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BACKGROUND We lack specific treatments for traumatic brain injury (TBI), which remains the leading cause of trauma-related morbidity and mortality. Treatment with valproic acid (VPA) improves outcomes in models of severe TBI with concurrent hemorrhage. However, it is unknown if VPA will have similar benefits after isolated nonlethal TBI, which is the more common clinical scenario. The goal of this study was to evaluate the effect of VPA treatment in a preclinical isolated TBI swine model on neurologic outcomes and brain lesion size and to perform detailed pharmacokinetic analyses for a future clinical trial. METHODS Yorkshire swine (n = 10; 5/cohort) were subjected to TBI (8-mm controlled cortical impact). An hour later, we randomized them to receive VPA (150 mg/kg) or saline placebo (control). Neuroseverity scores were assessed daily (0 [normal] to 36 [comatose]), brain lesion size was measured on postinjury 3, and serial blood samples were collected for pharmacokinetic studies. RESULTS Physiologic parameters and laboratory values were similar in both groups. Valproic acid-treated animals demonstrated significantly better neuroseverity scores on postinjury 1 (control, 9.2 ± 4.4; VPA, 0 ± 0; p = 0.001). Valproic acid-treated animals had significantly smaller brain lesion sizes (mean volume in microliter: control, 3,130 ± 2,166; VPA, 764 ± 208; p = 0.02). Pharmacokinetic data confirmed adequate plasma and tissue levels of VPA. CONCLUSION In this clinically relevant model of isolated TBI, a single dose of VPA attenuates neurological impairment and decreases brain lesion size.

Background Academic health centers have promoted initiatives to improve diversity, equity and inclusion in medicine. Despite this emphasis, there has been limited discussion on practical strategies for navigating bias within academic surgery. This study analyzes experiences of confronting bias within the department of surgery at the University of Michigan. Materials and methods We conducted telephone interviews (n = 15) from January 2019 to January 2020 with surgeon volunteers at one academic institution. Two investigators conducted interviews following a semi-structured guide based on personal experiences with bias between healthcare workers with diverse identities. Interviews were conducted concurrently with thematic coding, coded independently by two investigators, and discussed until consensus was reached. Analysis proceeded following the inductive and comparative approach of interpretive description. Results The most common incidents of bias were based on gender and race. They occurred along numerous relationship axes, including physician-patient and resident-faculty. A critical factor in bias response was unambiguously recognizing bias. Responding to bias consists of timing and nature of the response, defined as when the subject responded relative to the incident and the actions done in response to the incident respectively. Barriers to bias response were fear of retribution and extensive energy required to respond. Institutional culture was important, specifically in representation and support from peers and administration. Conclusions This study probes deeper into equity and inclusivity in the academic field of surgery, offering insight into common barriers to confronting bias. Overall, these findings offer a basic framework for allies to identify bias and to partner with colleagues to address biases in a supportive manner.

Objective We describe a multilevel, collaborative research group for trainees and faculty engaging in transplant surgery research within one institution. Design Transplant Research, Education, and Engagement (TREE) was designed to develop trainees’ research skills and foster enthusiasm in transplant surgery along the educational continuum. Our research model intentionally empowers junior researchers, including undergraduates and medical students, to assume active roles on a range of research projects and contribute new ideas within a welcoming research and learning environment. Setting Section of Transplant Surgery, Department of Surgery, Michigan Medicine, Ann Arbor, Michigan. Participants Undergraduate premedical students, first through fourth year medical students, general surgery residents, transplant surgery fellows, and transplant surgery faculty. Results TREE was founded in September 2019 and has grown to include over 30 active members who meet weekly and collaborate virtually on a range of research projects, many of which are led by students. Trainees can assume both mentee and mentor roles and build their research, presentation and writing skills while collaborating academically. Conclusions Our model has increased trainees’ engagement in transplant research projects and fosters early enthusiasm for the field. This model can be feasibly replicated at other institutions and within other subspecialties.

Background Trauma is the leading cause of death for young Americans. Nonspecific histone deacetylase inhibitors, such as valproic acid, have been shown to improve survival in preclinical models of lethal trauma, hemorrhage, and sepsis. The doses needed to achieve a survival benefit are higher than Food and Drug Administration-approved doses, and the nonspecificity raises concerns about unintended adverse effects. The isoform-specific histone deacetylase 6 inhibitor, ACY-1083, has been found to be as efficacious as valproic acid in a rodent model of hemorrhagic shock. We hypothesized that ACY-1083 treatment would improve survival in a swine model of lethal hemorrhage, polytrauma, and bacteremia. Methods Swine were subjected to 45% blood volume hemorrhage, brain injury, femur fracture, rectus crush, splenic and liver lacerations, and colon injury. After 1 hour of shock (mean arterial pressure, 30-35 mm Hg), animals were randomized to normal saline resuscitation (control) or normal saline plus ACY-1083 30 mg/kg treatment (n = 5/group). After 3 hours (simulating delayed evacuation), packed red blood cells and antibiotics were administered, the colon injury was repaired, and the abdomen was closed. Animals were then monitored for another 4 hours. Survival was assessed using Kaplan-Meier and log-rank test. Results This combination of injuries was lethal. All animals became bacteremic, in addition to the severe hemorrhagic shock. Survival in the control group was 0%, and ACY-1083 treatment increased survival to 80% (p = 0.019). There was no difference in the brain lesion size between the groups. Conclusion A single dose of ACY-1083 markedly improves survival in an otherwise lethal model of polytrauma, hemorrhagic shock, and bacteremia.

