Dynamics of cortical contrast adaptation predict perception of signals in noise.

Neurons throughout the sensory pathway adapt their responses depending on the statistical structure of the sensory environment. Contrast gain control is a form of adaptation in the auditory cortex, but it is unclear whether the dynamics of gain control reflect efficient adaptation, and whether they shape behavioral perception. Here, we trained mice to detect a target presented in background noise shortly after a change in the contrast of the background. The observed changes in cortical gain and behavioral detection followed the dynamics of a normative model of efficient contrast gain control; specifically, target detection and sensitivity improved slowly in low contrast, but degraded rapidly in high contrast. Auditory cortex was required for this task, and cortical responses were not only similarly affected by contrast but predicted variability in behavioral performance. Combined, our results demonstrate that dynamic gain adaptation supports efficient coding in auditory cortex and predicts the perception of sounds in noise.

Lived Experience-Led Research Agenda to Address Early Death in People With a Diagnosis of a Serious Mental Illness: A Consensus Statement.

Importance: People with serious mental illness (SMI), defined as a diagnosis of schizophrenia spectrum disorder, bipolar disorder, or disabling major depressive disorder) die approximately 10 to 25 years earlier than the general population. Objective: To develop the first-ever lived experience-led research agenda to address early mortality in people with SMI. Evidence Review: A virtual 2-day roundtable comprising 40 individuals convened on May 24 and May 26, 2022, and used a virtual Delphi method to arrive at expert group consensus. Participants responded to 6 rounds of virtual Delphi discussion via email that prioritized research topics and agreement on recommendations. The roundtable was composed of individuals with lived experience of mental health and/or substance misuse, peer support specialists, recovery coaches, parents and caregivers of people with SMI, researchers and clinician-scientists with and without lived experience, policy makers, and patient-led organizations. Twenty-two of 28 (78.6%) of the authors who provided data represented people with lived experiences. Roundtable members were selected by reviewing the peer-reviewed and gray literature on early mortality and SMI, direct email, and snowball sampling. Findings: The following recommendations are presented in order of priority as identified by the roundtable participants: (1) improve the empirical understanding of the direct and indirect social and biological contributions of trauma on morbidity and early mortality; (2) advance the role of family, extended families, and informal supporters; (3) recognize the importance of co-occurring disorders and early mortality; (4) redefine clinical education to reduce stigma and support clinicians through technological advancements to improve diagnostic accuracy; (5) examine outcomes meaningful to people with an SMI diagnosis, such as loneliness and sense of belonging, and stigma and their complex relationship with early mortality; (6) advance the science of pharmaceuticals, drug discovery, and choice in medication use; (7) use precision medicine to inform treatment; and (8) redefine the terms system literacy and health literacy. Conclusions and Relevance: The recommendations of this roundtable are a starting point for changing practice and highlighting lived experience-led research priorities as an option to move the field forward.

Sound Improves Neuronal Encoding of Visual Stimuli in Mouse Primary Visual Cortex.

In everyday life, we integrate visual and auditory information in routine tasks such as navigation and communication. While concurrent sound can improve visual perception, the neuronal correlates of audiovisual integration are not fully understood. Specifically, it remains unclear whether neuronal firing patters in the primary visual cortex (V1) of awake animals demonstrate similar sound-induced improvement in visual discriminability. Furthermore, presentation of sound is associated with movement in the subjects, but little is understood about whether and how sound-associated movement affects audiovisual integration in V1. Here, we investigated how sound and movement interact to modulate V1 visual responses in awake, head-fixed mice and whether this interaction improves neuronal encoding of the visual stimulus. We presented visual drifting gratings with and without simultaneous auditory white noise to awake mice while recording mouse movement and V1 neuronal activity. Sound modulated activity of 80% of light-responsive neurons, with 95% of neurons increasing activity when the auditory stimulus was present. A generalized linear model (GLM) revealed that sound and movement had distinct and complementary effects of the neuronal visual responses. Furthermore, decoding of the visual stimulus from the neuronal activity was improved with sound, an effect that persisted even when controlling for movement. These results demonstrate that sound and movement modulate visual responses in complementary ways, improving neuronal representation of the visual stimulus. This study clarifies the role of movement as a potential confound in neuronal audiovisual responses and expands our knowledge of how multimodal processing is mediated at a neuronal level in the awake brain.SIGNIFICANCE STATEMENT Sound and movement are both known to modulate visual responses in the primary visual cortex; however, sound-induced movement has largely remained unaccounted for as a potential confound in audiovisual studies in awake animals. Here, authors found that sound and movement both modulate visual responses in an important visual brain area, the primary visual cortex, in distinct, yet complementary ways. Furthermore, sound improved encoding of the visual stimulus even when accounting for movement. This study reconciles contrasting theories on the mechanism underlying audiovisual integration and asserts the primary visual cortex as a key brain region participating in tripartite sensory interactions.

