The porcine skin microbiome exhibits broad fungal antagonism.

The skin and its microbiome function to protect the host from pathogen colonization and environmental stressors. In this study, using the Wisconsin Miniature Swine™ model, we characterize the porcine skin fungal and bacterial microbiomes, identify bacterial isolates displaying antifungal activity, and use whole-genome sequencing to identify biosynthetic gene clusters encoding for secondary metabolites that may be responsible for the antagonistic effects on fungi. Through this comprehensive approach of paired microbiome sequencing with culturomics, we report the discovery of novel species of Corynebacterium and Rothia. Further, this study represents the first comprehensive evaluation of the porcine skin mycobiome and the evaluation of bacterial-fungal interactions on this surface. Several diverse bacterial isolates exhibit potent antifungal properties against opportunistic fungal pathogens in vitro. Genomic analysis of inhibitory species revealed a diverse repertoire of uncharacterized biosynthetic gene clusters suggesting a reservoir of novel chemical and biological diversity. Collectively, the porcine skin microbiome represents a potential unique source of novel antifungals.

The effect of anatomic location on porcine models of burn injury and wound healing.

Porcine models are frequently used for burn healing studies; however, factors including anatomic location and lack of standardised wound methods can impact the interpretation of wound data. The objectives of this study are to examine the influence of anatomical locations on the uniformity of burn creation and healing in porcine burn models. To optimise burn parameters on dorsal and ventral surfaces, ex vivo and in situ euthanized animals were first used to examine the location-dependence of the burn depth and contact time relationship. The location-dependent healing in vivo was then examined using burn and excisional wounds at dorsal, ventral, caudal and cranial locations. Lactate dehydrogenase (LDH) and H&E were used to assess burn depth and wound re-epithelialization. We found that burn depth on the ventral skin was significantly deeper than that of the dorsal skin at identical thermal conditions. Compared with burns created ex vivo, burns created in situ immediately post-mortem were significantly deeper in the ventral location. In live animals, 2 out of 12 burn wounds were fully re-epithelialized after 14 days in contrast to complete re-epithelialization of all excisional wounds. Among the burn wounds, those at the cranial-dorsal site exhibited faster healing than at the caudal-dorsal site. This study showed that anatomical location is an important consideration for the consistency of burn depth creation and healing. These data support symmetric localization of treatment and control for comparative assessment of burn healing in porcine models to prevent misinterpretation of results and increase the translatability of findings to humans.

Ex Vivo Human and Porcine Skin Effectively Model Candida auris Colonization, Differentiating Robust and Poor Fungal Colonizers.

Candida auris proliferates and persists on the skin of patients, often leading to health care-associated infections with high mortality. Here, we describe 2 clinically relevant skin models and show that C. auris grows similarly on human and porcine skin. Additionally, we demonstrate that other Candida spp., including those with phylogenetic similarity to C. auris, do not display high growth in the skin microenvironment. These studies highlight the utility of 2 ex vivo models of C. auris colonization that allow reproducible differentiation among Candida spp., which should be a useful tool for comparison of C. auris clinical isolates and genetically mutated strains.

Brachial plexus anatomy in the miniature swine as compared to human.

Brachial plexus injury (BPI) occurs when the brachial plexus is compressed, stretched, or avulsed. Although rodents are commonly used to study BPI, these models poorly mimic human BPI due to the discrepancy in size. The objective of this study was to compare the brachial plexus between human and Wisconsin Miniature SwineTM (WMSTM ), which are approximately the weight of an average human (68-91 kg), to determine if swine would be a suitable model for studying BPI mechanisms and treatments. To analyze the gross anatomy, WMS brachial plexuses were dissected both anteriorly and posteriorly. For histological analysis, sections from various nerves of human and WMS brachial plexuses were fixed in 2.5% glutaraldehyde, and postfixed with 2% osmium tetroxide. Subsequently paraffin sections were counter-stained with Masson's Trichrome. Gross anatomy revealed that the separation into three trunks and three cords is significantly less developed in the swine than in human. In swine, it takes the form of upper, middle, and lower systems with ventral and dorsal components. Histological evaluation of selected nerves revealed differences in nerve trunk diameters and the number of myelinated axons in the two species. The WMS had significantly fewer myelinated axons than humans in median (p = 0.0049), ulnar (p = 0.0002), and musculocutaneous nerves (p = 0.0454). The higher number of myelinated axons in these nerves for humans is expected because there is a high demand of fine motor and sensory functions in the human hand. Due to the stronger shoulder girdle muscles in WMS, the WMS suprascapular and axillary nerves were larger than in human. Overall, the WMS brachial plexus is similar in size and origin to human making them a very good model to study BPI. Future studies analyzing the effects of BPI in WMS should be conducted.

