A local drug delivery system prolongs graft survival by dampening T cell infiltration and neutrophil extracellular trap formation in vascularized composite allografts.

Introduction: The standard treatment for preventing rejection in vascularized composite allotransplantation (VCA) currently relies on systemic immunosuppression, which exposes the host to well-known side effects. Locally administered immunosuppression strategies have shown promising results to bypass this hurdle. Nevertheless, their progress has been slow, partially attributed to a limited understanding of the essential mechanisms underlying graft rejection. Recent discoveries highlight the crucial involvement of innate immune components, such as neutrophil extracellular traps (NETs), in organ transplantation. Here we aimed to prolong graft survival through a tacrolimus-based drug delivery system and to understand the role of NETs in VCA graft rejection. Methods: To prevent off-target toxicity and promote graft survival, we tested a locally administered tacrolimus-loaded on-demand drug delivery system (TGMS-TAC) in a multiple MHC-mismatched porcine VCA model. Off-target toxicity was assessed in tissue and blood. Graft rejection was evaluated macroscopically while the complement system, T cells, neutrophils and NETs were analyzed in graft tissues by immunofluorescence and/or western blot. Plasmatic levels of inflammatory cytokines were measured using a Luminex magnetic-bead porcine panel, and NETs were measured in plasma and tissue using DNA-MPO ELISA. Lastly, to evaluate the effect of tacrolimus on NET formation, NETs were induced in-vitro in porcine and human peripheral neutrophils following incubation with tacrolimus. Results: Repeated intra-graft administrations of TGMS-TAC minimized systemic toxicity and prolonged graft survival. Nevertheless, signs of rejection were observed at endpoint. Systemically, there were no increases in cytokine levels, complement anaphylatoxins, T-cell subpopulations, or neutrophils during rejection. Yet, tissue analysis showed local infiltration of T cells and neutrophils, together with neutrophil extracellular traps (NETs) in rejected grafts. Interestingly, intra-graft administration of tacrolimus contributed to a reduction in both T-cellular infiltration and NETs. In fact, in-vitro NETosis assessment showed a 62-84% reduction in NETs after stimulated neutrophils were treated with tacrolimus. Conclusion: Our data indicate that the proposed local delivery of immunosuppression avoids off-target toxicity while prolonging graft survival in a multiple MHC-mismatch VCA model. Furthermore, NETs are found to play a role in graft rejection and could therefore be a potential innovative therapeutic target.

Utility of Cadaveric Porcine Heads for Teaching Oral Surgical Procedures in an Australian Dental School: A Pilot Study.

Background/Objectives: Cadaveric models have traditionally been a mainstay of dental and medical education worldwide since their inception. In Australia, educators at dental schools were among the first to use cadaveric porcine heads in formal teaching in oral surgery. This practice has since fallen out of favour in most modern dental curricula. The aim of this pilot study was to determine the utility of cadaveric porcine models for oral surgery training from a student perspective (Griffith University, Gold Coast, Australia). Methods: Thirty participants who were all third-year dental students attended a two-hour session comprising a 30 min lecture followed by a 90 min practical workshop. The lecture outlined the steps and supervision of students during the practical and was provided by a consultant maxillofacial surgeon. At the conclusion of the workshop, participants were asked to anonymously complete a printed questionnaire with eight questions related to their experience. Results: Prior to the workshop, two-thirds (61%) of participants felt that they had been taught the surgical procedure for raising mucoperiosteal flaps adequately in their dental school curriculum during their third year, although only 43% of students had assisted specialty residents in raising a mucoperiosteal flap and 14% reported having performed the procedure themselves. Almost all students (96%) agreed that the porcine model was useful for their dental education and that they would practice the exercise using the model again if provided with the opportunity. The questionnaire had a 93.33% completion rate. Conclusions: This pilot study indicates that porcine heads present a useful, low-cost adjunct in the learning of basic oral surgical procedures.

Open cranium model for the study of cerebrovascular dynamics in intracranial hypertension.