Emerging role of positron emission tomography (PET) imaging in cardiac surgery.

Historically, structural and anatomical imaging has been the mainstay in the diagnosis and management of cardiovascular diseases. In recent years there has been a shift toward increased use of functional imaging studies, including positron emission tomography (PET). PET is a noninvasive nuclear medicine-imaging technique that uses radiotracers to generate images of a radionucleotide distribution by detecting the physiologic substrates that emit positron radionuclides. This article will focus on the applications of PET imaging for the cardiac surgeon and highlight the collaborative nature of using PET imaging for the management of complex heart disease. We present cases that demonstrate the value of using PET imaging in the diagnosis of coronary artery disease and management of complex endocarditis, and in targeted cardiovascular therapies.

Prediction of Postoperative Deterioration in Cardiac Surgery Patients Using Electronic Health Record and Physiologic Waveform Data.

BACKGROUND: Postoperative hemodynamic deterioration among cardiac surgical patients can indicate or lead to adverse outcomes. Whereas prediction models for such events using electronic health records or physiologic waveform data are previously described, their combined value remains incompletely defined. The authors hypothesized that models incorporating electronic health record and processed waveform signal data (electrocardiogram lead II, pulse plethysmography, arterial catheter tracing) would yield improved performance versus either modality alone. METHODS: Intensive care unit data were reviewed after elective adult cardiac surgical procedures at an academic center between 2013 and 2020. Model features included electronic health record features and physiologic waveforms. Tensor decomposition was used for waveform feature reduction. Machine learning-based prediction models included a 2013 to 2017 training set and a 2017 to 2020 temporal holdout test set. The primary outcome was a postoperative deterioration event, defined as a composite of low cardiac index of less than 2.0 ml min-1 m-2, mean arterial pressure of less than 55 mmHg sustained for 120 min or longer, new or escalated inotrope/vasopressor infusion, epinephrine bolus of 1 mg or more, or intensive care unit mortality. Prediction models analyzed data 8 h before events. RESULTS: Among 1,555 cases, 185 (12%) experienced 276 deterioration events, most commonly including low cardiac index (7.0% of patients), new inotrope (1.9%), and sustained hypotension (1.4%). The best performing model on the 2013 to 2017 training set yielded a C-statistic of 0.803 (95% CI, 0.799 to 0.807), although performance was substantially lower in the 2017 to 2020 test set (0.709, 0.705 to 0.712). Test set performance of the combined model was greater than corresponding models limited to solely electronic health record features (0.641; 95% CI, 0.637 to 0.646) or waveform features (0.697; 95% CI, 0.693 to 0.701). CONCLUSIONS: Clinical deterioration prediction models combining electronic health record data and waveform data were superior to either modality alone, and performance of combined models was primarily driven by waveform data. Decreased performance of prediction models during temporal validation may be explained by data set shift, a core challenge of healthcare prediction modeling.

Prediction of postoperative cardiac events in multiple surgical cohorts using a multimodal and integrative decision support system.