BACKGROUND We have shown that administration of mesenchymal stem cell-derived exosomes (single dose given within 1 hour) in models of traumatic brain injury (TBI) and hemorrhagic shock 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 hemorrhagic shock (40% estimated total blood volume). One hour into shock, animals were randomized (n = 5/cohort) to receive either lactated Ringer's (LR; 5 mL) or exosomes suspended in LR (LR + EXO; 1 × 10 exosome particles in 5 mL LR). Animals then underwent additional shock (1 hour) followed by normal saline resuscitation. After 6 hours of observation, brain swelling (% increase compared with the uninjured side) and lesion size (mm) were assessed. Periinjured brain tissue was processed for RNA sequencing, analyzed with high through-put RNA sequencing data analysis, and results compared between control and experimental groups. RESULTS Exosome treatment significantly increased (p < 0.005) gene expression associated with neurogenesis, neuronal development, synaptogenesis, and neuroplasticity. It also significantly reduced (p < 0.005) genes associated with stroke, neuroinflammation, neuroepithelial cell proliferation, and nonneuronal cell proliferation contributing to reactive gliosis. Exosome treatment also significantly increased (p < 0.005) the genes that are associated with stability of blood-brain barrier. CONCLUSIONS Administration of a single dose of exosomes induces transcriptomic changes suggestive of neuroprotection. Their use as a treatment for TBI is promising and requires further investigation for human translation.

BACKGROUND: No agents that are specifically neuroprotective are currently approved to emergently treat patients with traumatic brain injury (TBI). The histone deacetylase inhibitor, high-dose valproic acid (VPA) has been shown to have cytoprotective potential in models of combined TBI and hemorrhagic shock, but it not been tested in an isolated TBI model. We hypothesized that VPA, administered after isolated TBI, will penetrate the injured brain, attenuate the lesion size, and activate pro-survival pathways. METHODS: Yorkshire swine were subjected to severe TBI by cortical impact. One hour later, animals were randomized to VPA treatment (150 mg/kg delivered intravenously over 1 hour; n=4) or control (saline vehicle; n=4) groups. Seven hours after injury, animals were sacrificed, and brain lesion size was measured. Mass spectrometry (MS) imaging was used to visualize and quantitate brain tissue distribution of VPA. Sequential serum samples were assayed for key biomarkers, and subjected to proteomic and pathway analysis. RESULTS: Brain lesion size was 50% smaller (p=0.01) in the VPA treated animals (3837±948 mm(3)) compared to the controls (1900±614 mm(3)). Endothelial regions had 8-fold higher VPA concentrations than perivascular regions by MS-imaging, and it readily penetrated the injured brain tissues. Serum glial fibrillary acid protein was significantly lower in the VPA-treated compared to the control animals (p

BACKGROUND Early single-dose treatment with human mesenchymal stem cell-derived exosomes promotes neuroprotection and promotes blood-brain barrier 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 days), 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 1 hour of shock, animals were randomized (n = 4/cohort) to receive either lactated Ringer's (5 mL) or lactated Ringer's with exosomes (1 × 10 exosome particles). After an additional hour of shock, animals were resuscitated with normal saline. Daily neurologic severity scores were compared. At 7 days following injury, lesion size, inflammatory markers, and mediators of inflammation (NF-κB), apoptosis (BAX), and neural plasticity (brain-derived neurotrophic factor) in brain tissue were compared between groups. RESULTS Exosome-treated animals had significantly lower neurologic severity scores (first 4 days; p < 0.05) and faster neurologic recovery. At 7 days, exosome-treated animals had significantly smaller (p < 0.05) brain lesion sizes. Exosome-treated animals also had significantly lower levels of inflammatory markers (interleukin [IL]-1, IL-6, IL-8, and IL-18) and higher granulocyte-macrophage colony-stimulating factor levels compared with the control animals, indicating specific impacts on various cytokines. The BAX and NF-κB levels were significantly lower (p < 0.05) in exosome-treated animals, while brain-derived neurotrophic factor levels were significantly higher (p < 0.05) in the exosome-treated animals. CONCLUSION 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 7-day period.

Purpose of review The development and implementation of 'increased risk donor' (IRD) status by the Centers for Disease Control (CDC) was intended to guide patients and providers in decision making regarding risk of infectious transmission via solid organ transplantation. Several contemporary studies have shown underutilization of these organs. This review summarizes the issues surrounding IRD status as well as recent advances in our understanding of the risks and benefits of increased risk organs and their appropriate utilization. Recent findings Risk of window-period infection remains exceedingly low, and implementation of nucleic acid testing for HIV and hepatitis C virus (HCV) has resulted in decreasing risk of window-period infection often by an order of magnitude or more. Surgeons remain hesitant to utilize IRD organs. In addition, surgeon assessment of risk by donor behaviour was often discordant with known risks of those behaviours. Studies investigating outcomes of utilization of IRD organs suggest long-term mortality and graft survival is at least equivalent to non-IRD organs. Contemporary results suggest that IRD organs continue to be underutilized, particularly adult kidneys and lungs, with hundreds of wasted organs per year. Summary CDC IRD labelling has led to an underutilization of organs for transplantation. The risks associated with acceptance of an IRD organ are inflated by surgeons and patients, and outcomes for patients who undergo transplantation with increased risk organs are similar to or better than those for patients whom accept standard risk organs. The rate of transmission of window-period infection from IRD organs is exceptionally low. The harms regarding the utility of Public Health Service increased risk classification outweigh the benefits for patients in need of transplant.