BACKGROUND: Significant research has been devoted to developing noninvasive approaches to neuromonitoring. Clinical validation of such approaches is often limited, with minimal data available in the clinically relevant elevated ICP range. NEW METHOD: To allow ultrasound-guided placement of an intraventricular catheter and to perform simultaneous long-duration ICP and ultrasound recordings of cerebral blood flow, we developed a large unilateral craniectomy in a swine model. We also used a microprocessor-controlled actuator for intraventricular saline infusion to reliably and reversibly manipulate ICP according to pre-determined profiles. RESULTS: The model was reproducible, resulting in over 80 hours of high-fidelity, multi-parameter physiological waveform recordings in twelve animals, with ICP ranging from 2 to 78 mmHg. ICP elevations were reversible and reproducible according to two predetermined profiles: a stepwise elevation up to an ICP of 30-35 mmHg and return to normotension, and a clinically significant plateau wave. Finally, ICP was elevated to extreme levels of greater than 60 mmHg, simulating extreme clinical emergency. COMPARISON WITH EXISTING METHODS: Existing methods for ICP monitoring in large animals typically relied on burr-hole approaches for catheter placement. Accurate catheter placement can be difficult in pigs, given the thickness of their skull. Additionally, ultrasound is significantly attenuated by the skull. The open cranium model overcomes these limitations. CONCLUSIONS: The hemicraniectomy model allowed for verified placement of the intraventricular catheter, and reversible and reliable ICP manipulation over a wide range. The large dural window additionally allowed for long-duration recording of cerebral blood flow velocity from the middle cerebral artery.

Standardized porcine integrated robotic inguinal hernia training: the SPIRIT model.

BACKGROUND: Implementing a robotic system for minimally invasive surgical procedures necessitates a comprehensive training regimen. This involves not only mastering the technological aspects of the robotic system but also enhancing surgical proficiency in manipulating robotic instruments. Furthermore, procedural expertise in specific surgeries is critical. Minimally invasive inguinal hernia repair is particularly suitable as an initial procedure for human application. The development of a comprehensive training model for this type of repair is a crucial element of such an educational pathway. METHOD: Anatomical dissections were carried out on pigs to assess both the similarities and differences between pig and human anatomy. A structured minimally invasive inguinal hernia repair was performed to determine the suitability of the porcine inguinal region for training purposes. RESULTS: A detailed anatomical description of the porcine inguinal region is outlined, to provide a framework for assessing the critical view of the porcine myopectineal orifice. By integrating the human 'ten golden rules' for safe and effective minimally invasive inguinal hernia repair, the standardized porcine integrated robotic inguinal hernia training (SPIRIT) model describes a step-by-step approach to practice surgical techniques in a realistic setting. CONCLUSION: The SPIRIT model is designed to be a well-structured training model for minimally invasive inguinal hernia repair and incorporates the specific surgical steps as encountered in a human patient.

Infliximab Limits Injury in Myocardial Infarction.

BACKGROUND: The purpose of this study was to investigate a therapeutic approach targeting the inflammatory response and consequent remodeling from ischemic myocardial injury. METHODS AND RESULTS: Coronary thrombus aspirates were collected from patients at the time of ST-segment-elevation myocardial infarction and subjected to array-based proteome analysis. Clinically indistinguishable at myocardial infarction (MI), patients were stratified into vulnerable and resilient on the basis of 1-year left ventricular ejection fraction and death. Network analysis from coronary aspirates revealed prioritization of tumor necrosis factor-α signaling in patients with worse clinical outcomes. Infliximab, a tumor necrosis factor-α inhibitor, was infused intravenously at reperfusion in a porcine MI model to assess whether infliximab-mediated immune modulation impacts post-MI injury. At 3 days after MI (n=7), infliximab infusion increased proregenerative M2 macrophages in the myocardial border zone as quantified by immunofluorescence (24.1%±23.3% in infliximab versus 9.29%±8.7% in sham; P<0.01). Concomitantly, immunoassays of coronary sinus samples quantified lower troponin I levels (41.72±7.34 pg/mL versus 58.11±10.75 pg/mL; P<0.05) and secreted protein analysis revealed upregulation of injury-modifying interleukin-2, -4, -10, -12, and -18 cytokines in the infliximab-treated cohort. At 4 weeks (n=12), infliximab treatment resulted in significant protective influence, improving left ventricular ejection fraction (53.9%±5.4% versus 36.2%±5.3%; P<0.001) and reducing scar size (8.31%±10.9% versus 17.41%±12.5%; P<0.05). CONCLUSIONS: Profiling of coronary thrombus aspirates in patients with ST-segment-elevation MI revealed highest association for tumor necrosis factor-α in injury risk. Infliximab-mediated immune modulation offers an actionable pathway to alter MI-induced inflammatory response, preserving contractility and limiting adverse structural remodeling.

Safe and effective hybrid endoscopic submucosal dissection with ALL IN ONE snare in porcine gastric model (with video).

