A Bioinspired and Cost-Effective Device for Minimally Invasive Blood Sampling.

Conventional venipuncture is invasive and challenging in low and middle-income countries. Conversely, point-of-care devices paired with fingersticks, although less invasive, suffer from high variability and low blood volume collection. Recently approved microsampling devices address some of these issues but remain cost-prohibitive for resource-limited settings. In this work, a cost-effective microsampling device is described for the collection of liquid blood with minimal invasiveness and sufficient volume retrieval for laboratory analyses or immediate point-of-care testing. Inspired by the anatomy of sanguivorous leeches, the single-use device features a storage compartment for blood collection and a microneedle patch hidden within a suction cup. Finite Element Method simulations, corroborated by mechanical analyses, guide the material selection for device fabrication and design optimization. In piglets, the device successfully collects ≈195 µL of blood with minimal invasiveness. Additionally, a tailor-made lid and adapter enable safe fluid transportation and integration with commercially available point-of-care systems for on-site analyses, respectively. Taken together, the proposed platform holds significant promise for enhancing healthcare in the pediatric population by improving patient compliance and reducing the risk of needlestick injuries through concealed microneedles. Most importantly, given its cost-effective fabrication, the open-source microsampling device may have a meaningful impact in resource-limited healthcare settings.

Predator Odor Stressor, 2,3,5-Trimethyl-3-Thiazoline (TMT): Assessment of Stress Reactive Behaviors During an Animal Model of Traumatic Stress in Rats.

Animal models utilizing predator odor stress are important in understanding implications for post-traumatic stress disorder. 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) has been used to measure stress reactive behaviors during TMT exposure, indicative of stress coping behaviors. In addition, long-term consequences of stress including contextual-induced stress memory, anxiety-like and hyperarousal behaviors, and subsequent increases in alcohol self-administration can also be examined after TMT exposure. In this article, we describe the TMT exposure protocol used in our lab and how we measure different stress-reactive behaviors that rats engage in during the TMT exposure. Rats are placed in Plexiglass chambers that contain white bedding on the bottom of the chamber and a metal basket in the top right corner containing a filter paper that 10 µl of TMT is pipetted onto. During the 10 min exposure, rats can move around the chamber freely. Exposures are recorded by a video camera for later analysis. During TMT exposure, rats engage in a variety of stress-reactive behaviors, including digging and immobility behavior. These are two distinctly different types of stress-induced behavioral coping strategies to measure individual differences in stress responsivity. To examine individual differences, we group rats into TMT-subgroups based on time spent engaging in digging or immobility behavior. We calculate a digging/immobility ratio score in which we divide the total time spent digging by the total time spent immobile. A cut-off strategy is used such that rats with a criterion ratio score <1.0 are classified as TMT-1 (i.e., low digging/high immobility; greater passive coping) and rats with a ratio score >1.0 are classified as TMT-2 (i.e., high digging/low immobility; greater active coping). Here, we provide a detailed description of the TMT exposure protocol and step-by-step process in evaluation of stress-reactive behaviors. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Predator odor stressor exposure using TMT Basic Protocol 2: Description of stress-reactive behaviors during TMT exposure and formation of TMT-subgroups.

Ecotoxicological assessment of Cu-rich acid mine drainage of Sulitjelma mine using zebrafish larvae as an animal model.