Surgical videos are commonly utilized by trainees to prepare for surgical cases. However, currently available videos tend to be of excessive length, variable quality, and exist behind paywalls or in other exclusive formats. Our objective was to create a series of videos that would address these shortcomings, and further allow for dynamic engagement between learners and experts.Our group created surgical videos using principles of microlearning, an educational strategy which deconstructs content into small units and uses social media platforms where learners and educators may actively engage. We published a library of short (3 min) videos covering various steps of abdominal transplantation operations on a YouTube channel. We leveraged Twitter to disseminate the content and engage with experts and learners from around the world.Multi-institutional.Over the period from July 2020 to January 2021, 24 microlearning videos were created, stored on a YouTube channel, and posted to Twitter weekly using a newly created account. During that time period, the videos, averaging 124 seconds in length, were viewed 4393 times and watched for a total of 127 hours. The account gained 611 followers in 37 countries and 37 US states with 312,400 impressions (defined as tweet views). Twitter users who engaged with our microlearning content (favorite, retweet, or reply) included faculty (27%), residents (21%), fellows (8%), and medical students (11%).Broad participation with the educational material and discussion on Twitter demonstrated the potential for the microlearning technique to provide educational benefit for learners internationally. The spread of the tweets shows an opportunity to augment traditional surgical education, and the willingness of faculty to discuss alternative techniques with their peers. Our group will continue to develop a library of microlearning videos for surgical operations and engage with other institutions for collaboration and expansion.

Supplemental Digital Content is available in the text., Background. Obesity is a barrier to transplant, reducing access and leading to worse outcomes versus nonobese adults. Most transplant centers in the United States maintain body mass index (BMI) cutoffs to listing for kidney transplantation of 35 to 40 kg/m2. There is little contemporary data on the prevalence of obesity among patients with end-stage kidney disease (ESKD) despite its impact on clinical outcomes and healthcare expenditures. Methods. We utilized data from the US Renal Data System from 2008 to 2016 to identify a prevalent cohort of 1 079 410 patients with ESKD. Linear regression determined trends in the proportion of patients within each category of BMI. We also evaluated geographic variation in rates of obesity and transplantation across the United States. Results. Among the 1 079 410 ESKD patients, the largest cohort of patients were those with obesity (n = 423 270; 39.2%). There were 309 707 (28.7%) patients with an overweight BMI and 274 683 (25.4%) with a normal BMI. The proportion of patients with obesity increased significantly from 36.8% in 2008 to 40.2% in 2016 (trend 0.28; 95% confidence interval, 0.05-0.51). There was significant geographic variation by state with rates of obesity ranging from 32.3% to 45.4% and state transplant rates among those obese patients ranging from 22.5% to 46.8%. There is a weak correlation between states with increased rates of obese ESKD patients and states with an increased obesity transplant rate as indicated with r = 0.40 (P = 0.003). Conclusions. Beneficiaries with obesity are now the largest and fastest growing demographic among patients with ESKD in the United States.

Prehospital identification of the injured patient likely to require emergent care remains a challenge. End-tidal carbon dioxide (ETCO2) has been used in the prehospital setting to monitor respiratory physiology and confirmation of endotracheal tube placement. Low levels of ETCO2 have been demonstrated to correlate with injury severity and mortality in a number of in-hospital studies. We hypothesized that prehospital ETCO2 values would be predictive of mortality and need for massive transfusion (MT) in intubated patients.This was a retrospective multicenter trial with 24 participating centers. Prehospital, emergency department, and hospital values were collected. Receiver operating characteristic curves were created and compared. Massive transfusion defined as10 U of blood in 6 hours or death in 6 hours with at least 1 U of blood transfused.A total of 1,324 patients were enrolled. ETCO2 (area under the receiver operating characteristic curve [AUROC], 0.67; confidence interval [CI], 0.63-0.71) was better in predicting mortality than shock index (SI) (AUROC, 0.55; CI, 0.50-0.60) and systolic blood pressure (SBP) (AUROC, 0.58; CI, 0.53-0.62) (p0.0005). Prehospital lowest ETCO2 (AUROC, 0.69; CI, 0.64-0.75), SBP (AUROC, 0.75; CI, 0.70-0.81), and SI (AUROC, 0.74; CI, 0.68-0.79) were all predictive of MT. Analysis of patients with normotension demonstrated lowest prehospital ETCO2 (AUROC, 0.66; CI, 0.61-0.71), which was more predictive of mortality than SBP (AUROC, 0.52; CI, 0.47-0.58) or SI (AUROC, 0.56; CI, 0.50-0.62) (p0.001). Lowest prehospital ETCO2 (AUROC, 0.75; CI, 0.65-0.84), SBP (AUROC, 0.63; CI, 0.54-0.74), and SI (AUROC, 0.64; CI, 0.54-0.75) were predictive of MT in normotensive patients. ETCO2 cutoff for MT was 26 mm Hg. The positive predictive value was 16.1%, and negative predictive value was high at 98.1%.Prehospital ETCO2 is predictive of mortality and MT. ETCO2 outperformed traditional measures such as SBP and SI in the prediction of mortality. ETCO2 may outperform traditional measures in predicting need for transfusion in occult shock.Diagnostic test, level III.

