Increased risk donor criteria: The time for change is now

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155965/1/ctr13879.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155965/2/ctr13879_am.pd

Not Dying Alone — Modern Compassionate Care in the Covid-19 Pandemic

http://deepblue.lib.umich.edu/bitstream/2027.42/156077/1/nejmp2007781.pdfSEL

Frailty Is Associated With Increased Rates of Acute Cellular Rejection Within 3 Months After Liver Transplantation

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154606/1/lt25690.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154606/2/lt25690_am.pd

Increased risk donor criteria: The time for change is now

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155965/1/ctr13879.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155965/2/ctr13879_am.pd

Development of a large animal model of lethal polytrauma and intra-abdominal sepsis with bacteremia

Background Trauma and sepsis are individually two of the leading causes of death worldwide. When combined, the mortality is greater than 50%. Thus, it is imperative to have a reproducible and reliable animal model to study the effects of polytrauma and sepsis and test novel treatment options. Porcine models are more translatable to humans than rodent models due to the similarities in anatomy and physiological response. We embarked on a study to develop a reproducible model of lethal polytrauma and intra-abdominal sepsis, which was lethal, though potentially salvageable with treatment.Methods Our laboratory has a well-established porcine model that was used as the foundation. Animals were subjected to a rectus crush injury, long bone fracture, liver and spleen laceration, traumatic brain injury and hemorrhage that was used as a foundation. We tested various colon injuries to create intra-abdominal sepsis. All animals underwent injuries followed by a period of shock, then subsequent resuscitation.Results All animals had blood culture-proven sepsis. Attempts at long-term survival of animals after injury were ceased because of poor appetite and energy. We shifted to an 8-hour endpoint. The polytrauma injury pattern remained constant and the colon injury pattern changed with the intention of creating a model that was ultimately lethal but potentially salvageable with a therapeutic drug. An uncontrolled cecal injury (n=4) group resulted in very early deaths. A controlled cecal injury (CCI; n=4) group had prolonged time prior to mortality with one surviving to the endpoint. The sigmoid injury (n=5) produced a similar survival curve to CCI but no animals surviving to the endpoint.Conclusion We have described a porcine model of polytrauma and sepsis that is reproducible and may be used to investigate novel treatments for trauma and sepsis.Level of evidence Not applicable. Animal study

Early Treatment with Exosomes following Traumatic Brain Injury and Hemorrhagic Shock in a Swine Model Promotes Transcriptional Changes associated with Neuroprotection

BACKGROUND: We have shown that administration of mesenchymal stem cell (MSC)-derived exosomes (single dose given within 1 hour) in models of traumatic brain injury (TBI) and hemorrhagic shock (HS) is neuroprotective. The precise mechanisms responsible for the neuroprotection are not fully understood. This study was designed to investigate the transcriptomic changes in the brain that are associated with this treatment strategy. METHODS: Yorkshire swine (40-45 kg) were subjected to a severe TBI (12-mm cortical impact) and HS (40% estimated total blood volume). One hour into shock, animals were randomized (n=5/cohort) to receive either lactated Ringer\u27s (LR; 5mL) or exosomes suspended in LR (LR+EXO; 1 × 10 exosome particles in 5 mL LR). Animals then underwent additional shock (1 hr) followed by normal saline resuscitation. After 6 hours of observation, brain swelling (% increase compared to the uninjured side) and lesion size (mm) were assessed. Peri-injured brain tissue was processed for RNA sequencing, analyzed with high through-put RNA-seq data analysis, and results compared between control and experimental groups. RESULTS: Exosome treatment significantly increased (p \u3c 0.005) gene expression associated with neurogenesis, neuronal development, synaptogenesis, and neuroplasticity. It also significantly reduced (p \u3c 0.005) genes associated with stroke, neuroinflammation, neuroepithelial cell proliferation and non-neuronal cell proliferation contributing to reactive gliosis. Exosomes treatment also significantly increased (p \u3c 0.005) the genes that are associated with the stability of blood-brain barrier. CONCLUSIONS: Administration of a single dose of exosomes induces transcriptomic changes suggestive of neuroprotection. Their use as a treatment of TBI is promising, and requires further investigation for human translation. LEVEL OF EVIDENCE: Not applicable (pre-clinical study)

Early single-dose exosome treatment improves neurologic outcomes in a 7-day swine model of traumatic brain injury and hemorrhagic shock

BACKGROUND: Early single-dose treatment with human mesenchymal stem cell (MSC)-derived exosomes promotes neuroprotection and promotes blood-brain barrier (BBB) integrity in models of traumatic brain injury (TBI) and hemorrhagic shock (HS) in swine. The impact of an early single dose of exosomes on late survival (7-day), however, remains unknown. We sought to evaluate the impact of early single-dose exosome treatment on neurologic outcomes, brain lesion size, inflammatory cytokines, apoptotic markers, and mediators of neural plasticity in a 7-day survival model. METHODS: Yorkshire swine were subjected to a severe TBI (8-mm cortical impact) and HS (40% estimated total blood volume). After one hour of shock, animals were randomized (n=4/cohort) to receive either lactated Ringer\u27s (LR; 5mL) or LR + exosomes (LR+EXO; 1 × 10 exosome particles). After an additional hour of shock, animals were resuscitated with normal saline. Daily neurologic severity scores (NSS) were compared. At 7 days following injury, lesion size, inflammatory markers, and mediators of inflammation (NF-κB), apoptosis (BAX), and neural plasticity (BDNF) in brain tissue were compared between groups. RESULTS: Exosome-treated animals had significantly lower NSS (first 4 days; p \u3c 0.05) and faster neurologic recovery. At 7-days, exosome-treated animals had significantly smaller (p \u3c 0.05) brain lesion sizes. Exosome-treated animals also had significantly lower levels of inflammatory markers (IL-1, IL-6, IL-8, and IL-18) and higher granulocyte-macrophage colony stimulating factor (GM-CSF) levels compared to the control animals, indicating specific impacts on various cytokines. BAX and NF-κB levels were significantly lower (p \u3c 0.05) in exosome-treated animals, while BDNF levels were significantly higher (p \u3c 0.05) in the exosome-treated animals. CONCLUSIONS: In a large animal model of TBI and HS, early single-dose exosome treatment attenuates neurologic injury, decreases brain lesion size, inhibits inflammation and apoptosis, and promotes neural plasticity over a seven-day period. LEVEL OF EVIDENCE: Not applicable (pre-clinical study)