Aaron M. Williams

The Importance of Prehabilitation in Liver Transplantation

Over 15,000 patients are listed for liver transplantation across the USA while only 6500 transplants are performed each year. Given the realities of this profound organ shortage, optimal patient preparation is important to assure good outcomes. In recent years, frailty and sarcopenia have emerged as important predictors of post-transplant mortality. Potentially, these risk factors may be remediable with preoperative preparation. Efforts to improve disease management and physical conditioning could not only optimize patients for liver transplantation but could also improve outcomes among those who do not undergo transplantation.

Mesenchymal Stem Cell-Derived Exosomes Provide Neuroprotection and Improve Long-Term Neurologic Outcomes in a Swine Model of Traumatic Brain Injury and Hemorrhagic Shock

Combined traumatic brain injury (TBI) and hemorrhagic shock (HS) remains a leading cause of preventable death worldwide. Mesenchymal stem cell-derived exosomes have demonstrated promise in small animal models of neurologic injury. To investigate the effects of exosome treatment in a clinically realistic large animal model, Yorkshire swine underwent TBI and HS. Animals were maintained in shock for 2u2009h before resuscitation with normal saline (NS). Animals were then resuscitated either with NS (3u2009×u2009volume of shed blood) or with the same volume of NS with delayed exosome administration (1u2009×u20091013 particles/4u2009mL) (nu2009=u20095/cohort). Exosomes were administered 9u2009h post-injury, and on post-injury days (PID) 1, 5, 9, and 13. Neurologic severity scores (NSS) were assessed for 30 days, and neurocognitive functions were objectively measured. Exosome-treated animals had significantly lower NSS (pu2009<u20090.05) during the first five days of recovery. Exosome-treated animals also had a significantly shorter time to complete neurologic recovery (NSSu2009=u20090) compared with animals given NS alone (days to recovery: NSu2009=u200916.8u2009±u200910.6; NS + exosomesu2009=u20095.6u2009±u20092.8; pu2009=u20090.03). Animals treated with exosomes initiated neurocognitive testing earlier (days to initiation: NSu2009=u20099.6u2009±u20090.5 vs. NS + exosomesu2009=u20094.2u2009±u20090.8; pu2009=u20090.008); however, no difference was seen in time to mastery of tasks. In conclusion, treatment with exosomes attenuates the severity of neurologic injury and allows for faster neurologic recovery in a clinically realistic large animal model of TBI and HS.

Improvement of Blood-Brain Barrier Integrity in Traumatic Brain Injury and Hemorrhagic Shock Following Treatment with Valproic Acid and Fresh Frozen Plasma

Objective: Combined traumatic brain injury and hemorrhagic shock are highly lethal. Following injuries, the integrity of the blood-brain barrier can be impaired, contributing to secondary brain insults. The status of the blood-brain barrier represents a potential factor impacting long-term neurologic outcomes in combined injuries. Treatment strategies involving plasma-based resuscitation and valproic acid therapy have shown efficacy in this setting. We hypothesize that a component of this beneficial effect is related to blood-brain barrier preservation. Design: Following controlled traumatic brain injury, hemorrhagic shock, various resuscitation and treatment strategies were evaluated for their association with blood-brain barrier integrity. Analysis of gene expression profiles was performed using Porcine Gene ST 1.1 microarray. Pathway analysis was completed using network analysis tools (Gene Ontology, Ingenuity Pathway Analysis, and Parametric Gene Set Enrichment Analysis). Subjects: Female Yorkshire swine were subjected to controlled traumatic brain injury and 2 hours of hemorrhagic shock (40% blood volume, mean arterial pressure 30-35 mmHg). Interventions: Subjects were resuscitated with 1) normal saline, 2) fresh frozen plasma, 3) hetastarch, 4) fresh frozen plasma + valproic acid, or 5) hetastarch + valproic acid (n = 5 per group). After 6 hours of observation, brains were harvested for evaluation. Measurements and Main Results: Immunofluoroscopic evaluation of the traumatic brain injury site revealed significantly increased expression of tight-junction associated proteins (zona occludin-1, claudin-5) following combination therapy (fresh frozen plasma + valproic acid and hetastarch + valproic acid). The extracellular matrix protein laminin was found to have significantly improved expression with combination therapies. Pathway analysis indicated that valproic acid significantly modulated pathways involved in endothelial barrier function and cell signaling. Conclusions: Resuscitation with fresh frozen plasma results in improved expression of proteins essential for blood-brain barrier integrity. The addition of valproic acid provides significant improvement to these protein expression profiles. This is likely secondary to activation of key pathways related to endothelial functions.