Key Points Question What proportion of readmissions after major surgery are potentially preventable? Findings This cohort study using a weighted sample of 1 937 354 patients found that 18% of readmissions within 90 days of hospital discharge were for a potentially preventable cause. Public insurance, compared with private insurance, was associated with an increased risk of potentially preventable readmission. Meaning This study suggests that improved access to ambulatory care in the postoperative period, particularly for high-risk patients, may be associated with a substantial reduction in postoperative readmissions after major surgery., Importance Rehospitalization after major surgery is common and represents a significant cost to the health care system. Little is known regarding the causes of these readmissions and the degree to which they may be preventable. Objective To evaluate the degree to which readmissions after major surgery are potentially preventable. Design, Setting, and Participants This retrospective cohort study used a weighted sample of 1 937 354 patients from the 2017 National Readmissions Database to evaluate all adult inpatient hospitalizations for 1 of 7 common major surgical procedures. Statistical analysis was performed from January 14 to November 30, 2020. Main Outcomes and Measures The study calculated 90-day readmission rates as well as rates of readmissions that were considered potentially preventable. Potentially preventable readmissions (PPRs) were defined as those with a primary diagnosis code for superficial surgical site infection, acute kidney injury, aspiration pneumonitis, or any of the Agency for Healthcare Research and Quality–defined ambulatory care sensitive conditions. Multivariable logistic regression was used to identify factors associated with PPRs. Results A total weighted sample of 1 937 354 patients (1 048 046 women [54.1%]; mean age, 66.1 years [95% CI, 66.0-66.3 years]) underwent surgical procedures; 164 755 (8.5%) experienced a readmission within 90 days. Potentially preventable readmissions accounted for 29 321 (17.8%) of all 90-day readmissions, for an estimated total cost to the US health care system of approximately $296 million. The most common reasons for PPRs were congestive heart failure exacerbation (34.6%), pneumonia (12.0%), and acute kidney injury (22.5%). In a multivariable model of adults aged 18 to 64 years, patients with public health insurance (Medicare or Medicaid) had more than twice the odds of PPR compared with those with private insurance (adjusted odds ratio, 2.09; 95% CI, 1.94-2.25). Among patients aged 65 years or older, patients with private insured had 18% lower odds of PPR compared with patients with Medicare as the primary payer (adjusted odds ratio, 0.82; 95% CI, 0.74-0.90). Conclusions and Relevance This study suggests that nearly 1 in 5 readmissions after surgery are potentially preventable and account for nearly $300 million in costs. In addition to better inpatient care, improved access to ambulatory care may represent an opportunity to reduce costly readmissions among surgical patients., This cohort study uses data from the 2017 National Readmissions Database to evaluate the degree to which readmissions after major surgery are potentially preventable.

Background COVID-19 has mandated rapid adoption of telehealth for surgical care. However, many surgical providers may be unfamiliar with telehealth. This study evaluates the perspectives of surgical providers practicing telehealth care during COVID-19 to help identify targets for surgical telehealth optimization. Materials and Methods At a single tertiary care center with telehealth capabilities, all department of surgery providers (attending surgeons, residents, fellows, and advanced practice providers) were emailed a voluntary survey focused on telehealth during the pandemic. Descriptive statistics and Mann-Whitney U analyses were performed as appropriate on responses. Text responses were thematically coded to identify key concepts. Results The completion rate was 41.3% (145/351). Providers reported increased telehealth usage relative to the pandemic (p

Background Hemorrhage is a leading cause of mortality in trauma. Resuscitative endovascular balloon occlusion of the aorta (REBOA) can control hemorrhage, but distal ischemia, subsequent reperfusion injury, and the need for frequent balloon titration remain problems. Improved device design can allow for partial REBOA (pREBOA) that may provide hemorrhage control while also perfusing distally without need for significant provider titration. Methods Female Yorkshire swine (N = 10) were subjected to 40% hemorrhagic shock for 1 hour (mean arterial pressure [MAP], 28-32 mm Hg). Animals were then randomized to either complete aortic occlusion (ER-REBOA) or partial occlusion (novel pREBOA-PRO) without frequent provider titration or distal MAP targets. Detection of a trace distal waveform determined partial occlusion in the pREBOA-PRO arm. After 2 hours of zone 1 occlusion, the hemorrhaged whole blood was returned. After 50% autotransfusion, the balloon was deflated over a 10-minute period. Following transfusion, the animals were survived for 2 hours while receiving resuscitation based on objective targets: lactated Ringer's fluid boluses (goal central venous pressure, ≥ 6 mm Hg), a norepinephrine infusion (goal MAP, 55-60 mm Hg), and acid-base correction (goal pH, >7.2). Hemodynamic variables, arterial lactate, lactate dehydrogenase, aspartate aminotransferase, and creatinine levels were measured. Results All animals survived throughout the experiment, with similar increase in proximal MAPs in both groups. Animals that underwent partial occlusion had slightly higher distal MAPs. At the end of the experiment, the partial occlusion group had lower end levels of serum lactate (p = 0.006), lactate dehydrogenase (p = 0.0004) and aspartate aminotransferase (p = 0.004). Animals that underwent partial occlusion required less norepinephrine (p = 0.002), less bicarbonate administration (p = 0.006), and less fluid resuscitation (p = 0.042). Conclusion Improved design for pREBOA can decrease the degree of distal ischemia and reperfusion injury compared with complete aortic occlusion, while providing a similar increase in proximal MAPs. This can allow pREBOA zone-1 deployment for longer periods without the need for significant balloon titration.

BackgroundTraumatic brain injury (TBI) is a leading cause of morbidity and mortality. There are currently no cytoprotective treatments for TBI. There is growing evidence that the histone deacetylase inhibitor valproic acid (VPA) may be beneficial in the treatment of TBI associated with hemorrhagic shock and in isolation. We sought to further evaluate the mechanistic underpinnings of this demonstrated efficacy via proteomic analysis of injured brain tissue.MethodsSwine were subjected to TBI via controlled cortical impact, randomized to treatment with VPA or control and observed for 6 hours. The brains of the pigs were then sectioned, and tissue was prepared and analyzed for proteomic data, including gene ontology (GO), gene-set enrichment analysis and enrichment mapping, and network mapping.ResultsProteomic analysis demonstrated differential expression of hundreds of proteins in injured brain tissue after treatment with VPA. GO analysis and network analyses revealed groups of proteins and processes that are known to modulate injury response after TBI and impact cell fate. Processes affected included protein targeting and transport, cation and G-protein signaling, metabolic response, neurotransmitter response and immune function.DiscussionThis proteomic analysis provides initial mechanistic insight into the observed rescue of injured brain tissue after VPA administration in isolated TBI.Level of evidenceNot applicable (animal study).

