonance-guided focused ultrasound (MRgFUS) trials targeting the anterior limb of the internal capsule have shown promising results. We evaluated the long-term safety and efficacy of MRgFUS capsulotomy in patients with obsessive-compulsive disorder (OCD) and major depressive disorder (MDD). METHODS: This phase 1, single-center, open-label study recruited patients with treatment-resistant OCD and MDD. Outcomes were measured 6 months, 12 months, and 18 to 24 months (long term) after MRgFUS capsulotomy. Neuropsychological testing and neuroimaging were conducted at baseline and 12 months postoperatively. The primary outcome was safety. The secondary outcome was clinical response, defined for OCD as a ≥35% improvement in Yale-Brown Obsessive Compulsive Scale scores and for MDD as a ≥50% reduction in Hamilton Depression Rating Scale scores compared with baseline. RESULTS: No serious adverse effects were registered. In patients with OCD (n= 15), baseline Yale-Brown Obsessive Compulsive Scale scores (31.9 ± 1.2) were significantly reduced by 23% (p = .01) at 6 months and 35% (p < .0001) at 12 months. In patients with MDD (n = 12), a 26% and 25% nonsignificant reduction in Hamilton Depression Rating Scale scores (baseline 24.3 ± 1.2) was observed at 6 months and 12 months, respectively. Neuropsychological testing revealed no negative effects of capsulotomy. In the OCD and MDD cohorts, we found a correlation between clinical outcome and lesion laterality, with more medial left-placed lesions (OCD, p = .08) and more lateral right-placed lesions (MDD, p < .05) being respectively associated with a stronger response. In the MDD cohort, more ventral tracts appeared to be associated with a poorer response. CONCLUSIONS: MRgFUS capsulotomy is safe in patients with OCD and MDD and particularly effective in the former population.

Automated monitoring of electrocatalyst corrosion as a function of electrochemical history and electrolyte formulation.

Automated platforms assessing the stability of electrocatalysts are key to accelerate the deployment of clean energy technologies. Here, we present a robust system that allows the study of corrosion behavior in conjunction with the electrochemical protocol and electrolyte composition over many individual electrodes. Oxygen reduction reaction on Pt is used as a proof-of-concept platform, where the influence of the potential window and phosphoric acid (PA) addition on Pt dissolution is probed. A total of 72 hours of automated operation was realized with actions including liquid management, cell cleaning, aliquoting, PA injection, and bubble detection and removal, demonstrating further advancements in automated stability testing for electrocatalysts.

Investigating mechanical and inflammatory pathological mechanisms in osteoarthritis using MSC-derived osteocyte-like cells in 3D.

Introduction: Changes to bone physiology play a central role in the development of osteoarthritis with the mechanosensing osteocyte releasing factors that drive disease progression. This study developed a humanised in vitro model to detect osteocyte responses to either interleukin-6, a driver of degeneration and bone remodelling in animal and human joint injury, or mechanical loading, to mimic osteoarthritis stimuli in joints. Methods: Human MSC cells (Y201) were differentiated in 3-dimensional type I collagen gels in osteogenic media and osteocyte phenotype assessed by RTqPCR and immunostaining. Gels were subjected to a single pathophysiological load or stimulated with interleukin-6 with unloaded or unstimulated cells as controls. RNA was extracted 1-hour post-load and assessed by RNAseq. Markers of pain, bone remodelling, and inflammation were quantified by RT-qPCR and ELISA. Results: Y201 cells embedded within 3D collagen gels assumed dendritic morphology and expressed mature osteocytes markers. Mechanical loading of the osteocyte model regulated 7564 genes (Padj p<0.05, 3026 down, 4538 up). 93% of the osteocyte transcriptome signature was expressed in the model with 38% of these genes mechanically regulated. Mechanically loaded osteocytes regulated 26% of gene ontology pathways linked to OA pain, 40% reflecting bone remodelling and 27% representing inflammation. Load regulated genes associated with osteopetrosis, osteoporosis and osteoarthritis. 42% of effector genes in a genome-wide association study meta-analysis were mechanically regulated by osteocytes with 10 genes representing potential druggable targets. Interleukin-6 stimulation of osteocytes at concentrations reported in human synovial fluids from patients with OA or following knee injury, regulated similar readouts to mechanical loading including markers of pain, bone remodelling, and inflammation. Discussion: We have developed a reproducible model of human osteocyte like cells that express >90% of the genes in the osteocyte transcriptome signature. Mechanical loading and inflammatory stimulation regulated genes and proteins implicated in osteoarthritis symptoms of pain as well as inflammation and degeneration underlying disease progression. Nearly half of the genes classified as 'effectors' in GWAS were mechanically regulated in this model. This model will be useful in identifying new mechanisms underlying bone and joint pathologies and testing drugs targeting those mechanisms.