Acid mine drainage (AMD) is widely acknowledged as a substantial threat to the biodiversity of aquatic ecosystems. The present study aimed to study the toxicological effects of Cu-rich AMD from the Sulitjelma mine in zebrafish larvae. The AMD from this mine was found to contain elevated levels of dissolved metals including Mg (46.7 mg/L), Al (20.2 mg/L), Cu (18.3 mg/L), Fe (19.8 mg/L) and Zn (10.6 mg/L). To investigate the toxicological effects, the study commenced by exposing zebrafish embryos to various concentrations of AMD (ranging from 0.75% to 9%) to determine the median lethal concentration (LC50). Results showed that 96 h LC50 for zebrafish larvae following AMD exposure was 2.86% (95% CI: 2.32-3.52%). Based on acute toxicity results, zebrafish embryos (<2 hpf) were exposed to 0.1% AMD (Cu: 21.7 µg/L) and 0.45% AMD (Cu: 85.7 µg/L) for 96 h to assess development, swimming behaviour, heart rate, respiration and transcriptional responses at 116 hpf. Light microscopy results showed that both 0.1% and 0.45% AMD reduced the body length, eye size and swim bladder area of zebrafish larvae and caused phenotypic abnormalities. Swimming behaviour results showed that 0.45% AMD significantly decreased the locomotion of zebrafish larvae. Heart rate was not affected by AMD exposure. Furthermore, exposure caused a significant increase in oxygen consumption indicating vascular stress in developing larvae. Taken altogether, the study shows that even heavily diluted AMD with environmentally relevant levels of Cu caused toxicity in zebrafish larvae.

Novel quantitative assessment indicators for efficiency and precision of endoscopic submucosal dissection in animal training models by analyzing an electrical surgical unit.

OBJECTIVES: Although endoscopic submucosal dissection (ESD) training is important, quantitative assessments have not been established. This study aimed to explore a novel quantitative assessment system by analyzing an electrical surgical unit (ESU). METHODS: This was an ex vivo study. Step one: to identify the novel efficiency indicators, 20 endoscopists performed one ESD each, and we analyzed correlations between their resection speed and electrical status. Step two: to identify the novel precision indicators, three experts and three novices performed one ESD each, and we compared the stability of the electrical status. Step three: three novices in step two performed 19 additional ESDs, and we analyzed the learning curve using novel indicators. RESULTS: Step one: the percentage of total activation time (AT) of ESU in the procedure time (ß coefficient, 0.80; P < 0.01) and AT required for submucosal dissection (ß coefficient, -0.57; P < 0.01) were significantly correlated with the resection speed. Step two: coefficient of variation of the AT per one pulse (0.16 [range, 0.13-0.17] vs. 0.26 [range, 0.20-0.41], P = 0.049) and coefficient of variation of the peak electric power per pulse during mucosal incision (0.14 [range, 0.080-0.15] vs. 0.25 [range, 0.24-0.28], P = 0.049) were significantly lower in the experts than in the novices. Regarding the learning curve, the percentage of total AT of ESU in the procedure time and AT required for submucosal dissection had a trend of improvement. CONCLUSION: Novel indicators identified by analyzing ESU enable quantitative assessment for endoscopist's skill.

Chitosan bioactive glass scaffolds for in vivo subcutaneous implantation, toxicity assessment, and diabetic wound healing upon animal model.

This study aims to develop chitosan-bioactive glass (BG) scaffolds for diabetic wound healing, toxicity valuation, and subcutaneous implantation in animals for biocompatibility assessment. The scaffolds were prepared by lyophilization technique. In specific BG without sodium (Na), composited with chitosan for better biological activities. The equipped scaffolds were studied for their physiochemical, biological, in vitro and in vivo performances. The chitosan and chitosan-BG (Na free) scaffolds show reliable biocompatibility, cytocompatibility, anti-oxidant, and tissue regeneration. The biocompatibility, toxicity assessments, and diabetic skin wound healing experiments were examined through in vivo studies using Sprague Dawley rats. The extracted tissue samples were analyzed using hematoxylin-eosin- (H and E) and Masson's trichrome staining. Further, tissue excised after scaffold implantation declared non-toxic, non-allergic, and anti-inflammatory nature of chitosan scaffolds. Moreover, the total ribonucleic acid (RNA) expression levels were measured using reverse transcription-polymerase chain reaction (RT-PCR) for the scaffolds against vascular endothelial growth factor (VEGF), and collagen type one (Col-1) primers. Admirably, the scaffolds achieved the best level of skin wound healing via tissue regeneration by increasing epithetical cell formation and collagen deposition. Thus, the biocompatibility, non-toxicity, anti-inflammatory, and wound healing efficiency proved that the chitosan-BG (Na free) scaffold can be readily substantial for wound healing.

Animal models in peripheral nerve transection studies: a systematic review on study design and outcomes assessment.