The role of telemedicine in postoperative care

Telemedicine has become one of the most rapidly-expanding components of the health care system. Its adoption has afforded improved access to care, greater resource efficiency, and decreased costs associated with traditional office visits and has been well established in a wide array of fields. Telemedicine has been adopted in several domains of surgical care. In recent years, the role of telemedicine in postoperative care has caught attention as it has demonstrated excellent clinical outcomes, enhanced patient satisfaction, increased accessibility along with reduced wait times, and cost savings for patients and health care systems. In this narrative review, we describe the history of telemedicine, its adoption in the field of surgery and its various modalities, its use in the postoperative setting, and the potential benefits to both patients and healthcare systems. As telemedicine continues to emerge as a powerful tool for health care delivery, we also discuss several barriers to its widespread adoption as well as the future utility of telemedicine in postoperative care.

Complete and Partial Aortic Occlusion for the Treatment of Hemorrhagic Shock in Swine

Hemorrhage remains the leading cause of preventable deaths in trauma. Endovascular management of non-compressible torso hemorrhage has been at the forefront of trauma care in recent years. Since complete aortic occlusion presents serious concerns, the concept of partial aortic occlusion has gained a growing attention. Here, we present a large animal model of hemorrhagic shock to investigate the effects of a novel partial aortic balloon occlusion catheter and compare it with a catheter that works on the principles of complete aortic occlusion. Swine are anesthetized and instrumented in order to conduct controlled fixed-volume hemorrhage, and hemodynamic and physiological parameters are monitored. Following hemorrhage, aortic balloon occlusion catheters are inserted and inflated in the supraceliac aorta for 60 min, during which the animals receive whole-blood resuscitation as 20% of the total blood volume (TBV). Following balloon deflation, the animals are monitored in a critical care setting for 4 h, during which they receive fluid resuscitation and vasopressors as needed. The partial aortic balloon occlusion demonstrated improved distal mean arterial pressures (MAPs) during the balloon inflation, decreased markers of ischemia, and decreased fluid resuscitation and vasopressor use. As swine physiology and homeostatic responses following hemorrhage have been well-documented and are like those in humans, a swine hemorrhagic shock model can be used to test various treatment strategies. In addition to treating hemorrhage, aortic balloon occlusion catheters have become popular for their role in cardiac arrest, cardiac and vascular surgery, and other high-risk elective surgical procedures.

Valproic Acid Treatment Decreases Serum GFAP and UCH-L1 Level in Swine Subjected to Traumatic Brain Injury.

The primary aim of this study was to examine the effects of valproic acid (VPA) treatment on serum glial fibrillary acidic protein (GFAP) and neurofilament light chain (NF-L) levels. To achieve this aim, we obtained serum samples from: 1) 10 Yorkshire swine subjected to controlled cortical impact traumatic brain injury (CCI TBI) + polytrauma and randomized to receive either normal saline (NS) + VPA (nu2009=u20095) or NS alone (nu2009=u20095) and 2) five additional swine subjected to CCI TBI without polytrauma and treated with VPA. GFAP and NF-L levels were measured in samples obtained from baseline until 10 days post-injury using a digital immunoassay from Quanterix Corporation. We found that elevated GFAP and NF-L levels were first detected at 2u2009h post-injury; and peaked at 24u2009h and 72u2009h respectively. GFAP levels returned to baseline levels by Day 10, while NF-L remained elevated at Day 10. In TBI + polytrauma swine, the magnitude and duration of biomarker elevation, quantified by the area under the biomarker-concentration-versus-time curve during the first 10 days (AUC0-10days), was higher in the NS group, compared with the VPA group. For GFAP, the AUC0-10days was 45,535 (IQR: 35,741-105,711) and 22,837 (IQR: 8,082-46,627) for the NS and NS+VPA groups, respectively. For NF-L, the AUC0-10days was 43,073 (IQR: 18,739-120,794) and 4,475 (2,868-11,157) for the NS and NS+VPA groups, respectively. Twenty-four hour GFAP and NF-L levels had the strongest correlation with lesion size and time to normalization of behavior. Accordingly, we conclude that treatment with VPA results in significantly lower serum GFAP and NF-L levels. The time-point at which GFAP and NF-L levels have the strongest correlation with outcome is 24u2009h post-injury.Abstract The primary aim of this study was to examine the effects of valproic acid (VPA) treatment on serum glial fibrillary acidic protein (GFAP) and neurofilament light chain (NF-L) levels. To achieve this aim, we obtained serum samples from: 1) 10 Yorkshire swine subjected to controlled cortical impact traumatic brain injury (CCI TBI) + polytrauma and randomized to receive either normal saline (NS) + VPA (nu2009=u20095) or NS alone (nu2009=u20095) and 2) five additional swine subjected to CCI TBI without polytrauma and treated with VPA. GFAP and NF-L levels were measured in samples obtained from baseline until 10 days post-injury using a digital immunoassay from Quanterix Corporation. We found that elevated GFAP and NF-L levels were first detected at 2u2009h post-injury; and peaked at 24u2009h and 72u2009h respectively. GFAP levels returned to baseline levels by Day 10, while NF-L remained elevated at Day 10. In TBI + polytrauma swine, the magnitude and duration of biomarker elevation, quantified by the area under the biomarker-c...