Postoperative patients are at risk of life-threatening complications such as hemodynamic decompensation or arrhythmia. Automated detection of patients with such risks via a real-time clinical decision support system may provide opportunities for early and timely interventions that can significantly improve patient outcomes. We utilize multimodal features derived from digital signal processing techniques and tensor formation, as well as the electronic health record (EHR), to create machine learning models that predict the occurrence of several life-threatening complications up to 4 hours prior to the event. In order to ensure that our models are generalizable across different surgical cohorts, we trained the models on a cardiac surgery cohort and tested them on vascular and non-cardiac acute surgery cohorts. The best performing models achieved an area under the receiver operating characteristic curve (AUROC) of 0.94 on training and 0.94 and 0.82, respectively, on testing for the 0.5-hour interval. The AUROCs only slightly dropped to 0.93, 0.92, and 0.77, respectively, for the 4-hour interval. This study serves as a proof-of-concept that EHR data and physiologic waveform data can be combined to enable the early detection of postoperative deterioration events.

Management of a traumatic avulsion of the right upper lobe bronchus.

Tracheobronchial injuries are rare but life-threatening and require early diagnosis, appropriate airway management, and emergent surgical intervention. We report a case of a post-traumatic, isolated avulsion of the right upper lobe bronchus in a 60-year-old woman involved in a pedestrian versus motor vehicle accident. After transfer from an outside hospital with a single lumen endotracheal tube and multiple right sided chest tubes with large air leaks, the patient was taken to the OR for bronchoscopy and surgical exploration. Intraoperatively, a complete avulsion of the right upper lobe was noted. Due to the extended time period from original injury and excellent reported functional status, our patient underwent completion lobectomy of the right upper lobe, primary bronchial repair, with an azygous vein flap.

Ultrasonic Emulsification of Severe Mitral Annular Calcification During Mitral Valve Replacement.

PURPOSE: Severe mitral annular calcification (MAC) increases surgical complexity and is independently associated with increased operative mortality for mitral valve replacement (MVR). Recently we adopted ultrasonic emulsification/aspiration for annular decalcification to address these risks and describe our early experience with this new technology. DESCRIPTION: Excluding previous mitral valve surgery or endocarditis, 179 patients with MAC underwent MVR at a single institution between January 2015 and March 2020. Of these, 15 consecutive patients with severe MAC (≥50% of the annulus) underwent annular decalcification with ultrasonic emulsification/aspiration as an adjunct treatment during MVR from April 2019 to March 2020. EVALUATION: Mean patient age was 68 ± 12 years, and 72% (n = 128) were female. Mean preoperative left ventricular ejection fraction was 60% ± 11%, and mean mitral valve gradient was 9.1 ± 4.4 mm Hg. Concomitant procedures included antiarrhythmia (n = 52), aortic valve replacement (n = 32), and coronary artery bypass grafting (n = 20). There were no operative deaths or strokes in the group undergoing ultrasonic emulsification and aspiration. CONCLUSIONS: The use of ultrasonic emulsification and aspiration in severe MAC patients may help mitigate the risks of MVR and facilitate operative success in this challenging, high-risk population.

Similar Quality of Life After Conventional and Robotic Transhiatal Esophagectomy.

BACKGROUND: Patient-reported outcomes (PROs) for minimally invasive esophagectomy (MIE) have demonstrated benefits compared with open transthoracic or 3-hole esophagectomy. PROs, including quality of life (QoL) and fear of recurrence (FoR), comparing open transhiatal esophagectomy (THE) and transhiatal robotic-assisted MIE (Th-RAMIE) have been limited. METHODS: At a single, high-volume academic center, patients undergoing THE and Th-RAMIE with gastric conduit for clinical stage I to III esophageal cancer from 2013 to 2018 were evaluated. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), the EORTC Quality of Life Questionnaire in Esophageal Cancer (QLQ-OES18), and the FoR survey were administered preoperatively and at 1, 6, and 12 months postoperatively. Linear mixed-effects models were used for QoL and FoR score comparisons. Perioperative outcomes were also compared. RESULTS: A total of 309 patients (212 in the group and 97 in the Th-RAMIE group) were included. The Th-RAMIE cohort had a significantly higher number of lymph nodes harvested (14 ± 0.8 vs 11.2 ± 0.4; P = .01), a shorter length of stay (days, 10.0 ± 6.7 vs 12.1 ± 7.0; P = .03), lower rates of postoperative ileus (5% vs 15%; P = .02), and fewer opioids prescribed at discharge (71% vs 85%; P = .03). After adjustment, there were no significant differences in QLQ-C30, QLQ-OES18, and FoR scores between the groups out to 1 year postoperatively. CONCLUSIONS: There were no clear patient-reported benefits of Th-RAMIE over THE for esophageal cancer. However, Th-RAMIE conferred several perioperative benefits.