Aim: Peripheral nerve injury regeneration studies using animal models are crucial to different pre-clinical therapeutic approaches efficacy evaluation whatever the surgical technique explored. Materials & methods: A 944 articles systematic review on 'peripheral nerve injury in animal models' over the last 9 years was carried out. Results: It was found that 91% used rodents, and only 9% employed large animals. Different nerves are studied, with generated gaps (10,78 mm) and methods applied for regeneration evaluation uniformed. Sciatic nerve was the most used (88%), followed by median and facial nerves (2.6%), significantly different. Conclusion: There has not been a significant scale-up of the in vivo testing to large animal models (anatomically/physiologically closer to humans), allowing an improvement in translational medicine for clinical cases.

Rodents as an animal model for studying tooth extraction-related medication-related osteonecrosis of the jaw: assessment of outcomes.

OBJECTIVE: To assess the outcomes of several rodent animal models for studying tooth extraction-related medication-related osteonecrosis of the jaw (MRONJ). DESIGN: After a search of the databases, 2004 articles were located, and 118 corroborated the inclusion factors (in vivo studies in rodents evaluating tooth extraction as a risk factor for the development of MRONJ). RESULTS: Numerous studies attempting to establish an optimal protocol to induce MRONJ were found. Zoledronic acid (ZA) was the most used drug, followed by alendronate (ALN). Even when ZA did not lead to the development of MRONJ, its effect compromised the homeostasis of the bone and soft tissue. The association of other risk factors (dexamethasone, diabetes, and tooth-related inflammatory dental disease) besides tooth extraction also played a role in the development of MRONJ. In addition, studies demonstrated a relationship between cumulative dose and MRONJ. CONCLUSIONS: Both ZA and ALN can lead to MRONJ in rodents when equivalent human doses (in osteoporosis or cancer treatment) are used. Local oral risk factors and tooth-related inflammatory dental disease increase the incidence of MRONJ in a tooth extraction-related rodent model.

Molnupiravir Revisited-Critical Assessment of Studies in Animal Models of COVID-19.

Molnupiravir, a prodrug known for its broad antiviral activity, has demonstrated efficacy in animal models of COVID-19, prompting clinical trials, in which initial results indicated a significant effect against the disease. However, subsequent clinical studies did not confirm these findings, leading to the refusal of molnupiravir for permanent market authorization in many countries. This report critically assessed 22 studies published in 18 reports that investigated the efficacy of molnupiravir in animal models of COVID-19, with the purpose of determining how well the design of these models informed human studies. We found that the administered doses of molnupiravir in most studies involving animal COVID-19 models were disproportionately higher than the dose recommended for human use. Specifically, when adjusted for body surface area, over half of the doses of molnupiravir used in the animal studies exceeded twice the human dose. Direct comparison of reported drug exposure across species after oral administration of molnupiravir indicated that the antiviral efficacy of the dose recommended for human use was underestimated in some animal models and overestimated in others. Frequently, molnupiravir was given prophylactically or shortly after SARS-CoV-2 inoculation in these models, in contrast to clinical trials where such timing is not consistently achieved. Furthermore, the recommended five-day treatment duration for humans was exceeded in several animal studies. Collectively, we suggest that design elements in the animal studies under examination contributed to a preference favoring molnupiravir, and thus inflated expectations for its efficacy against COVID-19. Addressing these elements may offer strategies to enhance the clinical efficacy of molnupiravir for the treatment of COVID-19. Such strategies include dose increment, early treatment initiation, administration by inhalation, and use of the drug in antiviral combination therapy.

Assessment of Inner Blood-Retinal Barrier: Animal Models and Methods.

Proper functioning of the neural retina relies on the unique retinal environment regulated by the blood-retinal barrier (BRB), which restricts the passage of solutes, fluids, and toxic substances. BRB impairment occurs in many retinal vascular diseases and the breakdown of BRB significantly contributes to disease pathology. Understanding the different molecular constituents and signaling pathways involved in BRB development and maintenance is therefore crucial in developing treatment modalities. This review summarizes the major molecular signaling pathways involved in inner BRB (iBRB) formation and maintenance, and representative animal models of eye diseases with retinal vascular leakage. Studies on Wnt/ß-catenin signaling are highlighted, which is critical for retinal and brain vascular angiogenesis and barriergenesis. Moreover, multiple in vivo and in vitro methods for the detection and analysis of vascular leakage are described, along with their advantages and limitations. These pre-clinical animal models and methods for assessing iBRB provide valuable experimental tools in delineating the molecular mechanisms of retinal vascular diseases and evaluating therapeutic drugs.