This study aimed to evaluate the safety and efficiency of hybrid endoscopic submucosal dissection (H-ESD) using a newly developed ALL IN ONE (AIO) snare. This was a matched control study in a porcine model. Five paired simulated stomach lesions 2-2.5 cm in size were removed by H-ESD using an AIO snare or conventional ESD (C-ESD) using an endoscopic knife. The outcomes of the two procedures were compared, including en-bloc resection rates, procedure times, intraprocedural bleeding volumes, muscular injuries, perforations, thicknesses of the submucosal layer in resected specimens, and stomach defects. All simulated lesions were resected en-bloc. Specimens resected by H-ESD and C-ESD were similar in size (7.68 ± 2.92 vs. 8.42 ± 2.42 cm2; P = 0.676). H-ESD required a significantly shorter procedure time (13.39 ± 3.78 vs. 25.99 ± 4.52 min; P = 0.031) and submucosal dissection time (3.99 ± 1.73 vs. 13.1 ± 4.58 min; P = 0.003) versus C-ESD; H-ESD also yielded a faster dissection speed (241.37 ± 156.84 vs. 68.56 ± 28.53 mm2/min; P = 0.042) and caused fewer intraprocedural bleeding events (0.40 ± 0.55 vs. 3.40 ± 1.95 times/per lesion; P = 0.016) than C-ESD. The thicknesses of the submucosal layer of the resected specimen (1190.98 ± 134.07 vs. 1055.90 ± 151.76 µm; P = 0.174) and the residual submucosal layer of the stomach defect (1607.94 ± 1026.74 vs. 985.98 ± 445.58 µm; P = 0.249) were similar with both procedures. The AIO snare is a safe and effective device for H-ESD and improves the treatment outcomes of gastric lesions by shortening the procedure time.

Descriptive Anatomy of the Porcine Ventral Abdominal Wall as a Basis for Training Ventral Hernia Repair Techniques.

Background: In recent times there has been a surge in innovative techniques concerning complex abdominal wall surgery. The availability of simulation models for comprehensive training and skill set development remains limited. Methods: Cadaveric dissections of the porcine abdominal wall were conducted to assess the suitability of anesthetized porcine models for training in both minimally invasive and open surgical procedures. Results: The panniculus carnosus, a typical muscular layer in mammals, is the outermost layer covering the anterolateral abdominal wall. Beneath it, there are four main pairs of abdominal wall muscles, mirroring the human anatomy. The rectus abdominis muscle runs straight along the linea alba and is surrounded by the rectus sheath, which is formed by the fusion of the lateral abdominal wall muscles and differs along the different regions of abdominal wall. The orientation of the muscle fibers in the lateral abdominal wall muscles, i.e., musculus obliquus externus, internus and transversus, is comparable to human anatomy. Although the transition lines between their muscular and aponeurotic part differ to some extent. Relevant for the adoption of surgical techniques, the transversus abdominis muscle is well-developed and resembles a bell curve shape as it transitions from its muscular to aponeurotic part. Conclusion: Despite minor differences in abdominal wall anatomy between pigs and humans, the porcine model provides a high level of fidelity in terms of both anatomical features and the development of skill sets relevant to hernia surgery.

Effects of maternal supplementation with DHA and/or egg yolk powder on monoamine homeostasis in the perinatal piglet brain.

OBJECTIVES: Reports indicate that children of mothers who received docosahexaenoic acid (DHA) or egg yolk supplements during pregnancy have improved performance on cognitive tasks and brain growth; their combination has recently been demonstrated to modulate functional neuronal network connectivity in the human-relevant piglet brain. To expand upon this functional connectivity analysis, neurochemical evaluation to determine how dietary supplementation with one or both of these nutrients during the last trimester of pregnancy alters monoamine homeostasis in selected brain regions of piglets was done. METHODS: Beginning gestation days 60-69 through weaning, pregnant sows were fed either control diet or diets supplemented with egg yolk powder, DHA, or both. Brains were then collected, and monoamine neurotransmitters and their metabolites were quantified from various brain regions with HPLC-ECD. RESULTS: Relative to controls, egg yolk supplementation increased serotonin metabolite (5-HIAA) levels in the cerebellum, while DHA supplementation decreased serotonin (5-HT) levels in the prefrontal cortex; combined supplementation increased norepinephrine metabolite (MHPG) levels in the prefrontal cortex and cerebellum, but decreased 5-HT levels in the posterior hippocampus. Notably, all diets increased serotonin, dopamine, and their respective metabolite levels in the substantia nigra. DISSCUSSION: This suggests both overlapping and specific effects of DHA and components of egg yolk in the context of maternal supplementation during pregnancy and lactation that might facilitate optimal neurodevelopment, with the nigrostriatal pathway being particularly sensitive. Such supplementations might impact brain function and facilitate development later in life through modulating monoamine homeostasis.