Early Treatment With a Single Dose of Mesenchymal Stem Cell Derived Extracellular Vesicles Modulates the Brain Transcriptome to Create Neuroprotective Changes in a Porcine Model of Traumatic Brain Injury and Hemorrhagic Shock.

BACKGROUND: Cell-based therapies using mesenchymal stem cell derived extracellular vesicles (EVs) improve neurologic outcomes in animal models of traumatic brain injury (TBI), stroke, and hemorrhage. Using a porcine 7-day survival model of TBI and hemorrhagic shock (HS), we previously demonstrated that EV-treatment was associated with reduced brain lesion size, neurologic severity score, and cerebral inflammation. However, the underlying cellular and genomic mechanisms remain poorly defined. We hypothesize that EV treatment modulates the brain transcriptome to enhance neuroprotection and neurorestoration following TBI + HS. METHODS: Swine were subjected to severe TBI (8-mm cortical impact) and HS (40% blood volume). After 1 h of shock, animals were randomized (n = 4/group) to treatment with either lactated Ringer's (LR) or LR + EV. Both groups received fluid resuscitation after 2 h of shock, and autologous packed red blood cells 5 h later.After 7-days, brains were harvested and RNA-sequencing was performed. The transcriptomic data were imported into the iPathway pipeline for bioinformatics analyses. RESULTS: 5,273 genes were differentially expressed in the LR + EV group versus LR alone (total 9,588 measured genes). Genes with the greatest upregulation were involved in synaptic transmission and neuronal development and differentiation, while downregulated genes were involved in inflammation. GO-terms experiencing the greatest modulation were involved in inflammation, brain development, and cell adhesion. Pathway analysis revealed significant modulation in the glutamatergic and GABAergic systems. Network analysis revealed downregulation of inflammation, and upregulation of neurogenesis, and neuron survival and differentiation. CONCLUSIONS: In a porcine model of TBI + HS, EV treatment was associated with an attenuation of cerebral inflammatory networks and a promotion of neurogenesis and neuroplasticity. These transcriptomic changes could explain the observed neuroprotective and neurorestorative properties associated with EV treatment.

Increased Intraoperative Faculty Entrustment and Resident Entrustability Does Not Compromise Patient Outcomes After General Surgery Procedures.

BACKGROUND: Intraoperative resident autonomy has been compromised secondary to expectations for increased supervision without defined parameters for safe progressive independence, diffusion of training experience, and more to learn with less time. Surgical residents who are insufficiently entrusted during training attain less autonomy, confidence, and even clinical competency, potentially affecting future patient outcomes. OBJECTIVE: To determine if OpTrust, an educational intervention for increasing intraoperative faculty entrustment and resident entrustability, negatively impacts patient outcomes after general surgery procedures. METHODS: Surgical faculty and residents received OpTrust training and instruction to promote intraoperative faculty entrustment and resident entrustability. A post-intervention OpTrust cohort was compared to historical and pre-intervention OpTrust cohorts. Multivariable logistic and negative binomial regression was used to evaluate the impact of the OpTrust intervention and time on patient outcomes. SETTING: Single tertiary academic center. PARTICIPANTS: General surgery faculty and residents. MAIN OUTCOMES AND MEASURES: Thirty-day postoperative outcomes, including mortality, any complication, reoperation, readmission, and length of stay. RESULTS: A total of 8890 surgical procedures were included. After risk adjustment, overall patient outcomes were similar. Multivariable regression estimating the effect of the OpTrust intervention and time revealed similar patient outcomes with no increased risk (P > 0.05) of mortality {odds ratio (OR), 2.23 [95% confidence interval (CI), 0.87-5.6]}, any complication [OR, 0.98 (95% CI, 0.76-1.3)], reoperation [OR, 0.65 (95% CI, 0.42-1.0)], readmission [OR, 0.82 (95% CI, 0.57-1.2)], and length of stay [OR, 0.99 (95% CI, 0.86-1.1)] compared to the historic and pre-intervention OpTrust cohorts. CONCLUSIONS: OpTrust, an educational intervention to increase faculty entrustment and resident entrustability, does not compromise postoperative patient outcomes. Integrating faculty and resident development to further enhance entrustment and entrustability through OpTrust may help facilitate increased resident autonomy within the safety net of surgical training without negatively impacting clinical outcomes.