BACKGROUND Traumatic brain injury (TBI) and hemorrhage remain the leading causes of death after trauma. We have previously shown that a dose of valproic acid (VPA) at (150 mg/kg) can decrease brain lesion size and hasten neurologic recovery. The current Food and Drug Administration-approved dose of VPA is 60 mg/kg. We evaluate neurologic outcomes and brain lesion size of a single dose of VPA at a level currently within Food and Drug Administration-approved dose in swine subjected to TBI and hemorrhagic shock. METHODS Swine (n = 5/group) were subjected to TBI and 40% blood volume hemorrhage. Animals remained in shock for 2 hours before randomization to normal saline (NS) resuscitation alone (control), NS-VPA 150 mg/kg (VPA 150), or NS-VPA 50 mg/kg (VPA 50). Neurologic severity scores (range, 0-32) were assessed daily for 14 days, and brain lesion size was measured via magnetic resonance imaging on postinjury day (PID) 3. RESULTS Shock severity and laboratory values were similar in all groups. Valproic acid-treated animals demonstrated significantly less neurologic impairment on PID 1 and returned to baseline faster (PID 1 mean neurologic severity score, control = 22 ± 3 vs. VPA 150 mg/kg = 8 ± 7 or VPA 50 mg/kg = 6 ± 6; p = 0.02 and 0.003). Valproic acid-treated animals had significantly smaller brain lesion sizes (mean volume in mm3, control = 1,268.0 ± 241.2 vs. VPA 150 mg/kg = 620.4 ± 328.0 or VPA 50 mg/kg = 438.6 ± 234.8; p = 0.007 and 0.001). CONCLUSION In swine subjected to TBI and hemorrhagic shock, VPA treatment, in a dose that is approved for clinical use, decreases brain lesion size and reduces neurologic impairment compared with resuscitation alone.

Objective Valproic acid (VPA) treatment improves survival in animal models of injuries on doses higher than those allowed by Food and Drug Administration (FDA). We investigated the proteomic alterations induced by a single high-dose (140mg/kg) of VPA (VPA140) compared to the FDA-approved dose of 30mg/kg (VPA30) in healthy humans. We also describe the proteomic and transcriptomic changes induced by VPA140 in an injured patient. We hypothesized that VPA140 would induce cytoprotective changes in the study participants. Methods Serum samples were obtained from healthy subjects randomized to two groups; VPA140 and VPA30 at 3 timepoints: 0h(baseline), 2h, and 24h following infusion(n = 3/group). Samples were also obtained from an injured patient that received VPA140 at 0h, 6h and 24h following infusion. Proteomic analyses were performed using liquid chromatography-mass spectrometry (LC-MS/MS), and transcriptomic analysis was performed using RNA-sequencing. Differentially expressed (DE) proteins and genes were identified for functional annotation and pathway analysis using iPathwayGuide and gene set enrichment analysis (GSEA), respectively. Results For healthy individuals, a dose comparison was performed between VPA140 and VPA30 groups at 2 and 24 h. Functional annotation showed that top biological processes in VPA140 versus VPA30 analysis at 2 h included regulation of fatty acid (P = 0.002) and ATP biosynthesis (P = 0.007), response to hypoxia (P = 0.017), cell polarity regulation (P = 0.031), and sequestration of calcium ions (P = 0.031). Top processes at 24 h in VPA140 versus VPA30 analysis included amino acid metabolism (P = 0.023), collagen catabolism (P = 0.023), and regulation of protein breakdown (P = 0.023). In the injured patient, annotation of the DE proteins in the serum showed that top biological processes at 2 h included neutrophil chemotaxis (P = 0.002), regulation of cellular response to heat (P = 0.008), regulation of oxidative stress (P = 0.008) and regulation of apoptotic signaling pathway (P = 0.008). Top biological processes in the injured patient at 24 h included autophagy (P = 0.01), glycolysis (P = 0.01), regulation of apoptosis (P = 0.01) and neuron apoptotic processes (P = 0.02). Conclusions VPA140 induces cytoprotective changes in human proteome not observed in VPA30. These changes may be responsible for its protective effects in response to injuries.

Early identification of and response to barriers in telehealth settings will help patients receive optimal care. Here, the authors, based on institutional experience, provide advice on such strategies. This guidance focuses on standardizing expectations, assessing technological knowledge and resource access, evaluating understanding and comfort with telehealth, and assessing social support.

BackgroundTrauma 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.MethodsOur 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.ResultsAll 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.ConclusionWe 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 evidenceNot applicable. Animal study.

Objective Morning rounds are a bedrock learning opportunity during clinical rotations in medical school. Specific feedback is critical for students to improve presentation skills and build confidence, however, current feedback mechanisms are fragmented and nonstandard. We aimed to assess whether video-based coaching of morning rounds could improve student feedback and self-awareness without increasing anxiety during patient presentations. Design Medical students during core clinical clerkships were filmed presenting on morning rounds during their surgery clerkship. A designated faculty coach reviewed the video prior to an in-person coaching session. Students reviewed the video with faculty and were coached on content, presentation style, and presence. A short survey assessed students’ pre- and postcoaching confidence, skill, and the utility of the coaching session. Setting University of Michigan Health System, Department of Surgery, Division of General Surgery, Ann Arbor, Michigan Participants Eight medical student volunteers during their core clinical clerkships at University of Michigan Medical School during the surgery clerkship. Results Comparison of pre- and post self-assessments showed that students underestimated their knowledge of basic and clinical science and overestimated their clinical assessment skills and ability to appropriately address the core components of a presentation. Most students (75%) did not think that the filming process altered their performance and only 25% of students felt increased anxiety due to filming. All students agreed that the feedback session was useful and helped them understand how to improve their oral presentations. Conclusion This pilot demonstrates the feasibility and value of video-based coaching as an educational tool for medical students on clerkships. A larger sample size is needed to further evaluate the effectiveness of video-based coaching in establishing baseline clinical abilities and identifying potential areas for improvement.