Comprehensive analysis of brain injury parameters in a preclinical porcine model of acute liver failure.

Introduction: Acute liver failure (ALF) is defined as acute loss of liver function leading to hepatic encephalopathy associated with a high risk of patient death. Brain injury markers in serum and tissue can help detect and monitor ALF-associated brain injury. This study compares different brain injury parameters in plasma and tissue along with the progression of ALF. Method: ALF was induced by performing an 85% liver resection. Following the resection, animals were recovered and monitored for up to 48 h or until reaching the predefined endpoint of receiving standard medical therapy (SMT). Blood and serum samples were taken at Tbaseline, T24, and upon reaching the endpoint (Tend). Control animals were euthanized by exsanguination following plasma sampling. Postmortem brain tissue samples were collected from the frontal cortex (FCTx) and cerebellum (Cb) of all animals. Glial fibrillary acidic protein (GFAP) and tau protein and mRNA levels were quantified using ELISA and qRT-PCR in all plasma and brain samples. Plasma neurofilament light (NFL) was also measured using ELISA. Results: All ALF animals (n = 4) were euthanized upon showing signs of brain herniation. Evaluation of brain injury biomarkers revealed that GFAP was elevated in ALF animals at T24h and Tend, while Tau and NFL concentrations were unchanged. Moreover, plasma glial fibrillary acidic protein (GFAP) levels were negatively correlated with total protein and positively correlated with both aspartate transaminase (AST) and alkaline phosphatase (AP). Additionally, lower GFAP and tau RNA expressions were observed in the FCTx of the ALF group but not in the CB tissue. Conclusion: The current large animal study has identified a strong correlation between GFAP concentration in the blood and markers of ALF. Additionally, the protein and gene expression analyses in the FCTx revealed that this area appears to be susceptible, while the CB is protected from the detrimental impacts of ALF-associated brain swelling. These results warrant further studies to investigate the mechanisms behind this process.

Porcine computational modeling to investigate developmental dysplasia of the hip.

While it is well-established that early detection and initiation of treatment of developmental dysplasia of the hip (DDH) is crucial to successful clinical outcomes, research on the mechanics of the hip joint during healthy and pathological hip development in infants is limited. Quantification of mechanical behavior in both the healthy and dysplastic developing joints may provide insight into the causes of DDH and facilitate innovation in treatment options. In this study, subject-specific three-dimensional finite element models of two pigs were developed: one healthy pig and one pig with induced dysplasia in the right hindlimb. The objectives of this study were: (1) to characterize mechanical behavior in the acetabular articular cartilage during a normal walking cycle by analyzing six metrics: contact pressure, contact area, strain energy density, von Mises stress, principal stress, and principal strain; and (2) to quantify the effect on joint mechanics of three anatomic abnormalities previously identified as related to DDH: variation in acetabular coverage, morphological changes in the femoral head, and changes in the articular cartilage. All metrics, except the contact area, were elevated in the dysplastic joint. Morphological changes in the femoral head were determined to be the most significant factors in elevating contact pressure in the articular cartilage, while the effects of acetabular coverage and changes in the articular cartilage were less significant. The quantification of the pathomechanics of DDH in this study can help identify key mechanical factors that restore normal hip development and can lead to mechanics-driven treatment options.

Safety and Efficacy of IL-12 Plasmid DNA Transfection into Pig Skin: Supportive Data for Human Clinical Trials on Gene Therapy and Vaccination.

Gene electrotransfer (GET) of plasmids encoding interleukin 12 (IL-12) has already been used for the treatment of various types of tumors in human oncology and as an adjuvant in DNA vaccines. In recent years, we have developed a plasmid encoding human IL-12 (phIL12) that is currently in a phase I clinical study. The aim was to confirm the results of a non-clinical study in mice on pharmacokinetic characteristics and safety in a porcine model that better resembled human skin. The GET of phIL12 in the skin was performed on nine pigs using different concentrations of plasmid phIL12 and invasive (needle) or noninvasive (plate) types of electrodes. The results of our study demonstrate that the GET of phIL-12 with needle electrodes induced the highest expression of IL-12 at the protein level on day 7 after the procedure. The plasmid was distributed to all tested organs; however, its amount decreased over time and was at a minimum 28 days after GET. Based on plasmid copy number and expression results, together with blood analysis, we showed that IL-12 GET is safe in a porcine animal model. Furthermore, we demonstrated that pigs are a valuable model for human gene therapy safety studies.