Higher Long-term Quality of Life Metrics After Video-Assisted Thoracoscopic Surgery Lobectomy Compared With Robotic-Assisted Lobectomy.

BACKGROUND: Robotic-assisted thoracic surgery (RATS) lung lobectomy has emerged as an alternative approach to video-assisted thoracoscopic surgery (VATS). Patient-reported outcomes comparing these approaches have been limited. METHODS: At a single, high-volume academic center, patients undergoing VATS and RATS lobectomies for stage I and II non-small cell lung cancer from 2014 to 2018 were evaluated. The European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients Questionnaire (QLQ-C30) and Quality of Life Questionnaire in Lung Cancer (QLQ-LC13), along with the Fear of Recurrence (FoR) survey, were administered preoperatively and at 1, 6, and 12 months postoperatively. Raw scores underwent linear transformation (0-100 scale). Linear mixed-effects models were used for quality of life and FoR score comparisons. RESULTS: The study included 219 patients (139 VATS and 80 RATS). RATS patients had longer (P < .05) operative times and a higher incidence (P < .05) of postoperative myocardial infarction compared to VATS patients. VATS patients reported higher (P < .05) QLQ-C30 summary scores postoperatively and at 12 months, including higher (P < .05) Social Functioning and Cognitive scores, and less (P < .05) appetite loss. VATS patients reported decreased (P < .05) QLQ-LC13 symptom summary scores at 6 months postoperatively, including decreased (P < .05) dyspnea, neuropathy, and pain compared with RATS patients. VATS patients also reported lower (P < .05) FoR summary scores at 6 months postoperatively. CONCLUSIONS: VATS patients report improvement in select quality of life and FoR measures after lobectomy. Further study comparing these 2 approaches is required.

Hardship and Humanity: A Closer Qualitative Look at Surgical Training and Its Effects on Trainees From the Perspectives of Loved Ones.

OBJECTIVE: The aim of this study was to obtain novel perspectives regarding the effects that surgical training has on the well-being of trainees. SUMMARY BACKGROUND DATA: Improving trainee well-being is a national concern given high rates of burnout, depression, and suicide among physicians. Supporters of surgical trainees may offer new perspectives regarding the effects of surgical training and point to strategies to optimize trainee wellness. METHODS: This qualitative study employs semi-structured interviews of 32 support persons of trainees at a single tertiary care center with multiple surgical training programs. Interviews focused on perspectives related to supporting a surgical trainee. Interview transcripts underwent qualitative analysis with semantic and conceptual coding. Themes related to effects of training on trainee wellness are reported. RESULTS: Four themes were identified: Who Can Endure the Most Hardship?-trainee attributes and programmatic factors contribute to trainees feeling the need to constantly endure the most hardship; Consequences of Hardship-constantly enduring hardships has significant negative effects on wellness; Trainees are Humans-trainees are people with basic human needs, especially the need for worth; Research Time as Refuge-dedicated research time is treated as an oasis away from clinical hardships. CONCLUSIONS: Perspectives from support persons can offer valuable insight into the wellness needs of surgical trainees. According to support persons, surgical training profoundly negatively impacts trainee wellness. Unlike during clinical training, dedicated research time is a period during which wellness can be prioritized. Programs should provide greater attention to mitigating the negative ramifications of surgical training and promoting wellness in a longitudinal fashion throughout training.

Patient and Surgeon Predictors of Mitral and Tricuspid Valve Repair for Infective Endocarditis.