Trauma is the leading cause of death among young people. These patients have a high incidence of kidney injury, which independently increases the risk of mortality. As valproic acid (VPA) treatment has been shown to improve survival in animal models of lethal trauma, we hypothesized that it would also attenuate the degree of acute kidney injury.We analyzed data from two separate experiments where swine were subjected to lethal insults. Model 1: hemorrhage (50% blood volume hemorrhage followed by 72-h damage control resuscitation). Model 2: polytrauma (traumatic brain injury, 40% blood volume hemorrhage, femur fracture, rectus crush and grade V liver laceration). Animals were resuscitated with normal saline (NS) +/- VPA 150 mg/kg after a 1-h shock phase in both models (n = 5-6/group). Serum samples were analyzed for creatinine (Cr) using colorimetry on a Liasys 330 chemistry analyzer. Proteomic analysis was performed on kidney tissue sampled at the time of necropsy.VPA treatment significantly (P0.05) improved survival in both models. (Model 1: 80% vs 20%; Model 2: 83% vs. 17%). Model 1 (Hemorrhage alone): Cr increased from a baseline of 1.2 to 3.0 in NS control animals (P0.0001) 8 h after hemorrhage, whereas it rose only to 2.1 in VPA treated animals (P = 0.004). Model 2 (Polytrauma): Cr levels increased from baseline of 1.3 to 2.5 mg/dL (P = 0.01) in NS control animals 4 h after injury but rose to only 1.8 in VPA treated animals (P = 0.02). Proteomic analysis of kidney tissue identified metabolic pathways were most affected by VPA treatment.A single dose of VPA (150 mg/kg) offers significant protection against acute kidney injury in swine models of polytrauma and hemorrhagic shock.

BACKGROUND Hemorrhage is the leading cause of preventable death in trauma. Future military conflicts are likely to be in austere environments, where prolonged damage-control resuscitation (p-DCR) may be required for 72 hours before evacuation. There is a need to demonstrate that p-DCR is feasible and to optimize its logistics. Dried plasma (DP) is a practical alternative to conventional blood products in austere settings, and valproic acid (VPA) improves survival in preclinical models of trauma and hemorrhage. We performed the current experiment to study the synergistic effects of VPA and DP and hypothesized that VPA treatment would decrease the fluid resuscitation requirements in p-DCR. METHODS Female swine were subjected to 50% hemorrhage (associated with 20% survival using non-plasma-based p-DCR) and left unresuscitated for 1 hour to simulate medic response time. They were then randomized to receive VPA (150 mg/kg + DP 250 mL; DP-VPA group; n = 5) or DP alone (DP group; n = 6). All animals were resuscitated to a systolic blood pressure of 80 mm Hg with lactated Ringer according to the Tactical Combat Casualty Care Guidelines for 72 hours, after which packed red blood cells were transfused to simulate evacuation to higher levels of care. RESULTS The DP-VPA group needed significantly (p = 0.002) less volume of lactated Ringer to reach and maintain the target systolic blood pressure. This would translate to a 4.3 L volume sparing effect for a 70-kg person. CONCLUSION Addition of a single dose of VPA significantly decreases the volume of resuscitation required in a p-DCR model.

Not Dying Alone When the wife of a severely ill patient with Covid-19 is told she can’t visit him, her anger quickly gives way to pleading — “What if I only spent 5 minutes and left?” How can we ha...

With the growing use of telehealth, understanding factors affecting patient follow-up in traditional and telehealth settings is important. Few data exist examining the use of telehealth compared with traditional settings. Bridging this gap is critical to optimizing telehealth use and reducing barriers.This is a retrospective cohort study of return and postoperative (electronic video [eClinic] and traditional) visits from January 2018 to March 2020 at single tertiary care center. There were 12,359 unique first-encounter patients with 903 eClinic and 11,456 traditional visits; 11,547 patients completed visits, while 812 patients did not show up. Multivariable logistic regression modeling was performed to identify factors associated with no-show. County-level mapping was used to identify patterns in no-show rates.Patients from the eClinic had twice the odds of no-show compared with those from a traditional clinic (p0.001). Age was inversely proportional to odds of no-show, with each additional decade associated with a 16% decrease in these odds (p 0.001). African-American patients had greater odds of no-show compared to Caucasian patients (odds ratio [OR] 2.47; 95% CI 1.95-3.13, p0.001). Marital statuses of single and legal separation were associated with higher odds of no-show compared with married marital status (p0.001 and p = 0.04, respectively). Minimally invasive and endocrine surgery clinics had lower odds of no-show compared with acute care surgery clinic (p 0.001 for both). County-level no-show rates demonstrate similar patterns between clinic settings.Several factors are associated with increased odds of no-show, including the visit being in eClinic. County-level analysis suggests no-show variation is not dependent on geographic location. Understanding these patterns allows for prospective identification of barriers and development of interventions to optimize access and patient care.