Valproic Acid Treatment Decreases Serum Glial Fibrillary Acidic Protein and Neurofilament Light Chain Levels in Swine Subjected to Traumatic Brain Injury

The primary aim of this study was to examine the effects of valproic acid (VPA) treatment on serum glial fibrillary acidic protein (GFAP) and neurofilament light chain (NF-L) levels. To achieve this aim, we obtained serum samples from: 1) 10 Yorkshire swine subjected to controlled cortical impact traumatic brain injury (CCI TBI) + polytrauma and randomized to receive either normal saline (NS) + VPA (nu2009=u20095) or NS alone (nu2009=u20095) and 2) five additional swine subjected to CCI TBI without polytrauma and treated with VPA. GFAP and NF-L levels were measured in samples obtained from baseline until 10 days post-injury using a digital immunoassay from Quanterix Corporation. We found that elevated GFAP and NF-L levels were first detected at 2u2009h post-injury; and peaked at 24u2009h and 72u2009h respectively. GFAP levels returned to baseline levels by Day 10, while NF-L remained elevated at Day 10. In TBI + polytrauma swine, the magnitude and duration of biomarker elevation, quantified by the area under the biomarker-concentration-versus-time curve during the first 10 days (AUC0-10days), was higher in the NS group, compared with the VPA group. For GFAP, the AUC0-10days was 45,535 (IQR: 35,741-105,711) and 22,837 (IQR: 8,082-46,627) for the NS and NS+VPA groups, respectively. For NF-L, the AUC0-10days was 43,073 (IQR: 18,739-120,794) and 4,475 (2,868-11,157) for the NS and NS+VPA groups, respectively. Twenty-four hour GFAP and NF-L levels had the strongest correlation with lesion size and time to normalization of behavior. Accordingly, we conclude that treatment with VPA results in significantly lower serum GFAP and NF-L levels. The time-point at which GFAP and NF-L levels have the strongest correlation with outcome is 24u2009h post-injury.Abstract The primary aim of this study was to examine the effects of valproic acid (VPA) treatment on serum glial fibrillary acidic protein (GFAP) and neurofilament light chain (NF-L) levels. To achieve this aim, we obtained serum samples from: 1) 10 Yorkshire swine subjected to controlled cortical impact traumatic brain injury (CCI TBI) + polytrauma and randomized to receive either normal saline (NS) + VPA (nu2009=u20095) or NS alone (nu2009=u20095) and 2) five additional swine subjected to CCI TBI without polytrauma and treated with VPA. GFAP and NF-L levels were measured in samples obtained from baseline until 10 days post-injury using a digital immunoassay from Quanterix Corporation. We found that elevated GFAP and NF-L levels were first detected at 2u2009h post-injury; and peaked at 24u2009h and 72u2009h respectively. GFAP levels returned to baseline levels by Day 10, while NF-L remained elevated at Day 10. In TBI + polytrauma swine, the magnitude and duration of biomarker elevation, quantified by the area under the biomarker-c...