Miniature Swine for Preclinical Modeling of Complexities of Human Disease for Translational Scientific Discovery and Accelerated Development of Therapies and Medical Devices.

Noncommunicable diseases, including cardiovascular disease, diabetes, chronic respiratory disease, and cancer, are the leading cause of death in the world. The cost, both monetary and time, of developing therapies to prevent, treat, or manage these diseases has become unsustainable. A contributing factor is inefficient and ineffective preclinical research, in which the animal models utilized do not replicate the complex physiology that influences disease. An ideal preclinical animal model is one that responds similarly to intrinsic and extrinsic influences, providing high translatability and concordance of preclinical findings to humans. The overwhelming genetic, anatomical, physiological, and pathophysiological similarities to humans make miniature swine an ideal model for preclinical studies of human disease. Additionally, recent development of precision gene-editing tools for creation of novel genetic swine models allows the modeling of highly complex pathophysiology and comorbidities. As such, the utilization of swine models in early research allows for the evaluation of novel drug and technology efficacy while encouraging redesign and refinement before committing to clinical testing. This review highlights the appropriateness of the miniature swine for modeling complex physiologic systems, presenting it as a highly translational preclinical platform to validate efficacy and safety of therapies and devices.

Plasma diacylglycerol composition is a biomarker of metabolic syndrome onset in rhesus monkeys.

Metabolic syndrome is linked with obesity and is often first identified clinically by elevated BMI and elevated levels of fasting blood glucose that are generally secondary to insulin resistance. Using the highly translatable rhesus monkey (Macaca mulatta) model, we asked if metabolic syndrome risk could be identified earlier. The study involved 16 overweight but healthy, euglycemic monkeys, one-half of which spontaneously developed metabolic syndrome over the course of 2 years while the other half remained healthy. We conducted a series of biometric and plasma measures focusing on adiposity, lipid metabolism, and adipose tissue-derived hormones, which led to a diagnosis of metabolic syndrome in the insulin-resistant animals. Plasma fatty acid composition was determined by gas chromatography for cholesteryl ester, FFA, diacylglycerol (DAG), phospholipid, and triacylglycerol lipid classes; plasma lipoprotein profiles were generated by NMR; and circulating levels of adipose-derived signaling peptides were determined by ELISA. We identified biomarker models including a DAG model, two lipoprotein models, and a multiterm model that includes the adipose-derived peptide adiponectin. Correlations among circulating lipids and lipoproteins revealed shifts in lipid metabolism during disease development. We propose that lipid profiling may be valuable for early metabolic syndrome detection in a clinical setting.

Measurements of wall shear stress and aortic pulse wave velocity in swine with familial hypercholesterolemia.

PURPOSE: To assess measurements of pulse wave velocity (PWV) and wall shear stress (WSS) in a swine model of atherosclerosis. MATERIALS AND METHODS: Nine familial hypercholesterolemic (FH) swine with angioplasty balloon catheter-induced atherosclerotic lesions to the abdominal aorta (injured group) and 10 uninjured FH swine were evaluated with a 4D phase contrast (PC) magnetic resonance imaging (MRI) acquisition, as well as with radial and Cartesian 2D PC acquisitions, on a 3T MR scanner. PWV values were computed from the 2D and 4D PC techniques, compared between the injured and uninjured swine, and validated against reference standard pressure probe-based PWV measurements. WSS values were also computed from the 4D PC MRI technique and compared between injured and uninjured groups. RESULTS: PWV values were significantly greater in the injured than in the uninjured groups with the 4D PC MRI technique (P = 0.03) and pressure probes (P = 0.02). No significant differences were found in PWV between groups using the 2D PC techniques (P = 0.75-0.83). No significant differences were found for WSS values between the injured and uninjured groups. CONCLUSION: The 4D PC MRI technique provides a promising means of evaluating PWV and WSS in a swine model of atherosclerosis, providing a potential platform for developing the technique for the early detection of atherosclerosis.