A form of telehealth, a surgical electronic clinic (E-clinic, video or telephone visit) is a safe and efficient way for delivering care; however, factors leading to poor clinic utilization are not well-described. This study was performed to gather electronic clinic utilization data and to better define barriers to visit completion.A retrospective review of 199 patients cared for by a general surgery service with subsequent referral to the electronic clinic (January 2019 to June 2019) was performed. Data regarding demographics, medical characteristics, travel distance, and postoperative complications were collected. Patients were categorized based upon visit completion. The χMore than 1/5 of all patients (21.6%) failed to complete the visit. No differences were observed in completion rates according to the type of operation, American Society of Anesthesiologists classification, and age. The failed-completion group had a significantly (P.05) higher proportion of non-Caucasian patients and those with a marital status of single. Travel distance had no impact. Complication rates were low. Pre-clinic readmission within 30 days contributed to failed completion. Reasons for cancellation included medical issues, technical difficulties, and patient preference to have no follow-up in the electronic clinic.Several factors contribute to a patient's failure to complete an electronic clinic visit including marital status, medical complications, technical issues, and patient preference. Electronic clinic utilization patterns also demonstrate racial disparities. Successful electronic clinic program implementation requires understanding the factors that contribute to failed visits to address them and improve access.

The leading causes of death in military conflicts continue to be hemorrhagic shock (HS) and traumatic brain injury (TBI). Most of the mortality is a result of patients not surviving long enough to obtain surgical care. As a result, there is a significant unmet need for a therapy that stimulates a "prosurvival phenotype" that counteracts the cellular pathophysiology of HS and TBI to prolong survival. Valproic acid (VPA), a well-established antiepileptic therapy for more than 50 years, has shown potential as one such prosurvival therapy. This review details how VPA's role as a nonselective histone deacetylase inhibitor induces cellular changes that promote survival and decrease cellular pathways that lead to cell death. The review comprehensively covers more than two decades worth of studies ranging from preclinical (mice, swine) to recent human clinical trials of the use of VPA in HS and TBI. Furthermore, it details the different mechanisms in which VPA alters gene expression, induces cytoprotective changes, attenuates platelet dysfunction, provides neuroprotection, and enhances survival in HS and TBI. Valproic acid shows real promise as a therapy that can induce the prosurvival phenotype in those injured during military conflict.

Conducting research in an intensive care unit (ICU) is both challenging and rewarding. ICU patients are heterogeneous, complex, and critically ill. Despite these challenges, the ICU is a data-rich research environment that lends itself to cutting-edge clinical investigation. To optimize research outcomes, investigators must carefully consider the principles of study design. This review discusses the most commonly used observational, experimental, and meta-analytic study designs, as well as the theoretical underpinnings of each study type. Published ICU-based research studies are used as examples to highlight key concepts. This review contains 4 figures, 9 tables, and 33 references. Key words: clinical research, experimental studies, intensive care, meta-analyses, observational studies, study design

Anticoagulation pharmacy has been dramatically altered with US Food and Drug Administration (FDA) approval of 5 direct oral anticoagulants, 1 novel reversal agent and, a second designated for fast-track approval. Trial data surrounding current trends in anticoagulant choice for VTE, reversal, and bridging are constantly redefining practice. Extended therapy for unprovoked VTE has expanded to include low-dose direct oral anticoagulants, aspirin, and the use of the HERDOO2 system to identify women who can stop anticoagulant therapy without increased risk of recurrent VTE. Trends in thromboprophylaxis include extended duration low-dose direct oral anticoagulants to prevent VTE in high-risk patients.

Background Trauma is the leading cause of death in the United States for persons under 44 years and the fourth leading cause of death in the elderly. Advancements in clinical care and standardization of treatment protocols have reduced 30-day trauma mortality to less than 4%. However, these improvements do not seem to correlate with long-term outcomes. Some reports have shown a greater than 20% mortality rate when looking at long-term outcomes. The aim of this study was to systematically review the incongruence between short- and long-term mortality for trauma patients. Methods For this systematic review, we searched the Cochrane Library, EMBASE, Ovid Medline, Google Scholar, and Web of Science database to obtain relevant English, German, French, and Portuguese articles from 1965 to 2018. Results Trauma patients have decreased long-term survival when compared to the general population and when compared with age-matched cohorts. Postdischarge trauma mortality is significantly higher (mean, 4.6% at 3-6 months, 15.8% at 2-3 years, 26.3% at 5-25 years) compared with controls (mean, 1.3%, 2.2%, and 15.6%, respectively). Patient comorbidities likely contribute to long-term trauma deaths. Trauma patients discharged to a skilled nursing facility have worse mortality compared with those discharged either to home or a rehabilitation center. In contrast to data available which illustrate that short-term mortality has improved, quality of evidence was not sufficient to determine if any improvements in long-term trauma mortality outcomes have also occurred. Conclusions The decreased short-term mortality observed in trauma patients does not appear correlated with decreased long-term mortality. The extent to which increased long-term trauma mortality is related to the initial traumatic insult-versus rising population age and comorbidity burden as well as suboptimal discharge location-requires further study. Level of evidence Systematic Review, level IV.