Assessment of Hepatic Lesions After non-Thermal Tumor Ablation by Irreversible Electroporation in a Pig Model.

Irreversible electroporation (IRE) is a non-thermal and minimal invasive modality to ablate pathologic lesions such as hepatic tumors. Histological analysis of the initial lesions after IRE can help predict ablation efficacy. We aimed to investigate the histological characteristics of early hepatic lesions after IRE application using animal models. IRE (1500 V/cm, a pulse length of 100 µs, 60 or 90 pulses) was applied to the liver of miniature pigs. H&E and TUNEL staining were performed and analyzed. Ablated zones of pig liver were discolored and separated from the normal zone after IRE. Histologic characteristics of ablation zones included preserved hepatic lobular architecture with a unique hexagonal-like structure. Apoptotic cells were detected, and sinusoidal dilatation and blood congestion were observed, but hepatic arteries and bile ducts were intact around the ablation zones. The early lesions obtained by delivering monophasic square wave pulses through needle electrodes reflected typical histological changes induced by IRE. Therefore, it was found that the histological assessment of the early hepatic lesion after IRE can be utilized to predict the IRE ablation effect.

Hepatic Hypertrophy in Normal and Cirrhotic Livers Following Portal Vein Embolization: Comparative Assessment of 2 Different Embolic Regimens in a Large Animal Model.

PURPOSE: To compare the mechanistic effects and hypertrophy outcomes using 2 different portal vein embolization (PVE) regimens in normal and cirrhotic livers in a large animal model. METHODS AND MATERIALS: The Institutional Animal Care and Use Committee approved all experiments conducted in this study. Fourteen female Yorkshire pigs were separated into a cirrhotic group (CG, n = 7) and non-cirrhotic group (NCG, n = 7) and further subgrouped into those using microspheres and coils (MC, n = 3) or n-butyl cyanoacrylate (nBCA, n = 3) and their corresponding controls (each n = 1). A 3:1 ethiodized oil and ethanol mixture was administered intra-arterially in the CG to induce cirrhosis 4 weeks before PVE. Animals underwent baseline computed tomography (CT), PVE including pre-PVE and post-PVE pressure measurements, and CT imaging at 2 and 4 weeks after PVE. Immunofluorescence stainings for CD3, CD16, Ki-67, and caspase 3 were performed to assess immune cell infiltration, hepatocyte proliferation, and apoptosis. Statistical significance was tested using the Student's t test. RESULTS: Four weeks after PVE, the percentage of future liver remnant (FLR%) increased by 18.8% (standard deviation [SD], 3.6%) vs 10.9% (SD, 0.95%; P < .01) in the NCG vs CG. The baseline percentage of standardized future liver remnant (sFLR%) for the controls were 41.6% for CG vs 43.6% for NCG. Based on the embolic agents used, the sFLR% two weeks after PVE was 58.4% (SD, 3.7%) and 52.2% (SD, 0.9%) (P < .01) for MC and 46.0% (SD, 2.2%) and 47.2% (SD, 0.4%) for nBCA in the NCG and CG, respectively. Meanwhile, the sFLR% 4 weeks after PVE was 60.5% (SD, 3.9%) and 54.9% (SD, 0.8%) (P < .01) and 60.4% (SD, 3.5%) and 54.2% (SD, 0.95%) (P < .01), respectively. Ki-67 signal intensity increased in the embolized lobe in both CG and NCG (P < .01). CONCLUSIONS: This preclinical study demonstrated that MC could be the preferred embolic of choice compared to nBCA when a substantial and rapid FLR increase is needed for resection, in both cirrhotic and non-cirrhotic livers.

