Don't Let the Sun Rise on Small Bowel Obstruction Without Surgical Consultation-Redefining Nonoperative Management Pathways.

Introduction: Small bowel obstruction (SBO) is a common cause of hospital admission leading to resource utilization. The majority of these patients require non-operative management (NOM) which can lead to increased length of stay (LOS), readmissions, resource utilization, and throughput delays. Early surgical consultation (SC) for SBO may improve efficiency and outcomes. Methods: We implemented an institution-wide intervention (INT) to encourage early SC (<1 day of diagnosis) for SBO patients in July 2022. A retrospective analysis was performed on all patients with SBO requiring NOM from January 2021 to June 2023, categorized into pre- and post-INT groups. The primary outcome was the number of SC's and secondary outcomes were early SC (<1 day of diagnosis), utilization of SBFT, LOS, 30-day readmission, and costs of admission. Results: A total of 670 patients were included, 438 in the pre-INT and 232 in the post-INT group. Overall, SBFT utilization was significantly higher in cases with SC (17.2% vs 41.4%, P < .001). Post-INT patients were more likely to receive SC (94.0% vs 83.3%, P < .001) and increased SBFT utilization (47.0% vs 33.6%, P = .001). Additionally, early SC improved significantly in the post-INT group (74.3% vs 65.7%, P = .03). There was no difference in LOS between groups (4.0 vs 3.8 days, P = .48). There was a trend toward decreased readmission rates in the INT group at 30 days (7.3% vs 11.0%, P = .13) and reduced direct costs in the INT group (US$/admission = 8467 vs 8708, P = .1). Conclusion: Hospital-wide interventions to increase early surgical involvement proved effective by improving early SC, increased SBFT utilization, and showed a trend towards decreased readmission rates and direct costs.

Incorporating Robotic Cholecystectomy in an Acute Care Surgery Practice Model is Feasible.

INTRODUCTION: The role of robotic surgery in the nonelective setting remains poorly defined. Accessibility, patient acuity, and high turn-over may limit its applicability and utilization. The goal is to characterize the role of robotic cholecystectomy (CCY) in a busy acute care surgery (ACS) practice at a quaternary medical center, and compare surgical outcomes and resource utilization between robotic and laparoscopic CCY. METHODS: Adult patients who underwent robotic (Da Vinci Xi) or laparoscopic CCY between 01/2021-12/2022 by an ACS attending within 1 week of admission were included. Primary outcomes included time from admission to surgery, off hour (weekend and 6p-6a) cases, operation time, and hospital costs, to reflect "feasibility" of robotic compared to laparoscopic CCY. Secondary outcomes encompassed surgery-related outcomes and complications. RESULTS: The proportion of robotic CCY increased from 5% to 32% within 2 years. In total 361 laparoscopic and 89 robotic CCY were performed. Demographics and gallbladder disease severity were similar. Feasibility measures-operation time, case start time, time from admission to surgery, proportion of off-hour cases, and cost-were comparable between robotic and laparoscopic CCY. There were no differences in surgical complications, common bile duct injury, readmission, or mortality. Conversion to open surgery occurred more often in laparoscopic cases (5% vs 0%, P = .02, OR = 1.05). DISCUSSION: Robotic CCY is associated with fewer open conversions and otherwise similar outcomes compared to laparoscopic CCY in the non-elective setting. Incorporation of robotic CCY in a busy ACS practice model is feasible with available resources.

Trends in gastric surgery operative experience among general surgery residents in the United States: A nationwide retrospective analysis.

BACKGROUND: Gastric surgery is a crucial component of general surgery training. However, there is a paucity of high-quality data on operative volume and the diversity of surgical procedures that general surgery residents are exposed to. METHODS: We conducted a retrospective analysis of operative case logs of all general surgery residents graduating from the American College of Graduate Medical Education-accredited program from 2009 to 2022. Data on the mean number of gastric procedures, including the mean in each subcategory, were retrieved. A Mann-Kendall trend test was used to investigate trends in operative volume. RESULTS: Between 2009 and 2022, the mean overall logged gastric procedures rose significantly (τ = 0.722, P < .001) from 36.2 in 2009 to 49.2 in 2022 (35.9% increase). The most substantial growth was seen in laparoscopic gastric reduction for morbid obesity (mean 1.9 in 2017 to 19 in 2022; τ = 0.670, P = .009). A statistically significant increase was also seen in laparoscopic partial gastric resections, repair of gastric perforation, and "other major stomach procedures" (P < .05 for all comparisons). Open gastrostomy, open partial gastric resections, and open vagotomy all significantly decreased (P < .05 for all comparisons). There was no significant change in the volume of laparoscopic gastrectomy, total gastric resections, and non-laparoscopic gastric reductions for morbid obesity (P > .05 for all comparisons). CONCLUSION: There has been a substantial increase in the volume of gastric surgery during residency over the past 14 years, driven mainly by an increase in laparoscopic gastric reduction. However, there may still be a need for further gastric surgical training to ensure well-rounded general surgeons.