Development and validation of a deep learning-based microsatellite instability predictor from prostate cancer whole-slide images.

Microsatellite instability-high (MSI-H) is a tumor-agnostic biomarker for immune checkpoint inhibitor therapy. However, MSI status is not routinely tested in prostate cancer, in part due to low prevalence and assay cost. As such, prediction of MSI status from hematoxylin and eosin (H&E) stained whole-slide images (WSIs) could identify prostate cancer patients most likely to benefit from confirmatory testing to evaluate their eligibility for immunotherapy and need for Lynch syndrome testing. Prostate biopsies and surgical resections from prostate cancer patients referred to our institution were analyzed. MSI status was determined by next-generation sequencing. Patients sequenced before a cutoff date formed an algorithm development set (n = 4015, MSI-H 1.8%) and a paired validation set (n = 173, MSI-H 19.7%) that consisted of two serial sections from each sample, one stained and scanned internally and the other at an external site. Patients sequenced after the cutoff date formed a temporally independent validation set (n = 1350, MSI-H 2.3%). Attention-based multiple instance learning models were trained to predict MSI-H from H&E WSIs. The predictor achieved area under the receiver operating characteristic curve values of 0.78 (95% CI [0.69-0.86]), 0.72 (95% CI [0.63-0.81]), and 0.72 (95% CI [0.62-0.82]) on the internally prepared, externally prepared, and temporal validation sets, respectively, showing effective predictability and generalization to both external staining/scanning processes and temporally independent samples. While MSI-H status is significantly correlated with Gleason score, the model remained predictive within each Gleason score subgroup.

Comparison of Graft Type and Fixation Method in Anterior Cruciate Ligament Reconstruction: A Systematic Review and Meta-analysis Based on Randomized Control Studies.

BACKGROUND: The anterior cruciate ligament (ACL) is the most commonly injured ligament in the knee. ACL reconstruction (ACLR) proves the standard for treating this injury. However, graft choice and method of fixation remain a heavily debated topic. This study investigates the following: bone-patellar tendon-bone (BPTB) vs. hamstring tendon (HT) autograft, single-bundle vs. double-bundle hamstring graft, and metal vs. bioabsorbable screws in ACLR. METHODS: A systematic review was performed on PubMed and Google Scholar according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were collected on patient demographics, complications, and functionality scores including International Knee Documentation Committee (IKDC) and Lysholm scores. A systematic review and meta-analysis were conducted with Review Manager. Outcome measurements were determined using forest plots with significant differences considered p < 0.05. RESULTS: Twenty-five studies were included, accounting for 2,170 patients. No statistically significant difference was appreciated when comparing BPTB to hamstring autografts. Patients who received a double bundle HT autograft exhibited significantly superior outcomes in terms of revision (p = 0.05), failure (p = 0.002), normal pivot shift tests (p = 0.04), and normal IKDC (p = 0.008). When comparing screw types, bioabsorbable screws had a greater Lysholm score (p = 0.01) and lower failure rates for copolymer screws (p = 0.03). CONCLUSION: Overall, the data collected suggested that BPTB and HT autografts display similar postoperative results. However, if an HT autograft is used, the data suggest a double-bundle graft improves both functionality and decreases the possible complications. Finally, bioabsorbable screws prove superior to metal screws when looking at both functionality and failure rates. Further research into the superior graft type is still needed. LEVEL OF EVIDENCE: Level II. See Instructions for Authors for a complete description of levels of evidence.

Management of Locally Advanced Basal Cell Carcinoma with Sonic Hedgehog Pathway Targeted Therapy: A Case Report and Discussion.