Bioavailability, bioactivity and impact on health of dietary flavonoids and related compounds: an update.

There is substantial interest in the role of plant secondary metabolites as protective dietary agents. In particular, the involvement of flavonoids and related compounds has become a major topic in human nutrition research. Evidence from epidemiological and human intervention studies is emerging regarding the protective effects of various (poly)phenol-rich foods against several chronic diseases, including neurodegeneration, cancer and cardiovascular diseases. In recent years, the use of HPLC-MS for the analysis of flavonoids and related compounds in foods and biological samples has significantly enhanced our understanding of (poly)phenol bioavailability. These advancements have also led to improvements in the available food composition and metabolomic databases, and consequently in the development of biomarkers of (poly)phenol intake to use in epidemiological studies. Efforts to create adequate standardised materials and well-matched controls to use in randomised controlled trials have also improved the quality of the available data. In vitro investigations using physiologically achievable concentrations of (poly)phenol metabolites and catabolites with appropriate model test systems have provided new and interesting insights on potential mechanisms of actions. This article will summarise recent findings on the bioavailability and biological activity of (poly)phenols, focusing on the epidemiological and clinical evidence of beneficial effects of flavonoids and related compounds on urinary tract infections, cognitive function and age-related cognitive decline, cancer and cardiovascular disease.

Parenteral nutrition increases susceptibility of ileum to invasion by E coli.

BACKGROUND: Parenteral nutrition (PN), with the lack of enteral feeding, compromises mucosal immune function and increases the risk of infections. We developed an ex vivo intestinal segment culture (EVISC) model to study the ex vivo effects of PN on susceptibility of the ileum to invasion by extra-intestinal pathogenic Escherichia coli (ExPEC) and on ileal secretion of antimicrobial secretory phospholipase A2 (sPLA2) in response to the pathogen. MATERIALS AND METHODS: Study 1: Using mouse (n = 7) ileal tissue, we examined the effects of ileal region (proximal versus distal) and varying ExPEC inoculum concentrations on ex vivo susceptibility to ExPEC invasion and sPLA2 secretion. Study 2: Ten mice were randomized to oral chow or intravenous PN feeding for 5 d (n = 5/group). Using the EVISC model, we compared the susceptibility of ileal tissue to invasion by ExPEC and sPLA2 secretion in response to the pathogen. RESULTS: Study 1: The proximal ileum was more susceptible to invasion (P < 0.0001) and secreted lower amounts of sPLA2 (P = 0.0002) than the distal ileum. Study 2: Ileal tissue from PN-fed animals was more susceptible (approximately 4-fold, P = 0.018) to invasion than those from chow-fed animals. Ileal tissue from PN-fed animals secreted less sPLA2 (P < 0.02) than those from chow-fed animals. CONCLUSIONS: The data illustrate EVISC as a reproducible model for studying host-pathogen interactions and the effects of diet on susceptibility to infections. Specifically, the findings support our hypothesis that PN with the lack of enteral feeding decreases mucosal responsiveness to pathogen exposure and provides a plausible mechanism by which PN is associated with increased risk of infectious complication.

Robust quantification of CT-ventilation biomarker techniques and repeatability in a porcine model.