Forcefully engaging rods into tulips with gap discrepancy leading to pedicle screw loosening-a biomechanical analysis using long porcine spine segments.

BACKGROUND CONTEXT: Long-segment pedicle screw instrumentation is widely used to treat complex spinal disorders. Rods are routinely precontoured to maximize assistance on the correcting side of the deformity, but there often exists a residual gap discrepancy between the precontoured rods and screw tulips. No previous research has investigated the diminished pullout strength of the most proximal or distal pedicle screw resulting from a mismatched rod in long-segment pedicle screw instrumentation. PURPOSE: The present study aimed to investigate the decreased pullout force of pedicle screws affected by the gap discrepancy when forcefully engaging a mismatched rod into a tulip in a normal-density porcine spine. STUDY DESIGN: The pedicle screw fixation strength under axial pullout force was compared among three different gap discrepancies between rods and tulips using long porcine spine segments. METHODS: Twelve porcine lumbar vertebrae (L3-L6) were implanted with pedicle screws and rods. Screws on one side had no gap between the tulip and rod (0-mm group), while the most proximal screw on the other side had an intentional gap of 3 mm (3-mm group) or 6 mm (6-mm group). Three hours after forcefully engaging the rod into the tulips at room temperature, the set screws in all specimens were loosened, and each specimen was dissected into individual vertebrae for subsequent pullout testing. RESULTS: The control group exhibited significantly greater pullout strength (1987.68 ± 126.80 N) than the groups from different rod-tulip configurations (p<.05), with significantly greater strength in the 3-mm group (945.62 ± 97.43 N) than the 6-mm group (655.30 ± 194.49 N) (p<.05). Only 47.6% and 33.0% of the pullout strength was retained in the 3-mm and 6-mm groups, respectively, compared to the control group. CONCLUSIONS: Gap discrepancies between rods and tulips can significantly reduce pedicle screw pullout strength, with a correlation between decreased strength and increased gaps. Surgeons should avoid forcefully engaging mismatched rods and consider well-fitted contoured rods in spinal surgery to minimize the risk of screw loosening. CLINICAL SIGNIFICANCE: The gap discrepancy between rod and tulip significantly affected pullout strength, with greater gaps leading to reduced strength. Forcefully engaging mismatched rods into tulips in degenerative spinal surgery should be avoided to minimize the risk of early screw pullout.

The Assessment of a Novel Endoscopic Ultrasound-Compatible Cryocatheter to Ablate Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease that may be treated utilizing thermal therapies. Cryoablation is an effective, minimally invasive therapy that has been utilized for the treatment of various cancers, offering patients a quicker recovery and reduced side effects. Cryoablation has been utilized on a limited basis for the treatment of PDAC. With the recent reports on the success of cryoablation, there is a growing interest in the use of cryoablation as a standalone, minimally invasive procedure to treat PDAC. While offering a promising path, the application of cryoablation to PDAC is limited by current technologies. As such, there is a need for the development of new devices to support advanced treatment strategies for PDAC. To this end, this study investigated the performance of a new endoscopic ultrasound-compatible cryoablation catheter technology, FrostBite. We hypothesized that FrostBite would enable the rapid, effective, minimally invasive delivery of ultra-cold temperatures to target tissues, resulting in effective ablation via an endoscopic approach. Thermal properties and ablative efficacy were evaluated using a heat-loaded gel model, tissue-engineered models (TEMs), and an initial in vivo porcine study. Freeze protocols evaluated included single and repeat 3 and 5 min applications. Isotherm assessment revealed the generation of a 2.2 cm diameter frozen mass with the -20 °C isotherm reaching a diameter of 1.5 cm following a single 5 min freeze. TEM studies revealed the achievement of temperatures ≤ -20 °C at a diameter of 1.9 cm after a 5 min freeze. Fluorescent imaging conducted 24 h post-thaw demonstrated a uniformly shaped ellipsoidal ablative zone with a midline diameter of 2.5 cm, resulting in a total ablative volume of 6.9 cm3 after a single 5 min freeze. In vivo findings consistently demonstrated the generation of ablative areas measuring 2.03 cm × 3.2 cm. These studies demonstrate the potential of the FrostBite cryocatheter as an endoscopic ultrasound-based treatment option. The data suggest that FrostBite may provide for the rapid, effective, controllable freezing of cancerous pancreatic and liver tissues. This ablative power also offers the potential of improved safety margins via the minimally invasive nature of an endoscopic ultrasound-based approach or natural orifice transluminal endoscopic surgery (NOTES)-based approach. The results of this pre-clinical feasibility study show promise, affirming the need for further investigation into the potential of the FrostBite cryocatheter as an advanced, minimally invasive cryoablative technology.