Trends in Surgical Critical Care Fellowship Match: An Analysis of National Resident Matching Program Data.

INTRODUCTION: Surgical Critical Care (SCC) fellowship applications are made through March-July the year prior to the fellowship, while the match process takes place through the National Resident Matching Program (NRMP). There is paucity of high quality data on matching trends in SCC fellowship in the United States. METHODS: We conducted a retrospective cohort study of all applicants in the SCC match over a period of fifteen years (2009-2023). Publicly published data about the SCC fellowship match were retrieved from the NRMP online portal. Mann Kendall trend test was used to obtain a Tau statistic and p-values for temporal trends over time. Chi-square test was used to investigate association between categorical variables. RESULTS: From 2009 to 2023, the number of SCC fellowship positions increased from 143 to 340 (138% increase) while the number of applicants rose from 95 to 289 (204% increase). The overall match rate for applicants significantly rose from 89.5% to 93.4% (7.7% increase; t = 0.600, p = 0.002). The percentage of positions filled also increased from 59.4% in 2009 to 79.4% in 2023. The match rate over the past five years (2019-2023) was 90.8%. US-MD applicants had a significantly higher 94.8% match rate throughout the study period than non-US MD applicants (94.8% vs. 87.3%, p<0.001). While the match rate for US-MD applicants has stayed consistent from 2009 to 2023 (τ = 0.371, p = 0.054), the match rate for non-US-MD applicants increased from 77.3% in 2009 to 86.9% in 2023 (τ = 0.771, p<0.001). CONCLUSION: SCC fellowship continues to grow with more positions and applicants. Match rates into SCC fellowships have increased over the past fifteen years, primarily helping non-US MDs match successfully.

Colon and Rectal Surgery Fellowship Applicant and Matching Trends in the United States: An Analysis of National Resident Matching Program Data.

BACKGROUND: Colon and Rectal Surgery fellowships are training programs that aim to train surgeons in the management of small bowel, colon, rectal, and anal pathologies. OBJECTIVE: We investigated trends in Colon and Rectal Surgery fellowship match to help applicants anticipate future fellowship application cycles. DESIGN: This was a retrospective cohort study of applicants in the Colon and Rectal Surgery match from 2009 to 2023. Proportion of positions filled, match rates, and rank-order lists were collected. The impact of US-MD, non-US-MD, and DO status on match rate was assessed. We used the Mann Kendall trend test to obtain tau statistic and P-value for temporal trends over time, while associations between categorical variables were investigated by a chi-square test. RESULTS: Fellowship programs increased from 43 to 67, positions increased from 78 to 110, and number of applicants rose from 113 to 135. Nearly all positions were filled from 2009 to 2023 (range: 96.3%-100%). The overall match rate fluctuated between 67.3% and 80.7%. The match rate over the past 5 years was 72.0%. The match rate for US-MDs was 80.0%, while non-US-MDs had a 56.2% match rate. The percentage matching at each rank were first choice 28.0%, second choice 10.4%, third choice 6.9%, and fourth choice or lower 23.5%. CONCLUSION: Despite an increase in Colon and Rectal Surgery fellowship positions, the overall match rate has not changed significantly over the years, mainly as a result of increased applicants.

Antithrombin III levels in critically ill surgical patients: do they correlate with VTE?

Objective: Antithrombin III (ATIII) deficiency may result from hereditary or acquired reduction in ATIII levels and is associated with an increase in venous thromboembolism (VTE) in the general population. VTE is a potentially preventable complication in the critically ill surgical patients. The objective of this study was to evaluate the relation between ATIII levels and VTE in surgical intensive care unit (SICU) patients. Methods: All patients admitted to the SICU from January 2017 to April 2018 who had ATIII levels drawn were included in the study. An ATIII level below 80% of normal was considered low. The rate of VTE during the same admission was compared among patients with normal and low levels of ATIII. Prolonged length of stay (LOS >10 days) and mortality were also measured. Results: Of the 227 patients included, 59.9% were male. The median age was 60 years. Overall, 66.9% of patients had low ATIII levels. Trauma patients had a higher rate of normal ATIII levels, whereas those weighing more than 100 kg had a higher rate of low ATIII levels. Patients with low ATIII levels had higher VTE rates compared with those with normal ATIII levels (28.9% vs. 16%, p=0.04). Patients with low ATIII levels also had prolonged LOS (76.3% vs. 60%, p=0.01) and increased mortality (21.7% vs. 6.7%, p<0.01). Trauma patients with VTE were more likely to have normal ATIII levels (38.5% in low ATIII cohort vs. 61.5% VTE in normal ATIII cohort, p<0.01). Conclusion: Critically ill surgical patients with low ATIII levels have higher incidence of VTE, longer LOS, and higher mortality. In contrast, critically ill trauma patients may have high incidence of VTE even with normal ATIII levels. Level of evidence: III.