Introduction: Basal cell carcinoma (BCC) is the most common skin malignancy in the world. While most lesions are treated using surgical methods, others may present as locally advanced or metastatic disease and are not amenable to surgical therapy alone. Treatment with sonic hedgehog pathway inhibitors (vismodegib, sonidegib) is designed to inhibit key signaling proteins and gene pathways involved with BCC to reduce the uncontrolled proliferation of basal cells in complicated disease and can be invaluable in treating patients with advanced disease. Case Presentation: We describe the course of a 68-year-old man who presented with a 7.2 × 6 cm exophytic and ulcerated locally invasive BCC of his upper back. The patient was started on daily vismodegib treatment with the goal of eventual surgical resection. After 11 weeks of therapy, he had significant improvement in both wound size and appearance. After 18 weeks of therapy, he had achieved a near complete clinical response of the central aspect of lesion with three remaining small peripheral lesions. These lesions were biopsied, and two were found to be negative for malignancy, while a small inferior nodule was positive for squamous cell carcinoma (SCC). Vismodegib therapy was discontinued after a total of 26 weeks of therapy. Excision of the SCC was performed, and the patient remains disease free at 2 years. Conclusion: This case report shows the efficacy of hedgehog pathway inhibitor therapy in the treatment of a locally advanced BCC with complete pathologic response, not requiring surgical intervention.

PharmaMemory: an interactive, animated web application for learning autonomic physiology and pharmacology.

Medical students face challenging but important topics they must learn in short periods of time, such as autonomic pharmacology. Autonomic pharmacology is difficult in that it requires students to synthesize detailed anatomy, physiology, clinical reasoning, and pharmacology. The subject poses a challenge to learn as it is often introduced early in medical school curricula. To ease the difficulty of learning autonomic pharmacology, we created a free web application, PharmaMemory (www.pharmamemory.com), that interactively depicts the effects of high-yield autonomic drugs on the human body. PharmaMemory provides users with the opportunity to read and quiz themselves on the mechanisms, side effects, indications, and contraindications of these drugs while interacting with the application. We provided PharmaMemory to first-year medical students for three consecutive years of quality improvement and assessed the application's perceived effects on learning via user surveys. Survey feedback showed that users viewed PharmaMemory favorably and self-reported increased knowledge and confidence in the subject of autonomic pharmacology. Comments revealed that users liked the website's visuals, opportunity for challenged recall, and conciseness. PharmaMemory utilizes challenged recall, visual stimulation, and interactive learning to provide users with a multifaceted learning tool. Preliminary data suggest that students find this method of learning beneficial. Further studies are needed to assess PharmaMemory compared with more traditional learning methods such as PowerPoint or text-based learning. Additionally, further research is needed to quantitatively assess reduction in cognitive load.NEW & NOTEWORTHY PharmaMemory (www.pharmamemory.com) is a free web application that interactively depicts the effects of high-yield autonomic drugs on the human body.

Expanded Systematic Evidence Map for Hundreds of Per- and Polyfluoroalkyl Substances (PFAS) and Comprehensive PFAS Human Health Dashboard.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) encompass a class of chemically and structurally diverse compounds that are extensively used in industry and detected in the environment. The US Environmental Protection Agency (US EPA) 2021 PFAS Strategic Roadmap describes national research plans to address the challenge of PFAS. OBJECTIVES: Systematic Evidence Map (SEM) methods were used to survey and summarize available epidemiological and mammalian bioassay evidence that could inform human health hazard identification for a set of 345 PFAS that were identified by the US EPA's Center for Computational Toxicology and Exposure (CCTE) for in vitro toxicity and toxicokinetic assay testing and through interagency discussions on PFAS of interest. This work builds from the 2022 evidence map that collated evidence on a separate set of ∼150 PFAS. Like our previous work, this SEM does not include PFAS that are the subject of ongoing or completed assessments at the US EPA. METHODS: SEM methods were used to search, screen, and inventory mammalian bioassay and epidemiological literature from peer-reviewed and gray literature sources using manual review and machine-learning software. For each included study, study design details and health end points examined were summarized in interactive web-based literature inventories. Some included studies also underwent study evaluation and detailed extraction of health end point data. All underlying data is publicly available online as interactive visuals with downloadable metadata. RESULTS: More than 13,000 studies were identified from scientific databases. Screening processes identified 121 mammalian bioassay and 111 epidemiological studies that met screening criteria. Epidemiological evidence (available for 12 PFAS) mostly assessed the reproductive, endocrine, developmental, metabolic, cardiovascular, and immune systems. Mammalian bioassay evidence (available for 30 PFAS) commonly assessed effects in the reproductive, whole-body, nervous, and hepatic systems. Overall, 41 PFAS had evidence across mammalian bioassay and epidemiology data streams (roughly 11% of searched chemicals). DISCUSSION: No epidemiological and/or mammalian bioassay evidence were identified for most of the PFAS included in our search. Results from this SEM, our 2022 SEM on ∼150 PFAS, and other PFAS assessment products from the US EPA are compiled into a comprehensive PFAS dashboard that provides researchers and regulators an overview of the current PFAS human health landscape including data gaps and can serve as a scoping tool to facilitate prioritization of PFAS-related research and/or risk assessment activities. https://doi.org/10.1289/EHP13423.