BACKGROUND: Biomarkers estimating local lung ventilation have been derived from computed tomography (CT) imaging using various image acquisition and post-processing techniques. CT-ventilation biomarkers have potential clinical use in functional avoidance radiation therapy (RT), in which RT treatment plans are optimized to reduce dose delivered to highly ventilated lung. Widespread clinical implementation of CT-ventilation biomarkers necessitates understanding of biomarker repeatability. Performing imaging within a highly controlled experimental design enables quantification of error associated with remaining variables. PURPOSE: To characterize CT-ventilation biomarker repeatability and dependence on image acquisition and post-processing methodology in anesthetized and mechanically ventilated pigs. METHODS: Five mechanically ventilated Wisconsin Miniature Swine (WMS) received multiple consecutive four-dimensional CT (4DCT) and maximum inhale and exhale breath-hold CT (BH-CT) scans on five dates to generate CT-ventilation biomarkers. Breathing maneuvers were controlled with an average tidal volume difference <200 cc. As surrogates for ventilation, multiple local expansion ratios (LERs) were calculated from the acquired CT scans using Jacobian-based post-processing techniques. L E R 2 $LER_2$ measured local expansion between an image pair using either inhale and exhale BH-CT images or two 4DCT breathing phase images. L E R N $LER_N$ measured the maximum local expansion across the 4DCT breathing phase images. Breathing maneuver consistency, intra- and interday biomarker repeatability, image acquisition and post-processing technique dependence were quantitatively analyzed. RESULTS: Biomarkers showed strong agreement with voxel-wise Spearman correlation ρ > 0.9 $\rho > 0.9$ for intraday repeatability and ρ > 0.8 $\rho > 0.8$ for all other comparisons, including between image acquisition techniques. Intra- and interday repeatability were significantly different (p < 0.01). LER2 and LERN post-processing did not significantly affect intraday repeatability. CONCLUSIONS: 4DCT and BH-CT ventilation biomarkers derived from consecutive scans show strong agreement in controlled experiments with nonhuman subjects.

Quantifying robustness of CT-ventilation biomarkers to image noise.

Purpose: To quantify the impact of image noise on CT-based lung ventilation biomarkers calculated using Jacobian determinant techniques. Methods: Five mechanically ventilated swine were imaged on a multi-row CT scanner with acquisition parameters of 120 kVp and 0.6 mm slice thickness in static and 4-dimensional CT (4DCT) modes with respective pitches of 1 and 0.09. A range of tube current time product (mAs) values were used to vary image dose. On two dates, subjects received two 4DCTs: one with 10 mAs/rotation (low-dose, high-noise) and one with CT simulation standard of care 100 mAs/rotation (high-dose, low-noise). Additionally, 10 intermediate noise level breath-hold (BHCT) scans were acquired with inspiratory and expiratory lung volumes. Images were reconstructed with and without iterative reconstruction (IR) using 1 mm slice thickness. The Jacobian determinant of an estimated transformation from a B-spline deformable image registration was used to create CT-ventilation biomarkers estimating lung tissue expansion. 24 CT-ventilation maps were generated per subject per scan date: four 4DCT ventilation maps (two noise levels each with and without IR) and 20 BHCT ventilation maps (10 noise levels each with and without IR). Biomarkers derived from reduced dose scans were registered to the reference full dose scan for comparison. Evaluation metrics were gamma pass rate (Γ) with 2 mm distance-to-agreement and 6% intensity criterion, voxel-wise Spearman correlation (ρ) and Jacobian ratio coefficient of variation (CoV JR ). Results: Comparing biomarkers derived from low (CTDI vol = 6.07 mGy) and high (CTDI vol = 60.7 mGy) dose 4DCT scans, mean Γ, ρ and CoV JR values were 93% ± 3%, 0.88 ± 0.03 and 0.04 ± 0.009, respectively. With IR applied, those values were 93% ± 4%, 0.90 ± 0.04 and 0.03 ± 0.003. Similarly, comparisons between BHCT-based biomarkers with variable dose (CTDI vol = 1.35-7.95 mGy) had mean Γ, ρ and CoV JR of 93% ± 4%, 0.97 ± 0.02 and 0.03 ± 0.006 without IR and 93% ± 4%, 0.97 ± 0.03 and 0.03 ± 0.007 with IR. Applying IR did not significantly change any metrics (p > 0.05). Discussion: This work demonstrated that CT-ventilation, calculated using the Jacobian determinant of an estimated transformation from a B-spline deformable image registration, is invariant to Hounsfield Unit (HU) variation caused by image noise. This advantageous finding may be leveraged clinically with potential applications including dose reduction and/or acquiring repeated low-dose acquisitions for improved ventilation characterization.