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.

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.

Demonstrating competence in Endoscopic Retrograde Cholangiopancratico graphy (ERCP): Recently credentialed operator's performance for deep biliary cannulation over 1 year period from a tertiary care hospital in Pakistan.

OBJECTIVE: To measure the success rate of endoscopic retrograde cholangiopancreaticography biliary cannulation of a recently credentialed endoscopist at a tertiary hospital. METHODS: The clinical audit was conducted at the Aga Khan University Hospital. Karachi, and comprised data of all patients who underwent endoscopic retrograde cholangiopancreaticography under the care of a single operator during 2016. Data was retrospectively extracted from patient charts by an assistant blinded to the study. Data extracted included demographics, admission type, details and indication for the procedure, diagnosis, cannulation outcome, duct clearance, complications, follow-up surgical intervention, radiological imaging and mortality post-endoscopy. Data was analysed using SPSS 19. RESULTS: Of 143 procedures performed, 102(71.3%) were included. The mean age was 52±17 years and 54(52.9%) of them were females. Most common indication was choledocholithiasis in 70(68.6%). The average procedure time was 41.5±5.5 minutes. Cannulation success rate was 96(94.1%). Complications included post-procedure pancreatitis in 5(4.9%), minimal bleeding in 8(7.8%) and oesophageal perforation in 1(0.98%). There was no procedure-related mortality. CONCLUSIONS: The success rate was high and complications were low with zero mortality.

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.

Delay in Hip Fracture Repair in the Elderly: A Missed Opportunity Towards Achieving Better Outcomes.

BACKGROUND: Hip fractures are a major cause of morbidity and mortality in the elderly. The American Academy of Orthopedic Surgeons (AAOS) recommends surgical repair within 48 hours of admission, as this is associated with lower postoperative mortality and complications. This study demonstrates the association between patient demographics, level of care, and hospital region to delay in hip fracture repair in the elderly. METHODS: The National Trauma Data Bank (NTDB) was queried for elderly patients (age >65 years) who underwent proximal femoral fracture repair. Identified patients were subcategorized into two groups: hip fracture repair in <48 hours, and hip fracture repair > 48 hours after admission. Patient and hospital characteristics were collected. Outcome variables were timed from the day of admission to surgery and inpatient mortality. RESULTS: Out of 69,532 patients, 28,031 were included after inclusion criteria were applied. 23,470 (83.7%) patients underwent surgical repair within 48 hours. The overall median time to procedure was 21 (interquartile range [IQR] 7-38) hours. Females were less likely to undergo a delay in hip fracture repair (odds ratio [OR; 95% confidence interval {CI}]: 0.82 [0.76-0.88], P< 0.05), and patients with higher Injury Severity Score (ISS ≥25) had higher odds of delay in surgical repair (OR; 95% CI: 1.56 [1.07-2.29], P< 0.05). Patients treated at hospitals in the Western regions of the United States had lower odds of delay, and those treated in the Northeast and the South had higher odds of delay compared to the hospitals in the Midwest (taken as standard). There was no association between trauma level designation and odds of undergoing delay in hip fracture repair. CONCLUSION: Variables related to patient demographic and hospital characteristics are associated with delay in hip fracture repair in the elderly. This study delineates key determinants of delay in hip fracture repair in the elderly patients.

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.

Administration of valproic acid in clinically approved dose improves neurologic recovery and decreases brain lesion size in swine subjected to hemorrhagic shock and traumatic brain injury.

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.

Pharmacologic modulation of brain metabolism by valproic acid can induce a neuroprotective environment.

OBJECTIVE: Traumatic brain injury (TBI) is a leading cause of trauma-related morbidity and mortality. Valproic acid (VPA) has been shown to attenuate brain lesion size and swelling within the first few hours following TBI. Because injured neurons are sensitive to metabolic changes, we hypothesized that VPA treatment would alter the metabolic profile in the perilesional brain tissues to create a neuroprotective environment. METHODS: We subjected swine to combined TBI (12-mm cortical impact) and hemorrhagic shock (40% blood volume loss and 2 hours of hypotension) and randomized them to two groups (n = 5/group): (1) normal saline (NS; 3× hemorrhage volume) and (2) NS-VPA (NS, 3× hemorrhage volume; VPA, 150 mg/kg). After 6 hours, brains were harvested, and 100 mg of the perilesional tissue was used for metabolite extraction. Samples were analyzed using reversed-phase liquid chromatography-mass spectrometry in positive and negative ion modes, and data were analyzed using MetaboAnalyst software (McGill University, Quebec, Canada). RESULTS: In untargeted reversed-phase liquid chromatography-mass spectrometry analysis, we detected 3,750 and 1,955 metabolites in positive and negative ion modes, respectively. There were no significantly different metabolites in positive ion mode; however, 167 metabolite features were significantly different (p < 0.05) in the negative ion mode, which included VPA derivates. Pathway analysis showed that several pathways were affected in the treatment group, including the biosynthesis of unsaturated fatty acids (p = 0.001). Targeted amino acid analysis on glycolysis/tricarboxylic acid (TCA) cycle revealed that VPA treatment significantly decreased the levels of the excitotoxic amino acid serine (p = 0.001). CONCLUSION: Valproic acid can be detected in perilesional tissues in its metabolized form. It also induces metabolic changes in the brains within the first few hours following TBI to create a neuroprotective environment.