In Vitro and In Vivo Bone Regeneration Assessment of Titanium-Doped Waste Eggshell-Derived Hydroxyapatite in the Animal Model.

In this work, a titanium-doped hydroxyapatite (HAp) scaffold was produced from two different sources (natural eggshell and laboratory-grade reagents) to compare the efficacy of natural and synthetic resources of HAp materials on new bone regeneration. This comparative study also reports the effect of Ti doping on the physical, mechanical, and in vitro as well as in vivo biological properties of the HAp scaffold. Pellets were prepared in the conventional powder metallurgy route, compacted, and sintered at 900 °C, showing sufficient porosity for bony ingrowth. The physical-mechanical characterizations were performed by density, porosity evaluation, XRD, FTIR, SEM analysis, and hardness measurement. In vitro interactions were evaluated by bactericidal assay, hemolysis, MTT assay, and interaction with simulated body fluid. All categories of pellets showed absolute nonhemolytic and nontoxic character. Furthermore, significant apatite formation was observed on the Ti-doped HAp samples in the simulated body fluid immersion study. The developed porous pellets were implanted to assess the bone defect healing in the femoral condyle of healthy rabbits. A 2 month study after implantation showed no marked inflammatory reaction for any samples. Radiological analysis, histological analysis, SEM analysis, and oxytetracycline labeling studies depicted better invasion of mature osseous tissue in the pores of doped eggshell-derived HAp scaffolds as compared to the undoped HAp, and laboratory-made samples. Quantification using oxytetracycline labeling depicted 59.31 ± 1.89% new bone formation for Ti-doped eggshell HAp as compared to Ti-doped pure HAp (54.41 ± 1.93) and other undoped samples. Histological studies showed the presence of abundant osteoblastic and osteoclastic cells in Ti-doped eggshell HAp in contrast to other samples. Radiological and SEM data also showed similar results. The results indicated that Ti-doped biosourced HAp samples have good biocompatibility, new bone-forming ability, and could be used as a bone grafting material in orthopedic surgery.

Early assessment of acute kidney injury in severe acute pancreatitis with multimodal DWI: an animal model.

OBJECTIVES: To evaluate the feasibility of multimodal diffusion-weighted imaging (DWI) for detecting the occurrence and severity of acute kidney injury (AKI) caused by severe acute pancreatitis (SAP) in rats. METHODS: SAP was induced in thirty rats by the retrograde injection of 5.0% sodium taurocholate through the biliopancreatic duct. Six rats underwent MRI of the kidneys 24 h before and 2, 4, 6, and 8 h after this AKI model was generated. Conventional and functional MRI sequences were used, including intravoxel incoherent motion imaging (IVIM), diffusion tensor imaging (DTI), and diffusion kurtosis imaging (DTI). The main DWI parameters and histological results were analyzed. RESULTS: The fast apparent diffusion coefficient (ADC) of the renal cortex was significantly reduced at 2 h, as was the fractional anisotropy (FA) value of the renal cortex on DTI. The mean kurtosis (MK) values for the renal cortex and medulla gradually increased after model generation. The renal histopathological score was negatively correlated with the medullary slow ADC, fast ADC, and perfusion scores for both the renal cortex and medulla, as were the ADC and FA values of the renal medulla in DTI, whereas the MK values of the cortex and medulla were positively correlated (r = 0.733, 0.812). Thus, the cortical fast ADC, medullary MK, FADTI, and slow ADC were optimal parameters for diagnosing AKI. Of these parameters, cortical fast ADC had the highest diagnostic efficacy (AUC = 0.950). CONCLUSIONS: The fast ADC of the renal cortex is the core indicator of early AKI, and the medullary MK value might serve as a sensitive biomarker for grading renal injury in SAP rats. CLINICAL RELEVANCE STATEMENT: The multimodal parameters of renal IVIM, DTI, and DKI are potential beneficial for the early diagnosis and severity grading of renal injury in SAP patients. KEY POINTS: • The multimodal parameters of renal DWI, including IVIM, DTI, and DKI, may be valuable for the noninvasive detection of early AKI and the severity grading of renal injury in SAP rats. • Cortical fast ADC, medullary MK, FA, and slow ADC are optimal parameters for early diagnosis of AKI, and cortical fast ADC has the highest diagnostic efficacy. • Medullary fast ADC, MK, and FA as well as cortical MK are useful for predicting the severity grade of AKI, and the renal medullary MK value exhibits the strongest correlation with pathological scores.