Assessing renal tissue temperature changes and perfusion effects during laser activation in an in vivo porcine model.

INTRODUCTION: High fluid temperatures have been seen in both in vitro and in vivo studies with laser lithotripsy, yet the thermal distribution within the renal parenchyma has not been well characterized. Additionally, the heat-sink effect of vascular perfusion remains uncertain. Our objectives were twofold: first, to measure renal tissue temperatures in response to laser activation in a calyx, and second, to assess the effect of vascular perfusion on renal tissue temperatures. METHODS: Ureteroscopy was performed in three porcine subjects with a prototype ureteroscope containing a temperature sensor at its tip. A needle with four thermocouples was introduced percutaneously into a kidney with ultrasound guidance to allow temperature measurement in the renal medulla and cortex. Three trials of laser activation (40W) for 60 s were conducted with an irrigation rate of 8 ml/min at room temperature in each subject. After euthanasia, three trials were repeated without vascular perfusion in each subject. RESULTS: Substantial temperature elevation was observed in the renal medulla with thermal dose in two of nine trials exceeding threshold for tissue injury. The temperature decay time (t½) of the non-perfused trials was longer than in the perfused trials. The ratio of t½ between them was greater in the cortex than the medulla. CONCLUSION: High-power laser settings (40W) can induce potentially injurious temperatures in the in vivo porcine kidney, particularly in the medullary region adjacent to the collecting system. Additionally, the influence of vascular perfusion in mitigating thermal risk in this susceptible area appears to be limited.

Changes in Pulmonary Vascular Resistance and Obstruction Score Following Acute Pulmonary Embolism in Pigs.

OBJECTIVES: To investigate the contribution of mechanical obstruction and pulmonary vasoconstriction to pulmonary vascular resistance (PVR) in acute pulmonary embolism (PE) in pigs. DESIGN: Controlled, animal study. SETTING: Tertiary university hospital, animal research laboratory. SUBJECTS: Female Danish slaughter pigs (n = 12, ~60 kg). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: PE was induced by infusion of autologous blood clots in pigs. CT pulmonary angiograms were performed at baseline, after PE (first experimental day [PEd0]) and the following 2 days (second experimental day [PEd1] and third experimental day [PEd2]), and clot burden quantified by a modified Qanadli Obstruction Score. Hemodynamics were evaluated with left and right heart catheterization and systemic invasive pressures each day before, under, and after treatment with the pulmonary vasodilators sildenafil (0.1 mg/kg) and oxygen (Fio2 40%). PE increased PVR (baseline vs. PEd0: 178 ± 54 vs. 526 ± 160 dynes; p < 0.0001) and obstruction score (baseline vs. PEd0: 0% vs. 45% ± 13%; p < 0.0001). PVR decreased toward baseline at day 1 (baseline vs. PEd1: 178 ± 54 vs. 219 ± 48; p = 0.16) and day 2 (baseline vs. PEd2: 178 ± 54 vs. 201 ± 50; p = 0.51). Obstruction score decreased only slightly at day 1 (PEd0 vs. PEd1: 45% ± 12% vs. 43% ± 14%; p = 0.04) and remained elevated throughout the study (PEd1 vs. PEd2: 43% ± 14% vs. 42% ± 17%; p = 0.74). Sildenafil and oxygen in combination decreased PVR at day 0 (-284 ± 154 dynes; p = 0.0064) but had no effects at day 1 (-8 ± 27 dynes; p = 0.4827) or day 2 (-18 ± 32 dynes; p = 0.0923). CONCLUSIONS: Pulmonary vasoconstriction, and not mechanical obstruction, was the predominant cause of increased PVR in acute PE in pigs. PVR rapidly declined over the first 2 days after onset despite a persistent mechanical obstruction of the pulmonary circulation from emboli. The findings suggest that treatment with pulmonary vasodilators might only be effective in the acute phase of PE thereby limiting the window for such therapy.

Surgically induced aortic coarctation in a neonatal porcine model allows for longitudinal assessment of cardiovascular changes.