Cl-Amidine Improves Survival and Attenuates Kidney Injury in a Rabbit Model of Endotoxic Shock.

Objective: Sepsis causes millions of deaths on a global scale annually. Activation of peptidylarginine deiminase (PAD) enzymes in sepsis causes citrullination of histones, which results in neutrophil extracellular trap formation and sepsis progression. This study evaluates pan-PAD inhibitor, Cl-amidine, in a model of lipopolysaccharide (LPS)-induced endotoxic shock in rabbits. We hypothesized that Cl-amidine would improve survival and attenuate kidney injury. Methods: In the survival model, rabbits were injected injected intravenously with 1 mg/kg of LPS, and then randomly assigned either to receive dimethyl sulfoxide (DMSO; 1 mcL/g) or Cl-amidine (10 mg/kg diluted in 1 mcL/g DMSO). They were then monitored for 14 days to evaluate survival. In the non-survival experiment, the same insult and treatment were administered, however; the animals were euthanized 12 hours after LPS injection for kidney harvest. Acute kidney injury (AKI) scoring was performed by a histopathologist who was blinded to the group assignment. Serial blood samples were also collected and compared. Results: Rabbits that received Cl-amidine had a higher survival (72%) compared with the rabbits that received DMSO (14%; p < 0.05). Cl-amidine-treated rabbits had lower (p < 0.05) histopathologic AKI scores, as well as plasma creatinine and blood urea nitrogen (BUN) levels 12 hours after insult. Conclusions: Pan-PAD inhibitor Cl-amidine improves survival and attenuates kidney injury in LPS-induced endotoxic shock in rabbits.

Prognostic factors in patients with salivary gland malignancy: a retrospective cohort study.

Our objective was to determine the factors affecting the prognosis in patients with major salivary gland malignancy presenting to Aga Khan University Hospital in Karachi. Retrospective cohort study was carried out at our center on patients diagnosed and treated for salivary gland cancers. Presentation and treatment offered was reviewed from medical charts. Telephonic interviews were conducted to assess the survival of patients who were lost to follow-up. Log rank test was used to compare the mean survival times. A total of 36 patients were included in the study. The mean age was 45.1 +/- 14.6 years. Majority were male 21 (58.3%). The most common malignancy was mucoepidermoid carcinoma (36.1%) followed by adenoid cystic carcinoma (22.2%). Node positivity, grade of tumor, radiotherapy and chemotherapy were a significant indication of survival times on log rank test.

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-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.

Valproic acid decreases resuscitation requirements after hemorrhage in a prolonged damage-control resuscitation model.

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.

Inhibition of PAD2 Improves Survival in a Mouse Model of Lethal LPS-Induced Endotoxic Shock.

Endotoxemia induced by lipopolysaccharide (LPS) is an extremely severe syndrome identified by global activation of inflammatory responses. Neutrophil extracellular traps (NETs) play an important role in the development of endotoxemia. Histone hypercitrullination catalyzed by peptidylarginine deiminases (PADs) is a key step of NET formation. We have previously demonstrated that simultaneous inhibition of PAD2 and PAD4 with pan-PAD inhibitors can decrease NETosis and improve survival in a mouse model of LPS-induced endotoxic shock. However, the effects of PAD2 specific inhibition during NETosis and endotoxic shock are poorly understood. Therefore, in the present study, we aimed to investigate the effect of the specific PAD2 or PAD4 inhibitor on LPS-induced endotoxic shock in mice. We found that PAD2 inhibition but not PAD4 inhibition improves survival. Also, the levels of proinflammatory cytokines and NETosis were significantly reduced by PAD2 inhibitor. To our knowledge, this study demonstrates for the first time that PAD2 inhibition can reduce NETosis, decrease inflammatory cytokine production, and protect against endotoxin-induced lethality. Our findings provided a novel therapeutic strategy for the treatment of endotoxic shock.

Life on the battlefield: Valproic acid for combat applications.

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.