Nano eggshell-based slurry as a direct pulp-capping material: In vitro characterization and histopathological assessment in an experimental animal model.

AIM: Pulp vitality is essential for tooth integrity. Following pulp exposure, choosing a suitable pulp-capping material is crucial to maintain pulp vitality. However, the reparative dentine bridge created by calcium hydroxide (Ca(OH)2 ) is generally porous and incomplete. The aim of the current study is to assess the in vitro and in vivo bioactivities of nano eggshell-based slurry (NES), using NES as a direct pulp-capping material, compared with Ca(OH)2 in rabbit animal model. METHODOLOGY: Nano eggshell powder (NE) was characterized for particle morphology, chemical composition and ion release. In vitro bioactivity was tested by immersion in simulated body fluid (SBF) for 7 days. For histopathological evaluation, 36 adult New Zealand rabbits (72 pulp exposures) were divided into nine groups (n = 8) according to the pulp-capping material (NES, Ca(OH)2 and no capping as negative control group) and the animals were sacrificed after 7, 14 or 28 days. The pulps of the two lower central incisors were exposed and then directly capped by Ca(OH)2 or NES or left untreated. The cavities were then sealed with glass ionomer cement. Teeth were collected for histopathological evaluation using an optical microscope. Pulp haemorrhage, inflammation, fibrosis and calcific bridge formation were assessed. Results were statistically analysed using anova and Tukey's tests. RESULTS: Nano eggshell particles were spherical with a 20 nm diameter and were composed mainly of calcite. Statistical analysis showed that there was a significant increase in the release of all investigated ions between days 1 and 28, except for copper. NES group showed a significantly higher release of all elements as compared to Ca(OH)2 . Environmental scanning electron microscope micrographs of NES incubated for 7 days in SBF showed the formation of HAp with a Ca/P ratio (1.686). For histopathological evaluation, the difference between groups was statistically significant. At day 28, 75% of the pulps of the Ca(OH)2 group showed mild calcific bridge in comparison with 100% moderate calcific bridge in the NES group. The NES group showed significantly less inflammation at days 7 and 28, and higher fibrosis at day 7 compared with Ca(OH)2 . CONCLUSIONS: Nano eggshell-based slurry represents a promising novel direct pulp-capping material with favourable pulp tissue response.

Evaluation and assessment of clique arrangements for the estimation of omnipolar electrograms in high density electrode arrays: an experimental animal model study.

High-density catheters combined with Orientation Independent Sensing (OIS) methods have emerged as a groundbreaking technology for cardiac substrate characterisation. In this study, we aim to assess the arrangements and constraints to reliably estimate the so-called omnipolar electrogram (oEGM). Performance was evaluated using an experimental animal model. Thirty-eight recordings from nine retrospective experiments on isolated perfused rabbit hearts with an epicardial HD multielectrode were used. We estimated oEGMs according to the classic triangular clique (4 possible orientations) and a novel cross-orientation clique arrangement. Furthermore, we tested the effects of interelectrode spacing from 1 to 4 mm. Performance was evaluated by means of several parameters that measured amplitude rejection ratios, electric field loop area, activation pulse width and morphology distortion. Most reliable oEGM estimations were obtained with cross-configurations and interelectrode spacings [Formula: see text] mm. Estimations from triangular cliques resulted in wider electric field loops and unreliable detection of the direction of the propagation wavefront. Moreover, increasing interelectrode distance resulted in increased pulse width and morphology distortion. The results prove that current oEGM estimation techniques are insufficiently accurate. This study opens a new standpoint for the design of new-generation HD catheters and mapping software.

Of Men and Mice: Using Terrestrial Radiation Epidemiology Methods to Inform Analysis of Animal Models for Space Radiation Risk Assessment.