Noncritical aortic coarctation (COA) typically presents beyond early childhood with hypertension. Correction of COA does not ensure a return to normal cardiovascular health, but the mechanisms are poorly understood. Therefore, we developed a porcine COA model to study the secondary cardiovascular changes. Eight male neonatal piglets (4 sham, 4 COA) underwent left posterolateral thoracotomy with descending aorta (DAO) mobilization. COA was created via a 1-cm longitudinal DAO incision with suture closure, plication, and placement and an 8-mm external band. All animals had cardiac catheterization at 6 (11-13 kg), 12 (26-31 kg), and 20 (67-70 kg) wk of age. Aortic luminal diameters were similar along the thoracic aorta, except for the COA region [6.4 mm COA vs. 17.3 mm sham at 20 wk (P < 0.001)]. Collateral flow could be seen as early as 6 wk. COA peak systolic pressure gradient was 20 mmHg at 6 wk and persisted through 20 wk increasing to 40 mmHg with dobutamine. Pulse pressures distal to the COA were diminished at 12 and 20 wk. This model addresses many limitations of prior COA models including neonatal creation at an expected anatomic position with intimal injury and vessel sizes similar to humans.NEW & NOTEWORTHY A neonatal model of aortic coarctation was developed in a porcine model using a readily reproducible method of aortic plication and external wrap placement. This model addresses the limitations of existing models including neonatal stenosis creation, appropriate anatomic location of the stenosis, and intimal injury creation and mimics human somatic growth. Pigs met American Heart Association (AHA) criteria for consideration of intervention, and the stenoses were graded as moderate to severe.

A novel contact force sensing pulsed field ablation catheter in a porcine model.

BACKGROUND: Pulsed field ablation (PFA) has emerged as a novel non-thermal modality with highly myocardium-specific. However, the PFA catheter based on contact force (CF)-sensing has not been reported. The study aimed to evaluate the efficacy and safety of a novel CF-sensing PFA catheter. METHODS: First, different CF (5, 15, 25, and 35 g) of the novel PFA catheter were evaluated on lesion dimensions during ablation on right and left ventricle in two pigs. Next, this catheter was further evaluated on four typical sites of superior vena cava (SVC), cavotricuspid isthmus (CTI), right superior pulmonary vein (RSPV), and right inferior pulmonary vein (RIPV) for atrial ablation in another six pigs. Electrical isolation was evaluated immediately after ablation and 30-day survival. Chronic lesions were assessed via histopathology after euthanasia. Acute and chronic safety outcomes were observed peri- and post-procedurally. RESULTS: In ventricular ablation, increased CF from 5 to 15 g produced significantly greater lesion depth but nonsignificant increases from 15 to 35 g. In atrial ablation, the novel CF-sensing PFA deliveries produced an acute attenuation of local electrograms and formation of a continuous line of block in all 6 pigs. The ablation line remained sustained blockage at the 30-day survival period. The CF of SVC, CTI, RSPV, and RIPV was 9.4 ± 1.5, 14.5 ± 3.2, 17.2 ± 2.6, and 13.4 ± 2.8 g, respectively. Moreover, no evidence of damage to esophagus or phrenic nerve was observed. CONCLUSION: The novel CF-sensing PFA catheter potentiated efficient, safe, and durable ablation, without causing damage to the esophagus or phrenic nerve.

Development of a mini pig model of peanut allergy.

Introduction: The prevalence of peanut allergies is increasing, emphasizing the need for an animal model to enhance our understanding of peanut allergy pathogenesis and to advance diagnostic tools and therapeutic interventions. While mice are frequently used as model organisms, their allergic responses do not fully mirror those observed in humans, warranting the exploration of a higher animal model. The porcine gastrointestinal system closely resembles that of humans, and exhibits allergy symptoms akin to human responses, making pigs a promising model for peanut allergy research. Methods: In this study we compared two allergen sensitization protocols involving either topical allergen application after repeated tape stripping (TS) or intraperitoneal (IP) injections to induce peanut-specific allergy and anaphylaxis reactions in mini pigs. Mini pigs sensitized with a combination of peanut protein extract (PE) and cholera toxin (CT) through either the IP or the TS route. Results: Sensitized pigs via both methods developed systemic PE-specific IgG and IgE responses. Following peanut challenge via the IP route, both TS- and IP-sensitized pigs displayed allergy symptoms, including lethargy, skin rashes, vomiting, and a drop in body temperature. However, respiratory distress was observed exclusively in pigs sensitized through the TS route and not in those sensitized through the IP route. However, it is noteworthy that both groups of sensitized pigs maintained peanut hypersensitivity for up to two months post-sensitization, albeit with a reduction in the severity of allergy symptoms. Importantly, both groups exhibited sustained levels of PE-specific IgG, IgE, and elevated concentrations of mast cell protease in their blood following the IP challenges. Discussion: Overall, this study reports TS and IP as two different modes of sensitization leading to onset of peanut specific allergic reactions in mini pigs, but only the TS-sensitization led to systemic anaphylaxis (simultaneous presence of symptoms: breathing difficulty, intense skin rash, and impaired mobility). A distinctive feature of these sensitization protocols is the 100% success rate (N = 4 pigs per group) in sensitizing the subjects.