Validation of CT-based ventilation and perfusion biomarkers with histopathology confirms radiation-induced pulmonary changes in a porcine model.

Imaging biomarkers can assess disease progression or prognoses and are valuable tools to help guide interventions. Particularly in lung imaging, biomarkers present an opportunity to extract regional information that is more robust to the patient's condition prior to intervention than current gold standard pulmonary function tests (PFTs). This regional aspect has particular use in functional avoidance radiation therapy (RT) in which treatment planning is optimized to avoid regions of high function with the goal of sparing functional lung and improving patient quality of life post-RT. To execute functional avoidance, detailed dose-response models need to be developed to identify regions which should be protected. Previous studies have begun to do this, but for these models to be clinically translated, they need to be validated. This work validates two metrics that encompass the main components of lung function (ventilation and perfusion) through post-mortem histopathology performed in a novel porcine model. With these methods validated, we can use them to study the nuanced radiation-induced changes in lung function and develop more advanced models.

Single-cell RNA sequencing of neurofibromas reveals a tumor microenvironment favorable for neural regeneration and immune suppression in a neurofibromatosis type 1 porcine model.

Neurofibromatosis Type 1 (NF1) is one of the most common genetically inherited disorders that affects 1 in 3000 children annually. Clinical manifestations vary widely but nearly always include the development of cutaneous, plexiform and diffuse neurofibromas that are managed over many years. Recent single-cell transcriptomics profiling efforts of neurofibromas have begun to reveal cell signaling processes. However, the cell signaling networks in mature, non-cutaneous neurofibromas remain unexplored. Here, we present insights into the cellular composition and signaling within mature neurofibromas, contrasting with normal adjacent tissue, in a porcine model of NF1 using single-cell RNA sequencing (scRNA-seq) analysis and histopathological characterization. These neurofibromas exhibited classic diffuse-type histologic morphology and expected patterns of S100, SOX10, GFAP, and CD34 immunohistochemistry. The porcine mature neurofibromas closely resemble human neurofibromas histologically and contain all known cellular components of their human counterparts. The scRNA-seq confirmed the presence of all expected cell types within these neurofibromas and identified novel populations of fibroblasts and immune cells, which may contribute to the tumor microenvironment by suppressing inflammation, promoting M2 macrophage polarization, increasing fibrosis, and driving the proliferation of Schwann cells. Notably, we identified tumor-associated IDO1 +/CD274+ (PD-L1) + dendritic cells, which represent the first such observation in any NF1 animal model and suggest the role of the upregulation of immune checkpoints in mature neurofibromas. Finally, we observed that cell types in the tumor microenvironment are poised to promote immune evasion, extracellular matrix reconstruction, and nerve regeneration.

Displacement and strain estimation for evaluation of arterial wall stiffness using a familial hypercholesterolemia swine model of atherosclerosis.

PURPOSE: To track variations in the deformation of the arterial wall noninvasively by estimating the accumulated displacement and strain over a cardiac cycle may provide useful indicators of vascular health. METHODS: In this paper, we propose an approach to track a region of interest (ROI) locally and estimate arterial stiffness variation in a familial hypercholesterolemic swine model of spontaneous atherosclerosis that allows for systematic and reproducible study of progression of the disease mechanism. RESULTS: Strain and displacement indices may be derived from the variations of the accumulated displacement and accumulated strain (obtained from the gradient of the accumulated displacement) over a cardiac cycle to predict not only the likelihood of developing vascular diseases, but also the sites where they may occur. Currently, an ROI thickness value of less than one mm within the arterial wall is necessary for the axial accumulated displacement and strain to obtain reproducible estimates. CONCLUSIONS: Accumulated axial displacement and strain estimation on the artery wall shown in this paper indicate the repeatability of these measurements over several cardiac cycles and over five familial hypercholesterolemic swine. Our results also demonstrate the need for a small region of interest within the arterial walls for accurate and robust estimates of arterial function.