Prediction of cancer risk from space radiation exposure is critical to ensure spaceflight crewmembers are adequately informed of the risks they face when accepting assignments to ambitious long-duration exploratory missions. Although epidemiological studies have assessed the effects of exposure to terrestrial radiation, no robust epidemiological studies of humans exposed to space radiation exist to support estimates of the risk from space radiation exposure. Mouse data derived from recent irradiation experiments provides valuable information to successfully develop mouse-based excess risks models for assessing relative biological effectiveness for heavy ions that can provide information to scale unique space radiation exposures so that excess risks estimated for terrestrial radiation can be adjusted for space radiation risk assessment. Bayesian analyses were used to simulate linear slopes for excess risk models with several different effect modifiers for attained age and sex. Relative biological effectiveness values for all-solid cancer mortality were calculated from the ratio of the heavy-ion linear slope to the gamma linear slope using the full posterior distribution and resulted in values that were substantially lower than what is currently applied in risk assessment. These analyses provide an opportunity to improve characterization of parameters used in the current NASA Space Cancer Risk (NSCR) model and generate new hypotheses for future animal experiments using out-bred mouse populations.

Assessment of Large Animal Vascular Dimensions for Intra-Aortic Device Research and Development: A Systematic Review.

Animal studies are often required to evaluate new cardiovascular medical devices before they reach the market. Moreover, first-generation novel devices including aortic endovascular prostheses and circulatory support devices are often larger than later iterations or tested in a limited range of sizes. One of the challenges in evaluating these devices is finding a model that is both accessible and anatomically similar to humans, as there is a paucity of data on vascular dimensions in large animals. We set out to complete a comprehensive review of available reports on vascular dimensions in swine, ovine, and bovine models, with a particular focus on the descending aorta and ilio-femoral arteries. We searched Embase and MEDLINE databases for reports of descending aorta and peripheral vascular dimension in large animal models. Data from swine, ovine, and bovine models were separated by weight into 3 categories: 40 to 60 kg, 61 to 80 kg, and >80 kg. We also incorporate our computed tomography angiography data from 4 large sheep and 9 calves into this review. Swine, sheep, and calf >80 kg may serve as the best models to maximize aortic diameter resemblance to humans. If device implantation can be achieved in aortas of smaller dimensions, care should be taken to ensure access site suitability such as the common femoral artery in these smaller animals.

Assessment of genomic breeding values and their accuracies for carcass traits in Jeju Black cattle using whole-genome SNP chip panels.

The objective of the present study was to evaluate the breeding value and accuracy of genomic estimated breeding values (GEBVs) of carcass traits in Jeju Black cattle (JBC) using Hanwoo steers and JBC as a reference population using the single-trait animal model. Our research included genotype and phenotype information on 19,154 Hanwoo steers with 1097 JBC acting as the reference population. Likewise, the test population consisted of 418 genotyped JBC individuals with no phenotypic records for those carcass traits. For estimating the accuracy of GEBV, we divided the entire population into three groups. Hanwoo and JBC make up the first group; Hanwoo and JBC, who has both the genotype and phenotypic records, are referred to as the reference (training) population, and JBC, who lacks phenotypic information is referred to as the test (validation) population. The second group consists of the JBC (without phenotype) as the test population and Hanwoo as a reference population with phenotype and genotypic data. The only JBCs in the third group are those who have genotypic and phenotypic data on them as a reference population but no phenotypic data on them as a test population. The single-trait animal model was used in all three groups for statistical purposes. The reference populations estimated heritabilities for carcass weight (CWT), eye muscle area (EMA), backfat thickness (BF), and marbling score (MS) as 0.30, 0.26, 0.26, and 0.34 for the Hanwoo steer and 0.42, 0.27, 0.26, and 0.48 for JBC. The average accuracy for carcass traits in Group 1 was 0.80 for the Hanwoo and JBC reference population compared with 0.73 for the JBC test population. Although the average accuracy for carcass traits in Group 2 was 0.80, it was 0.80 for the Hanwoo reference population and only 0.56 for the JBC test population. The average accuracy for the JBC reference and test populations was 0.68 and 0.50, respectively, when they were included in the accuracy comparison without the Hanwoo reference population. Groups 1 and 2 used Hanwoo as reference population, which led to a better average accuracy; however, Group 3 only used the JBC reference and test population, which led to a lower average accuracy. This might be due to the fact that Group 3 used a smaller reference size than the group that came before it and that the genetic makeup of the Hanwoo and JBC breeds differed. The GEBV accuracy for MS was higher than that of other traits across all three analysis groups, followed by CWT, EMA, and BF, which may be partially explained by the MS traits' higher heritability. This study suggests that in order to achieve more accuracy, a large reference population particular to a breed should be established. Therefore, to increase the accuracy of GEBV prediction and the genetic benefit from genomic selection in JBC, individual reference breeds, and large populations are required.