ATI-1777, a Topical Jak1/3 Inhibitor, May Benefit Atopic Dermatitis without Systemic Drug Exposure: Results from Preclinical Development and Phase 2a Randomized Control Study ATI-1777-AD-201.

Introduction: Atopic dermatitis, a chronic, pruritic skin disease, affects 10-30% of children and up to 14% of adults in developed countries. ATI-1777, a potent and selective Jak1/3 inhibitor, was designed with multiple sites of metabolism to deliver local efficacy in the skin and limit systemic exposure. In preclinical studies, ATI-1777 selectively inhibited Jak1/3 with limited systemic exposure and without any adverse effects. Primary objective: The primary goal of this study was to assess the preliminary clinical efficacy of ATI-1777 topical solution in adults with moderate or severe atopic dermatitis. Design: ATI-1777-AD-201, a phase 2a, first-in-human, randomized, double-blind, vehicle-controlled, parallel-group study, evaluated the efficacy, safety, tolerability, and pharmacokinetics of ATI-1777 topical solution in 48 participants with atopic dermatitis over 4 weeks. Primary endpoint: The primary endpoint was a reduction of a modified Eczema Area and Severity Index score from baseline. Results: Reduction was significantly greater in the ATI-1777-treated group on day 28 than in vehicle-treated group (percentage reduction from baseline = 74.45% [standard error = 6.455] and 41.43% [standard error = 6.189], respectively [P < .001]). Average plasma concentrations of ATI-1777 were <5% of the half-maximal inhibitory concentration of ATI-1777 for inhibiting Jak1/3. No deaths or serious adverse events were reported. Conclusion: Topical ATI-1777 does not lead to pharmacologically relevant systemic drug exposure and may reduce clinical signs of atopic dermatitis. Trial Registration: The study was registered at ClinicalTrials.gov with the number NCT04598269.

Learning curve of ultrasound-guided surgeon-administered transversus abdominis plane (UGSA-TAP) block on a porcine model.

Background: Surgeons commonly perform ultrasound-guided Transversus Abdominis Plane blocks to manage acute pain following abdominal surgeries. There is no consensus on whether surgeons should undergo basic hands-on training to perform TAP blocks or if video-based learning is sufficient. We theorized that simulation-based learning is superior to video-based learning. In the present study, we present the analysis of technical skills of UGSA-TAP block performance on a live porcine model by general surgery trainees after undergoing video or simulation-based learning. Methods: We performed a prospective, double-blinded, randomized study. Ten surgery residents and two surgery critical-care fellows (n = 12) without prior experience in performing the TAP block were recruited. The participants were randomized either into a video-based or simulation-based training group. After that, all participants performed a TAP block on a live anesthetized pig, which was recorded and scored by three blinded anesthesiologists. All participants completed a post-performance survey to assess their confidence in gaining competency in the UGSA-TAP block. Statistical analyses were performed to assess the differences between the two groups. P < 0.05 was considered statistically significant. Results: All simulation-based learning participants successfully performed a survey scan, identified the three muscular layers of the abdominal wall, and identified the transversus abdominis plane compared to 50 %, 50 %, and 33 % video-based learning group participants for the respective parameters (p < 0.05). While some performance metrics showed no statistically significant differences between the groups, substantial effect sizes (Cohen's ℎ up to 1.07) highlighted notable differences in participants' performance. Both groups exhibited confidence in core competencies, with varied rates of satisfactory skill execution. Performance assessed using a global rating scale revealed a higher passing rate for the simulation group (83 % vs. 33 %). Participant feedback via the Likert scale reflected confidence post-training. Inter-rater reliability (0.83-1) confirmed the robustness of study evaluations. Conclusion: The UGSA-TAP block curriculum should be introduced into the surgical residency programs with an emphasis on simulation-based learning to enhance the procedural skills of the trainees before transitioning to surgical patients.