Modeling Candida auris Colonization on Porcine Skin Ex Vivo.

Candida auris spreads person to person in hospitals and other healthcare facilities. The heightened capacity for C. auris to colonize skin contributes to the difficulty in eradicating this drug-resistant and deadly pathogen in nosocomial settings. Models for the study of C. auris skin colonization are critical for understanding this virulence trait. In light of the similarities between the skin properties of humans and pigs, pigs represent an ideal model for the investigation of skin-C. auris interactions. Here, we describe how to utilize porcine skin for ex vivo studies of C. auris colonization.

Measuring Indirect Radiation-Induced Perfusion Change in Fed Vasculature Using Dynamic Contrast CT.

Recent functional lung imaging studies have presented evidence of an "indirect effect" on perfusion damage, where regions that are unirradiated or lowly irradiated but that are supplied by highly irradiated regions observe perfusion damage post-radiation therapy (RT). The purpose of this work was to investigate this effect using a contrast-enhanced dynamic CT protocol to measure perfusion change in five novel swine subjects. A cohort of five Wisconsin Miniature Swine (WMS) were given a research course of 60 Gy in five fractions delivered locally to a vessel in the lung using an Accuray Radixact tomotherapy system with Synchrony motion tracking to increase delivery accuracy. Imaging was performed prior to delivering RT and 3 months post-RT to yield a 28−36 frame image series showing contrast flowing in and out of the vasculature. Using MIM software, contours were placed in six vessels on each animal to yield a contrast flow curve for each vessel. The contours were placed as follows: one at the point of max dose, one low-irradiated (5−20 Gy) branching from the max dose vessel, one low-irradiated (5−20 Gy) not branching from the max dose vessel, one unirradiated (<5 Gy) branching from the max dose vessel, one unirradiated (<5 Gy) not branching from the max dose vessel, and one in the contralateral lung. Seven measurements (baseline-to-baseline time and difference, slope up and down, max rise and value, and area under the curve) were acquired for each vessel's contrast flow curve in each subject. Paired Student t-tests showed statistically significant (p < 0.05) reductions in the area under the curve in the max dose, and both fed contours indicating an overall reduction in contrast in these regions. Additionally, there were statistically significant reductions observed when comparing pre- and post-RT in slope up and down in the max dose, low-dose fed, and no-dose fed contours but not the low-dose not-fed, no-dose not-fed, or contralateral contours. These findings suggest an indirect damage effect where irradiation of the vasculature causes a reduction in perfusion in irradiated regions as well as regions fed by the irradiated vasculature.

CT-derived vessel segmentation for analysis of post-radiation therapy changes in vasculature and perfusion.

Vessel segmentation in the lung is an ongoing challenge. While many methods have been able to successfully identify vessels in normal, healthy, lungs, these methods struggle in the presence of abnormalities. Following radiotherapy, these methods tend to identify regions of radiographic change due to post-radiation therapytoxicities as vasculature falsely. By combining texture analysis and existing vasculature and masking techniques, we have developed a novel vasculature segmentation workflow that improves specificity in irradiated lung while preserving the sensitivity of detection in the rest of the lung. Furthermore, radiation dose has been shown to cause vascular injury as well as reduce pulmonary function post-RT. This work shows the improvements our novel vascular segmentation method provides relative to existing methods. Additionally, we use this workflow to show a dose dependent radiation-induced change in vasculature which is correlated with previously measured perfusion changes (R 2 = 0.72) in both directly irradiated and indirectly damaged regions of perfusion. These results present an opportunity to extend non-contrast CT-derived models of functional change following radiation therapy.

Staging Liver Fibrosis by Fibroblast Activation Protein Inhibitor PET in a Human-Sized Swine Model.