Determining the Delamanid Pharmacokinetics/Pharmacodynamics Susceptibility Breakpoint Using Monte Carlo Experiments.

Antimicrobial susceptibility testing, based on clinical breakpoints that incorporate pharmacokinetics/pharmacodynamics (PK/PD) and clinical outcomes, is becoming a new standard in guiding individual patient therapy as well as for drug resistance surveillance. However, for most antituberculosis drugs, breakpoints are instead defined by the epidemiological cutoff values of the MIC of phenotypically wild-type strains irrespective of PK/PD or dose. In this study, we determined the PK/PD breakpoint for delamanid by estimating the probability of target attainment for the approved dose administered at 100 mg twice daily using Monte Carlo experiments. We used the PK/PD targets (0- to 24-h area under the concentration-time curve to MIC) identified in a murine chronic tuberculosis model, hollow fiber system model of tuberculosis, early bactericidal activity studies of patients with drug-susceptible tuberculosis, and population pharmacokinetics in patients with tuberculosis. At the MIC of 0.016 mg/L, determined using Middlebrook 7H11 agar, the probability of target attainment was 100% in the 10,000 simulated subjects. The probability of target attainment fell to 25%, 40%, and 68% for PK/PD targets derived from the mouse model, the hollow fiber system model of tuberculosis, and patients, respectively, at the MIC of 0.031 mg/L. This indicates that an MIC of 0.016 mg/L is the delamanid PK/PD breakpoint for delamanid at 100 mg twice daily. Our study demonstrated that it is feasible to use PK/PD approaches to define a breakpoint for an antituberculosis drug.

Animal model assessment of a new design for a coated mitomycin-eluting biodegradable ureteral stent for intracavitary instillation as an adjuvant therapy in upper urothelial carcinoma.

BACKGROUND: A major limitation in the treatment of upper urinary tract urothelial carcinoma is the limited use of adjuvant therapy due to the drawbacks of current techniques for intracavitary instillation. The aim was to assess, in a large animal model, a biodegradable ureteral stent coated with silk fibroin for mitomycin release, i.e. BraidStent-SF-MMC. METHODS: A total of 14 female pigs with a solitary kidney underwent initial urinalysis, blood chemistry, nephrosonographic, and contrast fluoroscopy assessment of the urinary tract. Later, the BraidStent-SF-MMC was placed retrogradely to assess the mitomycin urine concentration from 0-48 hours. Follow-up was performed weekly until complete stent degradation to assess the macroscopic and microscopic changes in the urinary tract, stent complications. RESULTS: The drug eluting stent released mitomycin for the first 12 h. The main complication was the release of obstructive ureteral coating fragments during the first to third week in 28.5 and 7.1% of animals, respectively, related to urinary pH<7.0, which destabilized the stent coating. Another complication was ureteral strictures between the fourth and sixth week in 21%. The stents were completely degraded by 6-7 weeks. There were no stent-related systemic toxic effects. The success rate was 67.5% and the complication rate was 25.7%. CONCLUSIONS: For the first time, we have shown that a biodegradable anti-cancer drug eluting stent, BraidStent-SF-MMC, provides controlled and well-tolerated release of mitomycin into the upper urinary tract in an animal model. Mitomycin release from a silk fibroin coating could be a compelling approach for adjuvant chemotherapy instillation in upper tract urothelial carcinoma management.