Mitral repair (MVr) is superior to replacement for degenerative disease; however, its benefit is less established for endocarditis. We report outcomes of repair or replacement for mitral/tricuspid endocarditis and identify predictors of MVr. Patients undergoing first-time surgery for mitral (n = 260) or tricuspid (n = 71) endocarditis between 1992 to 2018 were identified. Patients with aortic endocarditis were excluded. Primary outcome was all-cause mortality and secondary outcome was MVr. Patients were stratified into active and treated endocarditis separately for mitral and tricuspid groups. Predictors of MVr were assessed through multivariable logistic regression and adjusted likelihood of MVr through marginal effects estimates. A mitral specialist was defined by performing ≥25 annual degenerative MVr. Among 331 patients, 70% (181/260) of those with mitral valve endocarditis and 52% (37/71) of those with tricuspid endocarditis underwent repair. The MVr group compared with replacement had a higher proportion of elective acuity and less diabetes, hypertension, active endocarditis, cardiogenic shock, and dialysis. Estimated 5-year survival did not differ between repair versus replacement for active mitral (68 ± 14% vs 60 ± 14%, P = 0.34) or tricuspid endocarditis (60 ± 17% vs 61 ± 19%, P = 0.67), but was superior after repair for treated mitral endocarditis (86 ± 7% vs 51 ± 24%, P = 0.014). Independent predictors of mortality included dialysis for active and treated mitral endocarditis, and mitral replacement (vs MVr) for treated mitral endocarditis. The likelihood of MVr was 82 ± 5% for mitral specialists and 47 ± 9% for non-specialists (P < 0.001). MVr for endocarditis should be pursued, if feasible. Importantly, achieving MVr was driven not only by patient factors, but also surgeon experience.

Cecal bascule herniation through the foramen of Winslow.

Bowel obstructions can have a variety of causes, including impacted feces, adhesions, volvulus, non-internal hernias, and in rare cases internal hernias. We report a 63-year-old woman who presented to the emergency department with severe abdominal pain, nausea, vomiting, and obstructive symptoms that had started 12 hours earlier. A computed tomographic scan of the abdomen and pelvis showed a right internal hernia with a cecal bascule traversing through the foramen of Winslow, concerning for a closed-loop obstruction. The patient underwent an exploratory laparotomy with cecal bascule reduction and cecopexy. Given the increased mortality risk if undiagnosed, it is important to remain aware of internal hernias. Patient outcomes are markedly improved with early diagnosis and surgical intervention.

Acute hemorrhagic cholecystitis with gallbladder rupture and massive intra-abdominal hemorrhage.

Acute hemorrhagic cholecystitis is a rare, life-threatening condition that can be further complicated by perforation of the gallbladder. We describe a patient with clinical and radiologic findings of acute cholecystitis with a gallbladder rupture and massive intra-abdominal bleeding. Our patient is a 67-year-old male who presented with an ischemic stroke and was treated with early tissue plasminogen activator. His hospital course was complicated by a fall requiring posterior spinal fusion surgery. He recovered well, but several days later developed subxiphoid and right upper quadrant pain and an episode of hemobilia and melena. A computed tomography scan revealed an inflamed, distended gallbladder with indistinct margins and a large hematoma in the gallbladder fossa extending to the right paracolic gutter. The patient also developed hemodynamic instability concerning for hemorrhagic shock. He underwent an emergent laparoscopic converted to open subtotal fenestrating cholecystectomy with abdominal washout for management of his acute hemorrhagic cholecystitis with massive intra-abdominal hemorrhage. Prompt recognition of this lethal condition in high-risk patients is crucial for optimizing patient care.

Valproic Acid Protects Against Acute Kidney Injury in Hemorrhage and Trauma.

INTRODUCTION: 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. METHODS: 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. RESULTS: VPA treatment significantly (P < 0.05) 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 (P < 0.0001) 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. CONCLUSIONS: A single dose of VPA (150 mg/kg) offers significant protection against acute kidney injury in swine models of polytrauma and hemorrhagic shock.

Assessment of the Cytoprotective Effects of High-Dose Valproic Acid Compared to a Clinically Used Lower Dose.

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.