The therapeutic potential of immunoengineering for systemic autoimmunity.

Disease-modifying drugs have transformed the treatment options for many systemic autoimmune diseases. However, an evolving understanding of disease mechanisms, which might vary between individuals, is paving the way for the development of novel agents that operate in a patient-tailored manner through immunophenotypic regulation of disease-relevant cells and the microenvironment of affected tissue domains. Immunoengineering is a field that is focused on the application of engineering principles to the modulation of the immune system, and it could enable future personalized and immunoregulatory therapies for rheumatic diseases. An important aspect of immunoengineering is the harnessing of material chemistries to design technologies that span immunologically relevant length scales, to enhance or suppress immune responses by re-balancing effector and regulatory mechanisms in innate or adaptive immunity and rescue abnormalities underlying pathogenic inflammation. These materials are endowed with physicochemical properties that enable features such as localization in immune cells and organs, sustained delivery of immunoregulatory agents, and mimicry of key functions of lymphoid tissue. Immunoengineering applications already exist for disease management, and there is potential for this new discipline to improve disease modification in rheumatology.

Inflammatory Rhabdomyoblastic Tumor of the Posterior Pharyngeal Wall.

This case report describes a healthy man in his 40s who presented with a 1-year history of snoring, sleep apnea, dysphonia, and dysphagia owing to a large mass of the posterior pharynx and was diagnosed with an inflammatory rhabdomyoblastic tumor.

Incidence and risk factors of peri-operative stroke in major non-cardiovascular, non-neurologic surgery-A retrospective register-based cohort study.

BACKGROUND: Peri-operative stroke is a rare but serious surgical complication. Both overt and covert stroke, occurring in approximately 0.1% and 7% of cases, respectively, are associated with significant long-term effects and increased morbidity. METHODS: Retrospective register data for patients >18 years old, presenting for major non-cardiovascular, non-neurosurgical and non-ambulatory surgical procedures at 23 hospitals in Sweden between 2007 and 2014 was collected and linked with various quality registers. The primary outcome was stroke within 30 days from surgery. Using multivariable logistic regression, significant independent risk factors influencing the primary outcome were identified and their adjusted odds ratios (ORs) were calculated. Mortality was assessed, along with the composite score of days alive and at home within 30 days after surgery (DAH 30). RESULTS: In total, 318,017 patients were included, with 687 (0.22%) suffering a stroke within 30 days of surgery. The strongest significant risk factors included: increasing ASA-class (OR [95% confidence interval, CI]: 2.23 [1.53-3.36], 3.91 [2.68-5.93] and 7.82 [5.03-12.5] for ASA 2, 3 and 4, respectively) and age (OR [95% CI]: 4.47 [2.21-10.3], 9.9 [5.15-22.1], 16.3 [8.48-36.5] and 21 [10.6-48.1], for age 45-59, 60-74, 75-89 and >90, respectively), along with non-elective procedures, male gender and a history of cerebrovascular disease (OR [95%]: 2.72 [2.25-3.27]). Mortality was increased and DAH 30 was reduced in patients suffering a stroke. CONCLUSIONS: Increasing ASA-class and age was clearly associated with an increased risk of peri-operative stroke, which in turn was associated with increased mortality and poorer outcome. Detailed pre-operative risk stratification and individualised peri-operative management could potentially improve patient-centred outcomes and, in turn, have positive implications for public health.

Immunomodulatory Nanoparticles for Modulating Arthritis Flares.