Nearly 9% of men and 30% of women in the United States experience symptoms or complications of gallstone disease. As such, nearly every general surgeon in the country encounters patients with this pathology numerous times during his or her career. Cholelithiasis can cause complications such as acute cholecystitis, choledocholithiasis, gallstone pancreatitis, and the rare entities of Mirizzi syndrome and gallstone ileus. Patients with gallstones have a 1 to 3% risk per year of a complication, and that risk increases significantly to 30% in those with biliary colic. Surgical management of the complications of gallstones is especially intriguing because the cases are often perceived as low complexity; however, it is an operation that can challenge even the most seasoned attending and result in significant complications. Studies demonstrate complication rates up to 10% following cholecystectomy, with bile duct injury rates hovering at 4 in 1,000. This chapter aims to provide the reader with knowledge of the presentation, imaging, work-up, and framework for the management of complicate gallbladder disease. Furthermore, we hope to provide you with a foundation of how to perform a safe cholecystectomy in a variety of circumstances and impart a few tips and tricks for some challenging intraoperative situations. This review contains 2 figures, and 55 references. Key Words: cholecystitis, choledocholithiasis, cholescintigraphy, common bile duct exploration, critical view of safety, ERCP, gallstone pancreatitis, subtotal cholecystectomy

BackgroundIntraosseous (IO) drug delivery may be necessary in emergency situations when intravenous access is unattainable. Valproic acid (VPA) is a histone deacetylase inhibitor that has previously been shown to improve survival in preclinical models of lethal polytrauma. In this study, we sought to compare serum levels of intravenously and IO-delivered VPA, and to analyze the effect of IO-delivered VPA.MethodsSwine were subjected to 40% blood volume hemorrhage, brain injury, femur fracture, rectus crush injury and liver laceration. After 1 hour of shock, animals were randomized (n=3/group) to receive normal saline resuscitation (control), normal saline+intravenous VPA 150 mg/kg (intravenous group) or normal saline +IO VPA 150 mg/kg (IO group). Serum levels of VPA were assessed between groups, and proteomics analyses were performed on IO and control groups on heart, lung and liver samples.ResultsIntravenous and IO serum VPA levels were similar at 1, 3, 5 and 7 hours after starting the infusion (p>0.05). IO-delivered VPA induced significant proteomics changes in the heart, lung and liver, which were most pronounced in the lung. Biologic processes affected included inflammation, metabolism and transcriptional & translational machinery. The control group had 0% survival, and the intravenous and IO group both had 100% survival to the end of the experiment (pDiscussionIO-delivered VPA is noninferior to intravenous administration and is a viable option in emergent situations when intravenous access is unattainable.Level of evidenceNot applicable (animal study).

BackgroundOutcome after traumatic injury has typically been limited to the determination at time of discharge or brief follow-up. This study investigates the natural history of long-term survival after trauma.MethodsAll highest-level activation patients prospectively enrolled in an ongoing cohort study from 2005 to 2012 were selected. To allow for long-term follow-up, patients had to be enrolled at least 1 year before the latest available data from the National Death Index (NDI, 2013). Time and cause of mortality was determined based on death certificates. Survival status was determined by the latest date of either care in our institution or NDI query. Kaplan-Meier curves were created stratified for Injury Severity Score (ISS). Survival was compared with estimated actuarial survival based on age, sex, and race.ResultsA total of 908 highest-level activation patients (median ISS, 18) were followed up for a median 1.7 years (interquartile range 1.0-2.9; maximum, 9.8 years). Survival data were available on 99.8%. Overall survival was 73% (663 of 908). For those with at least 2-year follow-up, survival was only 62% (317 of 509). Severity of injury predicted long-term survival (p < 0.0001) with those having ISS of 25 or greater with the poorest outcome (57% survival at 5 years). For all ISS groups, survival was worse than predicted actuarial survival (p < 0.001). When excluding early deaths (≤30 days), observed survival was still significantly lower than estimated actuarial survival (p < 0.002). Eighteen percent (44 of 245 deaths) of all deaths occurred after 30 days. Among late deaths, 53% occurred between 31 days and 1 year after trauma. Trauma-related mortality was the leading cause of postdischarge death, accounting for 43% of the late deaths.ConclusionPostdischarge deaths represent a significant percentage of total trauma-related mortality. Despite having "survived" to leave the hospital, long-term survival was worse than predicted actuarial survival, suggesting that the mortality from injury does not end at "successful" hospital discharge.Level of evidencePrognostic study, level III.

Author(s): Callcut, Rachael A; Moore, Sara; Wakam, Glenn; Hubbard, Alan E; Cohen, Mitchell J | Abstract: IntroductionDelayed notification and lack of early information hinder timely hospital based activations in large scale multiple casualty events. We hypothesized that Twitter real-time data would produce a unique and reproducible signal within minutes of multiple casualty events and we investigated the timing of the signal compared with other hospital disaster notification mechanisms.MethodsUsing disaster specific search terms, all relevant tweets from the event to 7 days post-event were analyzed for 5 recent US based multiple casualty events (Boston Bombing [BB], SF Plane Crash [SF], Napa Earthquake [NE], Sandy Hook [SH], and Marysville Shooting [MV]). Quantitative and qualitative analysis of tweet utilization were compared across events.ResultsOver 3.8 million tweets were analyzed (SH 1.8 m, BB 1.1m, SF 430k, MV 250k, NE 205k). Peak tweets per min ranged from 209-3326. The mean followers per tweeter ranged from 3382-9992 across events. Retweets were tweeted a mean of 82-564 times per event. Tweets occurred very rapidly for all events (l2 mins) and represented 1% of the total event specific tweets in a median of 13 minutes of the first 911 calls. A 200 tweets/min threshold was reached fastest with NE (2 min), BB (7 min), and SF (18 mins). If this threshold was utilized as a signaling mechanism to place local hospitals on standby for possible large scale events, in all case studies, this signal would have preceded patient arrival. Importantly, this threshold for signaling would also have preceded traditional disaster notification mechanisms in SF, NE, and simultaneous with BB and MV.ConclusionsSocial media data has demonstrated that this mechanism is a powerful, predictable, and potentially important resource for optimizing disaster response. Further investigated is warranted to assess the utility of prospective signally thresholds for hospital based activation.