Current methods of staging liver fibrosis have notable limitations. We investigated the utility of PET in staging liver fibrosis by correlating liver uptake of 68Ga-labeled fibroblast activation protein inhibitor (FAPI) with histology in a human-sized swine model. Methods: Five pigs underwent baseline 68Ga-FAPI-46 (68Ga-FAPI) PET/MRI and liver biopsy, followed by liver parenchymal embolization, 8 wk of oral alcohol intake, endpoint 68Ga-FAPI PET/MRI, and necropsy. Regions of interest were drawn on baseline and endpoint PET images, and SUVmean was recorded. At the endpoint, liver sections corresponding to regions of interest were identified and cut out. Fibrosis was histologically evaluated using a modified METAVIR score for swine liver and quantitatively using collagen proportionate area (CPA). Box-and-whisker plots and linear regression were used to correlate SUVmean with METAVIR score and CPA, respectively. Results: Liver 68Ga-FAPI uptake strongly correlated with CPA (r = 0.89, P < 0.001). 68Ga-FAPI uptake was significantly and progressively higher across F2 and F3/F4 fibrosis stages, with a respective median SUVmean of 2.9 (interquartile range [IQR], 2.7-3.8) and 7.6 (IQR, 6.7-10.2) (P < 0.001). There was no significant difference between 68Ga-FAPI uptake of baseline liver and endpoint liver sections staged as F0/F1, with a respective median SUVmean of 1.7 (IQR, 1.3-2.0) and 1.7 (IQR, 1.5-1.8) (P = 0.338). Conclusion: The strong correlation between liver 68Ga-FAPI uptake and the histologic stage of liver fibrosis suggests that 68Ga-FAPI PET can play an impactful role in noninvasive staging of liver fibrosis, pending validation in patients.

Radiation-induced airway changes and downstream ventilation decline in a swine model.

Purpose.To investigate indirect radiation-induced changes in airways as precursors to atelectasis post radiation therapy (RT).Methods.Three Wisconsin Miniature Swine (WMSTM) underwent a research course of 60 Gy in 5 fractions delivered to a targeted airway/vessel in the inferior left lung. The right lung received a max point dose <5 Gy. Airway segmentation was performed on the pre- and three months post-RT maximum inhale phase of the four-dimensional (4D) computed tomography (CT) scans. Changes in luminal area (Ai) and square root of wall area (WA) for each airway were investigated. Changes in ventilation were assessed using the Jacobian ratio and were measured in three different regions: the inferior left lung <5 Gy (ILL), the superior left lung <5 Gy (SLL), and the contralateral right lung <5 Gy (RL).Results.Airways (n = 25) in the right lung for all swine showed no significant changes (p = 0.48) in Ai post-RT compared to pre-RT. Airways (n = 28) in the left lung of all swine were found to have a significant decrease (p < 0.001) in Ai post-RT compared to pre-RT, correlated (Pearson R = -0.97) with airway dose. Additionally,WAdecreased significantly (p < 0.001) with airway dose. Lastly, the Jacobian ratio of the ILL (0.883) was lower than that of the SLL (0.932) and the RL (0.955).Conclusions.This work shows that for the swine analyzed, there were significant correlations between Ai andWAchange with radiation dose. Additionally, there was a decrease in lung function in the regions of the lung supplied by the irradiated airways compared to the regions supplied by unirradiated airways. These results support the hypothesis that airway dose should be considered during treatment planning in order to potentially preserve functional lung and reduce lung toxicities.

Augmenting the Activity of Chlorhexidine for Decolonization of Candida auris from Porcine skin.

Candida auris readily colonizes skin and efficiently spreads among patients in healthcare settings worldwide. Given the capacity of this drug-resistant fungal pathogen to cause invasive disease with high mortality, hospitals frequently employ chlorhexidine bathing to reduce skin colonization. Using an ex vivo skin model, we show only a mild reduction in C. auris following chlorhexidine application. This finding helps explain why chlorhexidine bathing may have failures clinically, despite potent in vitro activity. We further show that isopropanol augments the activity of chlorhexidine against C. auris on skin. Additionally, we find both tea tree (Melaleuca alternifolia) oil and lemongrass (Cymbopogon flexuosus) oil to further enhance the activity of chlorhexidine/isopropanol for decolonization. We link this antifungal activity to individual oil components and show how some of these components act synergistically with chlorhexidine/isopropanol. Together, the studies provide strategies to improve C. auris skin decolonization through the incorporation of commonly used topical compounds.