Disease-modifying drugs have improved the treatment for autoimmune joint disorders, such as rheumatoid arthritis, but inflammatory flares are a common experience. This work reports the development and application of flare-modulating poly(lactic-co-glycolic acid)-poly(ethylene glycol)-maleimide (PLGA-PEG-MAL)-based nanoparticles conjugated with joint-relevant peptide antigens, aggrecan70-84 and type 2 bovine collagen256-270. Peptide-conjugated PLGA-PEG-MAL nanoparticles encapsulated calcitriol, which acted as an immunoregulatory agent, and were termed calcitriol-loaded nanoparticles (CLNP). CLNP had a ∼200 nm hydrodynamic diameter with a low polydispersity index. In vitro, CLNP induced phenotypic changes in bone marrow derived dendritic cells (DC), reducing the expression of costimulatory and major histocompatibility complex class II molecules, and proinflammatory cytokines. Bulk RNA sequencing of DC showed that CLNP enhanced expression of Ctla4, a gene associated with downregulation of immune responses. In vivo, CLNP accumulated in the proximal lymph nodes after intramuscular injection. Administration of CLNP was not associated with changes in peripheral blood cell numbers or cytokine levels. In the collagen-induced arthritis and SKG mouse models of autoimmune joint disorders, CLNP reduced clinical scores, prevented bone erosion, and preserved cartilage proteoglycan, as assessed by high-resolution microcomputed tomography and histomorphometry analysis. The disease protective effects were associated with increased CTLA-4 expression in joint-localized DC and CD4+ T cells but without generalized suppression of T cell-dependent immune response. The results support the potential of CLNP as modulators of disease flares in autoimmune arthropathies.

Auditory masking in odobenid and otariid carnivoresa).

As the only living species within the odobenid lineage of carnivores, walruses (Odobenus rosmarus) have no close relatives from which auditory information can be extrapolated. Sea lions and fur seals in the otariid lineage are the nearest evolutionary outgroup. To advance understanding of odobenid and otariid hearing, we conducted behavioral testing with two walruses and one California sea lion (Zalophus californianus). Detection thresholds for airborne sounds were measured from 0.08 to at least 16 kHz in ambient noise conditions and then re-measured in the presence of octave-band white masking noise. Walruses were more sensitive than the sea lion at lower frequencies and less sensitive at higher frequencies. Critical ratios for the walruses ranged from 20 dB at 0.2 kHz to 32 dB at 10 kHz, while critical ratios for the sea lion ranged from 16 dB at 0.2 kHz to 35 dB at 32 kHz. The masking values for these species are comparable to one another and to those of terrestrial carnivores, increasing by about 3 dB per octave with increasing frequency. Despite apparent differences in hearing range and sensitivity, odobenids and otariids have a similar ability to hear signals in noisy conditions.

Three-dimensional super resolution ultrasound imaging with a multi-frequency hemispherical phased array.

BACKGROUND: High resolution imaging of the microvasculature plays an important role in both diagnostic and therapeutic applications in the brain. However, ultrasound pulse-echo sonography imaging the brain vasculatures has been limited to narrow acoustic windows and low frequencies due to the distortion of the skull bone, which sacrifices axial resolution since it is pulse length dependent. PURPOSE: To overcome the detect limit, a large aperture 256-module sparse hemispherical transmit/receive array was used to visualize the acoustic emissions of ultrasound-vaporized lipid-coated decafluorobutane nanodroplets flowing through tube phantoms and within rabbit cerebral vasculature in vivo via passive acoustic mapping and super resolution techniques. METHODS: Nanodroplets were vaporized with 55 kHz burst-mode ultrasound (burst length = 145 µs, burst repetition frequency = 9-45 Hz, peak negative acoustic pressure = 0.10-0.22 MPa), which propagates through overlying tissues well without suffering from severe distortions. The resulting emissions were received at a higher frequency (612 or 1224 kHz subarray) to improve the resulting spatial resolution during passive beamforming. Normal resolution three-dimensional images were formed using a delay, sum, and integrate beamforming algorithm, and super-resolved images were extracted via Gaussian fitting of the estimated point-spread-function to the normal resolution data. RESULTS: With super resolution techniques, the mean lateral (axial) full-width-at-half-maximum image intensity was 16 ± 3 (32 ± 6) µm, and 7 ± 1 (15 ± 2) µm corresponding to ∼1/67 of the normal resolution at 612 and 1224 kHz, respectively. The mean positional uncertainties were ∼1/350 (lateral) and ∼1/180 (axial) of the receive wavelength in water. In addition, a temporal correlation between nanodroplet vaporization and the transmit waveform shape was observed, which may provide the opportunity to enhance the signal-to-noise ratio in future studies. CONCLUSIONS: Here, we demonstrate the feasibility of vaporizing nanodroplets via low frequency ultrasound and simultaneously performing spatial mapping via passive beamforming at higher frequencies to improve the resulting spatial resolution of super resolution imaging techniques. This method may enable complete four-dimensional vascular mapping in organs where a hemispherical array could be positioned to surround the target, such as the brain, breast, or testicles.

Emissions and energy impacts of the Inflation Reduction Act.

Economy-wide emissions drop 43 to 48% below 2005 levels by 2035 with accelerated clean energy deployment.