Protective Effect of Tubastatin A in CLP-Induced Lethal Sepsis

We have found earlier that Tubastatin A (TubA), a selective inhibitor of histone deacetylase 6 (HDAC6), improves survival in a mouse model of lethal cecal ligation and puncture (CLP)-induced sepsis. However, the underlying mechanisms have not been fully established. This study sought to test the hypothesis that TubA could affect both lung and splenic functions. C57BL/6J mice were subjected to CLP, and randomized to receive either TubA (70xa0mg/kg) dissolved in dimethyl sulfoxide (DMSO), or DMSO alone, 1xa0h following CLP. Sham animals acted as control. Twenty-four hours later, lung tissue was harvested for pathological examination, and splenic tissue was harvested for bacterial colonization. In a parallel study, the spleen was collected 48xa0h following CLP, and single cell suspension was prepared. Splenocytes then underwent flow cytometry to analyze the immune cell population. RAW264.7 macrophages were treated with lipopolysaccharide (LPS) with or without the presence of TubA (10xa0μM) at 37xa0°C for 3xa0h to assess the effect on macrophage phagocytosis. We found that acute lung injury secondary to lethal sepsis was attenuated by TubA. Treatment with TubA restored the percentage of B lymphocytes, and significantly increased percentages of innate immune cells and macrophages compared to the vehicle-treated CLP group. Moreover, TubA significantly decreased the bacterial load in the spleen, and improved the phagocytic ability of RAW264.7 murine macrophages in vitro. Such findings may help to explain the beneficial effects of TubA treatment in a model of lethal sepsis, as previously reported.

Inhibition of peptidylarginine deiminase alleviates LPS-induced pulmonary dysfunction and improves survival in a mouse model of lethal endotoxemia

Abstract Immune cell death caused by neutrophil extracellular traps (NETs), referred to as NETosis, can contribute to the pathogenesis of endotoxemia and organ damage. Although the mechanisms by which infection induces NETosis and how that leads to organ dysfunction remain largely unknown, NET formation is often found following citrullination of histone H3 (CitH3) by peptidylarginine deiminase (PAD). We hypothesized that lipopolysaccharide (LPS)‐induced activation of PAD and subsequent CitH3‐mediated NET formation increases endothelial permeability and pulmonary dysfunction and, therefore, that inhibition of PAD can mitigate damage and improve survival in lethal endotoxemia. Here, we showed that treatment with YW3–56, a PAD2/PAD4 inhibitor, significantly diminished PAD activation, blocked LPS‐induced pulmonary vascular leakage, alleviated acute lung injury, and improved survival in a mouse model of lethal LPS‐induced endotoxemia. We found CitH3 in the bloodstream 30 min after intraperitoneal injection of LPS (35 mg/kg) into mice. Additionally, CitH3 production was induced in cultured neutrophils exposed to LPS, and NETs derived from these LPS‐treated neutrophils increased the permeability of endothelial cells. However, YW3–56 reduced CitH3 production and NET formation by neutrophils following LPS exposure. Moreover, treatment with YW3–56 decreased the levels of circulating CitH3 and abolished neutrophil activation and NET formation in the lungs of mice with endotoxemia. These data suggest a novel mechanism by which PAD‐NET‐CitH3 can play a pivotal role in pulmonary vascular dysfunction and the pathogenesis of lethal endotoxemia.

Resident perceptions and evaluations of fellow-led and resident-led surgical services

BACKGROUNDnThe impact of fellowship training on general surgery residency has remained challenging to assess. Surgical resident perceptions of fellow-led and resident-led surgical services have not been well described.nnnMETHODSnRetrospective cross-sectional data were collected from residents service evaluations from 7/2014 through 7/2017. Surgical services were categorized as resident-led or fellow-led. 31 variables were evaluated and collapsed into 7 factors including clinical experience, educational experiences, clinical staff, workload, feedback, treatment of residents, and overall rotation.nnnRESULTSnAmong all PGY levels, fellow-led surgical services were rated significantly higher (pu202f<u202f0.05) regarding clinical experience, clinical staff, treatment of residents, and overall rotation. PGY1-2 residents rated resident-led services significantly higher in the area of educational experiences, while PGY 3 residents rated resident-led services higher in the area of workload. However, PGY4-5 residents rated fellow-led services significantly higher in all 7 categories. Individual fellow-led services were rated significantly higher for various categories at different PGY levels.nnnCONCLUSIONSnSurgical residents appear to value the educational experiences of fellow-led services. Each fellow-led service may ultimately provide unique educational opportunities and resources for different PGY levels.